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Abstract

Stearoyl-CoA desaturase 1 (SCD1) is a delta-9 fatty acid desaturase that catalyzes the synthesis of mono-unsaturated fatty acids (MUFA). SCD1 is a critical control point regulating hepatic lipid synthesis and β-oxidation. Scd1 KO mice are resistant to the development of diet-induced non-alcoholic fatty liver disease (NAFLD). Using a chronic-binge protocol of ethanol-mediated liver injury, we aimed to determine if these KO mice are also resistant to the development of alcoholic fatty liver disease (AFLD).

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... It is believed that upregulation of the DNL pathway can contribute to the development of hepatic steatosis in ALD. Indeed, increases in Srebp1c, Acc, Scd1, and Fasn expression have been reported in alcohol exposed liver [52][53][54] . Alcohol-fed Scd1 −/− mice were well protected against ALD relative to their WT control, including normal hepatic TG levels and serum liver enzymes (AST and ALT) as well as a decrease in markers of hepatic inflammation. ...
... Alcohol-fed Scd1 −/− mice were well protected against ALD relative to their WT control, including normal hepatic TG levels and serum liver enzymes (AST and ALT) as well as a decrease in markers of hepatic inflammation. Mechanistically, a previous study has shown strong induction of the DNL pathway in alcohol-fed WT mice, including increases in the expression of Srebp1c, Acc, Fasn, and Scd1, which was normal in Scd1 −/− mice [53] . Similarly, PPE was found to decrease the expression of Fasn, Scd1, and Scd2 in AML12 cells in this study (Figs. ...
... Stearoyl-CoA desaturase (SCD) (∆9 desaturase) is the rate-limiting enzyme for the biosynthesis of the major MUFA present in cells and tissues, oleic acid (cis-9-octadecenoic acid, 18:1n-9) [3]. Thus, pharmacological manipulation of SCD activity has repeatedly been suggested as a strategy to treat metabolic diseases and cancer [4][5][6]. Two SCD isoforms are present in humans, SCD-1 and SCD-5. While the former is ubiquitously expressed, the latter appears to be mainly expressed in brain. ...
... Finally, 16:1n-10 is formed by the desaturation of palmitic acid at C6 by the enzyme fatty acid desaturase (FADS) 2. In turn, 16:1n-10 can be elongated to form cis-8-octadecenoic acid (18:1n-10). [4][5][6]. Two SCD isoforms are present in humans, SCD-1 and SCD-5. While the former is ubiquitously expressed, the latter appears to be mainly expressed in brain. ...
Article
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In the last few years, the monounsaturated hexadecenoic fatty acids are being increasingly considered as biomarkers of health with key functions in physiology and pathophysiology. Palmitoleic acid (16:1n-7) and sapienic acid (16:1n-10) are synthesized from palmitic acid by the action of stearoyl-CoA desaturase-1 and fatty acid desaturase 2, respectively. A third positional isomer, hypogeic acid (16:1n-9) is produced from the partial β-oxidation of oleic acid. In this review, we discuss the current knowledge of the effects of palmitoleic acid and, where available, sapienic acid and hypogeic acid, on metabolic diseases such as diabetes, cardiovascular disease, and nonalcoholic fatty liver disease, and cancer. The results have shown diverse effects among studies in cell lines, animal models and humans. Palmitoleic acid was described as a lipokine able to regulate different metabolic processes such as an increase in insulin sensitivity in muscle, β cell proliferation, prevention of endoplasmic reticulum stress and lipogenic activity in white adipocytes. Numerous beneficial effects have been attributed to palmitoleic acid, both in mouse models and in cell lines. However, its role in humans is not fully understood, and is sometimes controversial. Regarding sapienic acid and hypogeic acid, studies on their biological effects are still scarce, but accumulating evidence suggests that they also play important roles in metabolic regulation. The multiplicity of effects reported for palmitoleic acid and the compartmentalized manner in which they often occur, may suggest the overlapping actions of multiple isomers being present at the same or neighboring locations.
... As introduced above, it is thought that upregulation of the DNL pathway is one of the contributors to the development of hepatic steatosis in ALD. Indeed, the literature includes reports of increased Srebp1c, Acc, Scd1, and Fasn expression in the alcohol exposed liver (Foufelle and Ferre, 2002;Ntambi et al., 2002;You et al., 2002;MacDonald et al., 2008;Huang et al., 2013;Lounis et al., 2016). As discussed below, key insight into the role of altered DNL in ALD comes from alcohol feeding studies in Srebp1c −/− and Scd1 −/− mice. ...
... In the context of alcohol abuse, it has been shown that both chronic and binge alcohol consumption increases Scd1 expression in mice (Huang et al., 2013;Zhang et al., 2015). These observations lead to the hypothesis that SCD1 deficiency might protect against ALD, which was tested by Lounis et al. (2016). These authors compared WT and Scd1 −/− mice using the chronic-binge model of ALD, which consists of mice consuming LDeC diets with 5% (v/v) alcohol for 10 days, followed by a single binge dose of alcohol (5 g/kg body weight) (Bertola et al., 2013). ...
Article
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Alcohol-associated liver disease (ALD) is a major public health issue that significantly contributes to human morbidity and mortality, with no FDA-approved therapeutic intervention available. The health burden of ALD has worsened during the COVID-19 pandemic, which has been associated with a spike in alcohol abuse, and a subsequent increase in hospitalization rates for ALD. A key knowledge gap that underlies the lack of novel therapies for ALD is a need to better understand the pathogenic mechanisms that contribute to ALD initiation, particularly with respect to hepatic lipid accumulation and the development of fatty liver, which is the first step in the ALD spectrum. The goal of this review is to evaluate the existing literature to gain insight into the pathogenesis of alcohol-associated fatty liver, and to synthesize alcohol’s known effects on hepatic lipid metabolism. To achieve this goal, we specifically focus on studies from transgenic mouse models of ALD, allowing for a genetic dissection of alcohol’s effects, and integrate these findings with our current understanding of ALD pathogenesis. Existing studies using transgenic mouse models of ALD have revealed roles for specific genes involved in hepatic lipid metabolic pathways including fatty acid uptake, mitochondrial β-oxidation, de novo lipogenesis, triglyceride metabolism, and lipid droplet formation. In addition to reviewing this literature, we conclude by identifying current gaps in our understanding of how alcohol abuse impairs hepatic lipid metabolism and identify future directions to address these gaps. In summary, transgenic mice provide a powerful tool to understand alcohol’s effect on hepatic lipid metabolism and highlight that alcohol abuse has diverse effects that contribute to the development of alcohol-associated fatty liver disease.
... Rodent models suggest that this pathway may also be involved in ALD. For example, SCD1 knockout mice do not exhibit upregulated de novo lipogenesis in response to alcohol and are resistant to ALD (Lounis et al., 2016). Targeting several regulators of SCD1 expression attenuates the deleterious impact of alcohol on the liver in animal models (Hodson & Karpe, 2013). ...
... Nonetheless, it is vital to characterize SCD1 activity in early-stage ALD, as it could be useful in predicting advanced ALD. Furthermore, despite the observed association between elevated SCD1 activity, the effect of SCDs on liver disease is unclear, in both preclinical studies of ALD (Lounis et al., 2016;Tomita et al., 2004) and clinical studies of nonalcohol-associated fatty liver disease (Maciejewska et al., 2015). For example, a preclinical study found that the SCD1 product, palmitoleic acid, is protective against steatosis through stimulation of insulin signaling . ...
Article
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Chronic binge drinking induces hepatic lipid accumulation, but only certain individuals develop alcohol-associated liver disease (ALD). Specific patterns of lipid accumulation are thought to be associated with ALD, but this has not been comprehensively investigated to date. We analyzed plasma fatty acid levels quantified by gas chromatography-mass spectrometry in a sample of patients with alcohol use disorder (AUD). Given that elevation in serum alanine aminotransferase (ALT) levels are strongly associated with ALD, patients were stratified into two groups based on ALT levels: an ALD group (ALT > 40 IU/L) and a non-ALD group (ALT ≤ 40 IU/L). There was a shift towards greater concentrations of monounsaturated fatty acids in the ALD group compared to the non-ALD group. Steroyl-CoA desaturase (SCD1) activity in the ALD group was then estimated as the ratio of palmitoleic acid (16:1) to palmitic acid (16:0). SCD1 activity was greater in the ALD than the non-ALD group. A series of linear regression models demonstrated that SCD1 activity mediated the association between binge drinking and ALD. These findings provide initial evidence that SCD1 activity may be associated with ALD. If validated prospectively, elevated SCD1 activity could potentially be used as a biomarker to identify individuals at high risk for developing ALD.
... Of 78 DE genes in the liver-specific Phb1 +/− group, forkhead box M1 (Foxm1), Timp1, Usp2, stearoyl-CoA-desaturase 1 (Scd1), and Sult1e1 are known to be associated with hepatic system disease (Haimerl et al., 2009;Wang et al., 2011;Hu et al., 2014;Lounis et al., 2016;Matsushita et al., 2017). We verified the five DE genes obtained RNA-seq data, using RT-PCR in the same liver tissues, in addition to qRT-PCR in normal murine hepatocytes transfected with siPhb1. ...
... Thus, we can explain that there is no defense response against a high-stress environment, such as an increasing susceptibility of liver injuries by the drastic shortage of Phb1, represented to Phb1 −/− . Stearoyl-CoA desaturase-1 (SCD1) plays an important role in the conversion of saturated fatty acids to monosaturated fatty acids and further synthesis of TG (Lounis et al., 2016). We expected that Scd1 expression in Phb1 +/− , compared with WT, also increased in transcriptome analysis, since our previous research on the effect of Phb1 deficiency with siPhb1 knockdown on impaired lipid metabolism demonstrated that palmitic acid promoted Scd1 mRNA expression levels (unpublished data, under review). ...
Article
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Prohibitin 1 (PHB1) is an evolutionarily conserved and ubiquitously expressed protein that stabilizes mitochondrial chaperone. Our previous studies showed that liver-specific Phb1 deficiency induced liver injuries and aggravated lipopolysaccharide (LPS)-induced innate immune responses. In this study, we performed RNA-sequencing (RNA-seq) analysis with liver tissues to investigate global gene expression among liver-specific Phb1−/−, Phb1+/−, and WT mice, focusing on the differentially expressed (DE) genes between Phb1+/− and WT. When 78 DE genes were analyzed for biological functions, using ingenuity pathway analysis (IPA) tool, lipid metabolism-related genes, including insulin receptor (Insr), sterol regulatory element-binding transcription factor 1 (Srebf1), Srebf2, and SREBP cleavage-activating protein (Scap) appeared to be downregulated in liver-specific Phb1+/− compared with WT. Diseases and biofunctions analyses conducted by IPA verified that hepatic system diseases, including liver fibrosis, liver hyperplasia/hyperproliferation, and liver necrosis/cell death, which may be caused by hepatotoxicity, were highly associated with liver-specific Phb1 deficiency in mice. Interestingly, of liver disease-related 5 DE genes between Phb1+/− and WT, the mRNA expressions of forkhead box M1 (Foxm1) and TIMP inhibitor of metalloproteinase (Timp1) were matched with validation for RNA-seq in liver tissues and AML12 cells transfected with Phb1 siRNA. The results in this study provide additional insights into molecular mechanisms responsible for increasing susceptibility of liver injuries associated with hepatic Phb1.
... Promotion of the synthesis of monounsaturated fatty acids could play an important role in the development of steatosis and liver injury with chronic-plus-binge alcohol exposure [95]. Study on SCD1 knockout mice showed significant resistance to alcohol-induced hepatic inflammation in comparison to the control group, emphasizing the critical role of SCD1 in AH [52]. SCD1 activity can be measured indirectly by the palmitoleic acid to palmitic acid ratio via serum lipid measurements [52,96]. ...
... Study on SCD1 knockout mice showed significant resistance to alcohol-induced hepatic inflammation in comparison to the control group, emphasizing the critical role of SCD1 in AH [52]. SCD1 activity can be measured indirectly by the palmitoleic acid to palmitic acid ratio via serum lipid measurements [52,96]. SCD1 remains as a possible therapeutic target that needs more clinical and translational investigations to elucidate its role in inhibiting the hepatic inflammation. ...
Article
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Alcohol use disorder is associated with a wide array of hepatic pathologies ranging from steatosis to alcoholic-related cirrhosis (AC), alcoholic hepatitis (AH), or hepatocellular carcinoma (HCC). Biomarkers are categorized into two main categories: biomarkers associated with alcohol consumption and biomarkers of alcoholic liver disease (ALD). No ideal biomarker has been identified to quantify the degree of hepatocyte death or severity of AH, even though numerous biomarkers have been associated with AH. This review provides information of some of the novel and latest biomarkers that are being investigated and have shown a substantial association with the degree and severity of liver injury and inflammation. Importantly, they can be measured noninvasively. In this manuscript, we consolidate the present understanding and prospects of these biomarkers; and their application in assessing the severity and progression of the alcoholic liver disease (ALD). We also review current and upcoming management options for AH.
... Accordingly, reduced protein expression of AR in mice with AR inhibitor treatment was observed [33]. Previous studies have highlighted the roles of glutathione peroxidase-1 and stearoyl-CoA desaturase 1 in ethanol-induced damage [34,35]. AR involves in carbohydrate metabolism, whereas glutathione peroxidase-1 and stearoyl-CoA desaturase 1 involve in amino acid metabolism and lipid metabolism, respectively. ...
... High fatty diet enhances ethanol-induced steatosis in a mouse model of chronic liver injury [36]. The deficiency of stearoyl-CoA desaturase 1 that catalyzes the conversion of stearic acid to oleic acid alleviates alcoholic liver injury in mice [35]. Steatosis, multiple metabolites, metabolite supplementation and gene knockout collectively indicate fatty acid biosynthesis is a key player in alcoholic fatty liver. ...
Article
Alcoholic liver injury results in morbidity and mortality worldwide, but there are currently no effective and safe therapeutics. Previously we demonstrated that aldose reductase (AR) inhibitor ameliorated alcoholic hepatic steatosis. To clarify the mechanism whereby AR inhibitor improves alcoholic hepatic steatosis, herein we investigated the effect of AR inhibitor on hepatic metabolism in mice fed a Lieber-DeCarli liquid diet with 5% ethanol. Nontargeted metabolomics showed carbohydrates and lipids were characteristic categories in ethanol diet-fed mice with or without AR inhibitor treatment, whereas AR inhibitor mainly affected carbohydrates and amino acids. Ethanol-induced galactose metabolism and fatty acid biosynthesis are important for the induction of hepatic steatosis, while AR inhibitor impaired galactose metabolism without perturbing fatty acid biosynthesis. In parallel with successful treatment of steatosis, AR inhibitor suppressed ethanol-activated galactose metabolism and saturated fatty acid biosynthesis. Sorbitol in galactose metabolism and stearic acid in saturated fatty acid biosynthesis were potential biomarkers responsible for ethanol or ethanol plus AR inhibitor treatment. In vitro analysis confirmed that exogenous addition of sorbitol augmented ethanol-induced steatosis and stearic acid. These findings not only reveal metabolic patterns associated with disease and treatment, but also shed light on functional biomarkers contribute to AR inhibition therapy.
... A recent study found that SCD-1-deficient mice are protected against obesity, MetS, CVD, and NAFLD [34][35][36]. In addition, those animals showed greater thermogenesis and insulin sensitivity [37], although the mechanisms are not completely elucidated. In the studied population, the ability of SCD-18 to increase cardiovascular risk was estimated at 673% for each unit increased in the index (p = 0.023). ...
Article
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Background: Metabolic syndrome (MetS) is a set of conditions associated with an increased cardiovascular risk. Several serum fatty acids (FAs) seem to play an essential role in the development of cardiometabolic diseases and mortality. Thus, it is imperative to explore the impact of FAs on MetS parameters, using an early MetS screening tool such as MetScore, which is readily available in clinical practice. Aim: The aim of this study was to assess the potential correlation between serum FAs and cardiovascular risk using a MetScore. Methods: This cross-sectional study involved 41 women with severe obesity. The MetScore was calculated, and participants were categorized into high- and low-cardiovascular-risk groups based on the median MetScore value. Gas chromatography was used to quantify serum FAs. Generalized Linear Models were used to compare group means. The association was assessed through simple logistic regression, and an adjusted logistic regression was conducted to validate the association between Metscore and serum FAs. Results: The high-cardiovascular-risk group exhibited elevated values of HOMA-IR, palmitic, oleic, cis-vaccenic, and monounsaturated fatty acids, as well as the SCD-18C, indicating a heightened cardiovascular risk. Conversely, HDL-c, QUICK, gamma-linolenic, and eicosatetraenoic fatty acids showed lower values compared to the low-risk group. Conclusions: Women with severe obesity and high cardiovascular risk have lower values of some omega-3 and omega-6 FAs, considered cardioprotective and anti-inflammatory, and have higher lipogenic activity and FAs, correlated with high cardiovascular risk. These findings emphasize the need to address lipid metabolism in this population as a therapeutic target to reduce cardiovascular risk. Future research should explore clinical interventions that modulate fatty acid metabolism to mitigate cardiometabolic complications.
... For example, transgenic mice lacking SCD do not develop obesity or insulin resistance when exposed to high-calorie diets. They exhibit lower body adiposity, enhanced insulin sensitivity in the liver, adipose tissu e, and skeletal muscle, decreased hepatic triglycerides and cholesterol esters, elevated metabolic rates, and resistance to the development of non-alcoholic fatty liver disease (Rahman et al., 2005;Gutiérrez-Juárez et al., 2006;Miyazaki et al., 2009;Liu et al., 2010;Lounis et al., 2016). Recently, pharmaceutical companies have been developing synthetic SCD inhibitors as potential therapies for various liver diseases, dermatological conditions, Alzheimer's disease, and cancer (Uto, 2016). ...
Chapter
Metabolic syndrome (MetS) represents a significant health concern globally, necessitating diverse strategies for its management. Non-pharmacological approaches, including lifestyle modifications, dietary adjustments, and the incorporation of nutraceutical and functional foods, play a crucial role in addressing MetS. Among the plant genera showing promise in alleviating MetS is Sterculia, a member of the Malvaceae family encompassing over 200 species with documented ethnopharmacological uses. The seeds composition of certain Sterculia species has been studied, revealing compounds with therapeutic potential. This chapter focuses on the promising effects of antioxidant compounds and cyclic fatty acids found in Sterculia seeds. These bioactive constituents hold the potential for preventing or treating the metabolic abnormalities of MetS.
... Scd1 is widely expressed in the liver, skin, adipose tissue, and intestine, and its inhibition protects against diet-induced obesity, steatosis, and symptoms of metabolic syndrome. [1][2][3][4] The mechanism of action may involve altered bile acid physiology; in addition to their roles as physiological detergents, bile acids bind metabolic receptors to promote lipid and energy metabolism. Bile acids also shape the gut microbiota composition, and the microbiota reciprocally alters bile acid composition. ...
... Indeed, in work presented by Leroux and colleagues, it was argued that the upregulation of triglyceride storage in KCs from HFD-fed mice is triggered as part of a normal immune response. In HFD-fed mice, lipidomic and RT-qPCR analysis revealed that KCs become lipid-laden and up-regulate lipogenesis genes Dgat1 and Scd1 (100,113,114). This upregulation is associated with a functional adaptation, that is lipid-laden KCs are primed to recruit lymphocytes more efficiently (CD4+ T cells and B cells in their investigation), of note this adaptation is reversible with the inhibition of lipogenesis. ...
Article
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The liver is the site of first pass metabolism, detoxifying and metabolizing blood arriving from the hepatic portal vein and hepatic artery. It is made up of multiple cell types, including macrophages. These are either bona fide tissue-resident Kupffer cells (KC) of embryonic origin, or differentiated from circulating monocytes. KCs are the primary immune cells populating the liver under steady state. Liver macrophages interact with hepatocytes, hepatic stellate cells, and liver sinusoidal endothelial cells to maintain homeostasis, however they are also key contributors to disease progression. Generally tolerogenic, they physiologically phagocytose foreign particles and debris from portal circulation and participate in red blood cell clearance. However as immune cells, they retain the capacity to raise an alarm to recruit other immune cells. Their aberrant function leads to the development of non-alcoholic fatty liver disease (NAFLD). NAFLD refers to a spectrum of conditions ranging from benign steatosis of the liver to steatohepatitis and cirrhosis. In NAFLD, the multiple hit hypothesis proposes that simultaneous influences from the gut and adipose tissue (AT) generate hepatic fat deposition and that inflammation plays a key role in disease progression. KCs initiate the inflammatory response as resident immune effectors, they signal to neighbouring cells and recruit monocytes that differentiated into recruited macrophages in situ. Recruited macrophages are central to amplifying the inflammatory response and causing progression of NAFLD to its fibro-inflammatory stages. Given their phagocytic capacity and their being instrumental in maintaining tissue homeostasis, KCs and recruited macrophages are fast-becoming target cell types for therapeutic intervention. We review the literature in the field on the roles of these cells in the development and progression of NAFLD, the characteristics of patients with NAFLD, animal models used in research, as well as the emerging questions. These include the gut-liver-brain axis, which when disrupted can contribute to decline in function, and a discussion on therapeutic strategies that act on the macrophage-inflammatory axis.
... Wang et al. demonstrated that inhibition of SCD1 activity attenuated alcoholic liver injury in female mice [92,93]. SCD1knockout (KO) mice are resistant to AFL development, and hepatic TG accumulation, activation of de novo adipogenesis, and increases in inflammatory marker levels are inhibited [94]. A diet enriched with saturated FAs has been shown to reduce endotoxaemia, lipid peroxidation, and TNF-α and cyclooxygenase-2 (COX2) levels, effectively preventing ethanol-induced liver damage, including fibrosis [95]. ...
Article
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Alcoholism is a widespread and damaging behaviour of people throughout the world. Long-term alcohol consumption has resulted in alcoholic liver disease (ALD) being the leading cause of chronic liver disease. Many metabolic enzymes, including alcohol dehydrogenases such as ADH, CYP2E1, and CATacetaldehyde dehydrogenases ALDHsand nonoxidative metabolizing enzymes such as SULT, UGT, and FAEES, are involved in the metabolism of ethanol, the main component in alcoholic beverages. Ethanol consumption changes the functional or expression profiles of various regulatory factors, such as kinases, transcription factors, and microRNAs. Therefore, the underlying mechanisms of ALD are complex, involving inflammation, mitochondrial damage, endoplasmic reticulum stress, nitrification, and oxidative stress. Moreover, recent evidence has demonstrated that the gut-liver axis plays a critical role in ALD pathogenesis. For example, ethanol damages the intestinal barrier, resulting in the release of endotoxins and alterations in intestinal flora content and bile acid metabolism. However, ALD therapies show low effectiveness. Therefore, this review summarizes ethanol metabolism pathways and highly influential pathogenic mechanisms and regulatory factors involved in ALD pathology with the aim of new therapeutic insights.
... SCD1 is located in the endoplasmic reticulum and mainly expressed in the mammary glands, liver, and adipose tissue [12,13]. SCD1 is crucial for the c9, t11-CLA content in milk [14][15][16][17]. Factors that regulate the SCD1 activity or the synthesis of TVA in rumen can alter the milk content of cis9, trans11-CLA [4]. ...
Article
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The objective of the study was to elucidate the stearoyl-coenzyme A desaturase (SCD1)-dependent gene network of c9, t11-CLA biosynthesis in MAC-T cells from an energy metabolism perspective. The cells were divided into the CAY group (firstly incubated with CAY10566, a chemical inhibitor of SCD1, then incubated with trans-11-octadecenoic acid, (TVA)), the TVA group (only TVA), and the control group (without CAY, TVA). The c9, t11-CLA, and TVA contents were determined by gas chromatography. The mRNA levels of SCD1 and candidate genes were analyzed via real-time PCR. Tandem mass tag (TMT)-based quantitative proteomics, bioinformatic analysis, parallel reaction monitoring (PRM), and small RNA interference were used to explore genes involved in the SCD1-dependent c9, t11-CLA biosynthesis. The results showed that the SCD1 deficiency led by CAY10566 blocked the biosynthesis of c9, t11-CLA. In total, 60 SCD1-related proteins mainly involved in energy metabolism pathways were primarily screened by TMT-based quantitative proteomics analysis. Moreover, 17 proteins were validated using PRM analysis. Then, 11 genes were verified to have negative relationships with SCD1 after the small RNA interference analysis. Based on the above results, we concluded that genes involved in energy metabolism pathways have an impact on the SCD1-dependent molecular mechanism of c9, t11-CLA biosynthesis.
... Earlier work showed that germline Scd1 null mice were protected against hepatic steatosis when fed an MCD diet yet exhibited more severe injury (35), while other work showed that Scd1 null mice were protected against both hepatic steatosis and inflammation in the setting of alcohol induced injury (36). Those findings, coupled with the current observations in Mttp-IKO mice suggest that the adaptive induction of Scd1 expression and function may mitigate the reversal of J o u r n a l P r e -p r o o f inflammatory signaling in the setting of established steatosis and fibrotic injury and further suggest that the overall distribution of FA species rather than simply the quantity of hepatic lipid is a key component of the injury phenotypes observed. ...
Article
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Regulating dietary fat absorption may impact progression of nonalcoholic fatty liver disease (NAFLD). Here we asked if inducible inhibition of chylomicron assembly, as observed in intestine-specific microsomal triglyceride transfer protein knockout mice (Mttp-IKO), could retard NAFLD progression and/or reverse established fibrosis in two dietary models. Mttp-IKO mice fed a methionine/choline deficient (MCD) diet exhibited reduced hepatic triglycerides (TG), inflammation and fibrosis, associated with reduced oxidative stress and downstream activation of JNK and NFκB signaling pathways. However, when Mttpflox mice were fed a MCD for 5 weeks and then administered tamoxifen to induce Mttp-IKO, hepatic TG was reduced but inflammation and fibrosis were increased after 10 days reversal along with adaptive changes in hepatic lipogenic mRNAs. Extending the reversal time, following 5 weeks MCD feeding, to 30 days led to sustained reductions in hepatic TG but neither inflammation nor fibrosis were decreased and both intestinal permeability and hepatic lipogenesis were increased. In a second model, similar reductions in hepatic TG were observed when mice were fed a high fat/fructose/cholesterol diet for 10weeks, then switched to chow ± tamoxifen (HFFC→chow) or (HFFC→ Mttp-IKO chow), but again neither inflammation or fibrosis were affected. In conclusion, we found that blocking chylomicron assembly attenuates MCD-induced NAFLD progression by reducing steatosis, oxidative stress and inflammation. In contrast, blocking chylomicron assembly in the setting of established hepatic steatosis and fibrosis caused increased intestinal permeability and compensatory shifts in hepatic lipogenesis that mitigate resolution of inflammation and fibrogenic signaling despite 50-90 fold reductions in hepatic TG.
... SCD1 activity results in the synthesis of monounsaturated fatty acids (MUFAs), the major FA of TGs, cholesteryl esters, and membrane phospholipids. SCD1 deficiency in mice has been demonstrated to reduce lipid synthesis and increase mitochondrial FA b-oxidation and insulin sensitivity [137]. Accordingly, the inhibition of SCD1 results in several beneficial effects, including reduction of liver fat, protection against insulin resistance, and protection against obesity. ...
Article
Type 2 diabetes mellitus (T2DM) associated non-alcoholic fatty liver disease (NAFLD) is the fourth-leading cause of death. Hyperglycemia induces various complications, including nephropathy, cirrhosis and eventually hepatocellular carcinoma (HCC). There are several etiological factors leading to liver disease development, which involve insulin resistance and oxidative stress. Free fatty acid (FFA) accumulation in the liver exerts oxidative and endoplasmic reticulum (ER) stresses. Hepatocyte injury induces release of inflammatory cytokines from Kupffer cells (KCs), which are responsible for activating hepatic stellate cells (HSCs). In this review, we will discuss various molecular targets for treating chronic liver diseases, including homeostasis of FFA, lipid metabolism, and decrease in hepatocyte apoptosis, role of growth factors, and regulation of epithelial-to-mesenchymal transition (EMT) and HSC activation. This review will also critically assess different strategies to enhance drug delivery to different cell types. Targeting nanocarriers to specific liver cell types have the potential to increase efficacy and suppress off-target effects.
... 11 Transgenic mice deficient in SCD do not develop obesity or IR under hypercaloric diets, have reduced body adiposity, and show increased insulin sensitivity in the liver, adipose tissue, and skeletal muscle. 7,[12][13][14][15][16] They are deficient in triglycerides (TG) and hepatic cholesterol esters, show a high metabolic rate, and are resistant to the development of alcoholic and nonalcoholic fatty liver disease (NAFLD). 5,17 During recent years, scientific research and pharmaceutical companies have made attempts to develop synthetic SCD1 inhibitors to find new therapies for the treatment of MD. 18 Sterculia apetala ( Jacq.) is a tree found in the tropical rainforests of southeastern Mexico in the states of Veracruz, Tabasco, Oaxaca, and Chiapas. ...
Article
Prostate cancer (PCa) is a common type of cancer affecting male population. PCa treatments have side effects and are temporarily effective, so new therapeutic options are being investigated. Due to the high demand of energy for cell proliferation, an increase in the expression and activity of lipogenic enzymes such as the stearoyl-CoA desaturase (SCD) have been observed in PCa. Sterculic acid, contained in the seed's oil of Malvales, is a natural inhibitor of SCD. The objective of our investigation was to evaluate the effects of sterculic oil (SO) from Sterculia apetala seeds on proliferation, cell cycle and apoptosis in prostate cancer cells. SO was administered to PC3 and LNCaP cells, and to prostate normal cells; cell viability, cell cycle, apoptosis, SCD gene and protein expression and enzymatic activity were analyzed. SO administration (4 mM sterculic acid) diminished cell viability in LNCaP and PC3 cells, arrested cell cycle in G2 and promoted apoptosis. SO diminished SCD enzymatic activity with no effects on gene nor protein expression. Our results suggest that SO might offer benefits as an adjuvant in hormonal and chemotherapy prostate cancer treatments. This is the first study to analyze the effect of SO on cancer cells.
... SCD-1 is the main isoform in the liver and has a key role in the promotion of hepatic de novo triglyceride synthesis. 46,47 Both SREBP-1c and SCD-1 are downregulated in rodent models by leptin administration therapy in concordance with the improvement in hepatic steatosis. 43,44 In addition, there is evidence that serum fatty acid composition is associated with insulin resistance and hepatic steatosis. ...
Article
Background Recombinant leptin therapy reverses nonalcoholic steatohepatitis (NASH) in leptin-deficient lipodystrophy. We inquired if leptin therapy would improve NASH in more common forms of this heterogeneous condition. Methods Nine male patients with relative leptin deficiency (level, <25th percentile of body mass index- and sex-matched United States population) and biopsy-proven NASH and 23 patients with partial lipodystrophy and NASH were recruited for 2 distinctive open-label trials. Participants received leptin therapy in the form of metreleptin for 12 months. The primary endpoints were the global NASH scores from paired liver biopsies scored blindly. Findings Of 9 participants recruited in the relative leptin deficiency treatment study, 7 completed 12 months of therapy. Mean global NASH scores were reduced from 8 ± 3 to 5 ± 2 (range, from 1 to 6; p = 0.004). In the partial lipodystrophy study, 19 of 22 subjects completed 12 months of treatment and 18 completed a second liver biopsy. Global NASH scores also reduced significantly from 6 ± 2 to 5 ± 2 (range, from −2 to 4; p = 0.008). In both studies, the predominant changes were in steatosis and hepatic injury scores. Conclusions Our findings show that patients with NASH associated with both relative leptin deficiency and partial lipodystrophy have reductions in hepatic steatosis and injury in response to exogenous leptin therapy. Moreover, leptin deficiency may have regulatory effects in mediating fat deposition and ensuing injury in the liver. Funding NIH grants R03 DK074488 (E.A.O.) and R01 DK088114 (E.A.O. and H.S.C.).
... Modulation of SCD activity has been implicated in the development of the metabolic syndrome and its associated inflammatory state. Therefore, several studies have suggested targeting SCDs in order to treat various aspects of the metabolic syndrome, including type 2 diabetes and cardiovascular diseases [63][64][65]. ...
Article
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Obesity is an important aspect of the metabolic syndrome and is often associated with chronic inflammation. In this context, inflammation of organs participating in energy homeostasis (such as liver, adipose tissue, muscle and pancreas) leads to the recruitment and activation of macrophages, which secrete pro-inflammatory cytokines. Interleukin-1β secretion, sustained C-reactive protein plasma levels and activation of the NLRP3 inflammasome characterize this inflammation. The Stearoyl-CoA desaturase-1 (SCD1) enzyme is a central regulator of lipid metabolism and fat storage. This enzyme catalyzes the generation of monounsaturated fatty acids (MUFAs)—major components of triglycerides stored in lipid droplets—from saturated fatty acid (SFA) substrates. In this review, we describe the molecular effects of specific classes of fatty acids (saturated and unsaturated) to better understand the impact of different diets (Western versus Mediterranean) on inflammation in a metabolic context. Given the beneficial effects of a MUFA-rich Mediterranean diet, we also present the most recent data on the role of SCD1 activity in the modulation of SFA-induced chronic inflammation.
... SCD1 is a key enzyme for de novo lipogenesis of TG in liver. [41][42][43] Dysregulation of SCD1 has been implicated in NAFLD, hyperlipidemia and obesity. 44 Studies have shown that SCD1 deficiency in mice reduced liver TG accumulation, increased fatty acid oxidation, and reduced TG de novo synthesis. ...
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Fatty liver disease is one of the main hepatic complications associated with obesity. To date, there are no therapeutic drugs approved for this pathology. Insulin resistance (IR) is implicated both in pathogenesis of nonalcoholic fatty liver disease (NAFLD) and in disease progression from steatosis to nonalcoholic steatohepatitis. In this study, we have characterized effects of an α2 -adrenoceptor agonist, dexmedetomidine (DEX), which can alleviate IR in hepatocytes in high-fat diet (HFD)-induced NAFLD mice. The NAFLD mice received a daily intraperitoneal administration of DEX (100 μg·kg-1 ) after 16 days exhibited lower body weight, fewer and smaller fat droplets in the liver, markedly reduced the plasma triglyceride levels, accompanied by improvement of liver damage. This inhibition of lipid accumulation activity in obese mice was associated with a robust reduction in the mRNA and protein expression of the lipogenic enzyme stearyl-coenzyme A desaturase 1 (SCD1), which was probably mediated by the inhibition of C/EBP β, PPAR γ and C/EBP α through suppressing α2A -adrenoceptor (α2A -AR) via negative feedback. Additionally, DEX can also improve IR and inflammation by inhibiting the mitogen-activated protein kinases (MAPK) and nuclear factor kappa beta (NFκB) signaling pathway in vivo. Our findings implicate that DEX may act as a potential anti-steatotic drug which ameliorates obesity-associated fatty liver and improves IR and inflammation, probably by suppressing the expression of SCD1 and the inhibition of MAPK/NFκB pathway and suggest the potential adjuvant use for the treatment of NAFLD.
... SCD1-mediated ceramide synthesis has been reported to induce mitochondrial dysfunction, ROS generation and cell apoptosis (26). The protective effects of SCD1 inhibition has been reported to ameliorate ethanol-induced liver injury (27). A SCD1 inhibitor has also been developed to attenuate lipid accumulation and liver injury in a rat model of NASH (28). ...
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Garlic and its sulfur constituents have numerous biological functions, such as antioxidant, anti-inflammatory, anti-microbial, anticancer, antidiabetic and cardioprotective effects. Fatty liver diseases, such as non-alcoholic steatohepatitis, which is characterized by the accumulation of lipids and oxidative stress in hepatocytes and continual liver damage, has attracted much attention, and it is believed that it will become the leading etiology of liver cancer. We have previously reported that the growth-suppressive effects of arachidonic acid (AA), an unsaturated fatty acid known to be a pro-inflammatory precursor, is accompanied by the production of reactive oxygen species followed by the nuclear accumulation and activation of the protein crosslinking enzyme, transglutaminase (TG)2. In this study, we examined the potential role of garlic extracts in preventing the growth-suppressive effects of AA on human hepatic cells. We also aimed to provide a mechanistic insight regarding the association between the hepatoprotective effects of garlic extract and the inhibition of the TG-related crosslinking of nuclear proteins, which is not associated with hepatic lipid partitioning mediated by stearoyl-CoA desaturase-1. Given the critical roles of unsaturated fatty acids in the regulation of cancer cell stemness and immune surveillance in the context of chronic injury, we propose that garlic extracts may serve as a therapeutic option for the prevention of chronic liver injury and inflammation, as well as for the prevention of the carcinogenesis of fatty livers.
... 11 Transgenic mice deficient in SCD do not develop obesity or IR under hypercaloric diets, have reduced body adiposity, and show increased insulin sensitivity in the liver, adipose tissue, and skeletal muscle. 7,[12][13][14][15][16] They are deficient in triglycerides (TG) and hepatic cholesterol esters, show a high metabolic rate, and are resistant to the development of alcoholic and nonalcoholic fatty liver disease (NAFLD). 5,17 During recent years, scientific research and pharmaceutical companies have made attempts to develop synthetic SCD1 inhibitors to find new therapies for the treatment of MD. 18 Sterculia apetala ( Jacq.) is a tree found in the tropical rainforests of southeastern Mexico in the states of Veracruz, Tabasco, Oaxaca, and Chiapas. ...
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The metabolic syndrome (MS) underlies metabolic disorders considered risk factors for the development of diabetes and cardiovascular diseases, which are major causes of morbidity and mortality in most of the world. Sterculic acid has been proposed as a potential tool for the treatment of MS since it inhibits the activity of the stearoyl-CoA desaturase-1 (SCD1), a central enzyme in lipid metabolism. We analyzed the effect of sterculic oil (SO) co-administration with 30% fructose in drinking water on the development of MS in male Wistar rats. After 8 weeks, 0.4% SO exerted a protective effect from MS development since parameters altered by fructose (blood pressure, insulin resistance, serum glucose and triglycerides, steatosis, and adiposity) were similar to those of control rats.
... Furthermore, the expression level of SCD1 and fatty acid synthase along with endoplasmic reticulum (ER) stress markers was downregulated in response to the inhibition of poly ADP-ribose polymerase (PARP), which is overexpressed in long-term high-fat high-sucrose diet in mice, indicating the PARP-SCD1 interaction as a major mechanism in the induction of non-alcoholic fatty liver disease (33). The role of SCD1 in an alcoholic fatty liver disease model was studied by Louinis et al. (34). In that study, mice fed with a low-MUFA diet containing 5% ethanol for 10 days and a single ethanol gavage (5 g/kg) developed severe hepatic injury. ...
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Stearoyl-coenzyme A desaturase 1 (SCD1) is a microsomal enzyme that controls fatty acid metabolism and is highly expressed in hepatocytes. SCD1 may play a key role in liver development and hepatic lipid homeostasis through promoting monounsaturated protein acylation and converting lipotoxic saturated fatty acids into monounsaturated fatty acids. Imbalanced activity of SCD1 has been implicated in fatty liver induction, inflammation and stress. In this review, the role of SCD1 in hepatic development, function and pathogenesis is discussed. Additionally, emerging novel therapeutic agents targeting SCD1 for the treatment of liver disorders are presented.
... These reports suggest stearic acid, oleic acid and linoleic acid that are targets of ethanol can also function as regulator of fatty liver disease. Additionally, stearoyl-CoA desaturase can synthesize oleic acid from stearic acid and stearoyl-CoA desaturase deficiency protects mice against alcoholic liver injury (Lounis et al., 2016). Collectively, correlation between pathway enrichment and phenotypic change, metabolite modulation and gene knockout demonstrate fatty acid biosynthesis and biosynthesis of unsaturated fatty acids are pathological pathways in alcoholic fatty liver. ...
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Alcoholic fatty liver is a threat to human health. It has been long known that abstinence from alcohol is the most effective therapy, other effective therapies are not available for the treatment in humans. Curcumin has a great potential for anti-oxidation and anti-inflammation, but the effect on metabolic reconstruction remains little known. Here we performed metabolomic analysis by gas chromatography/mass spectrometry and explored ethanol pathogenic insight as well as curcumin action pattern. We identified seventy-one metabolites in mouse liver. Carbohydrates and lipids were characteristic categories. Pathway analysis results revealed that ethanol-induced pathways including biosynthesis of unsaturated fatty acids, fatty acid biosynthesis and pentose and glucuronate interconversions were suppressed by curcumin. Additionally, ethanol enhanced galactose metabolism and pentose phosphate pathway. Glyoxylate and dicarboxylate metabolism and pyruvate metabolism were inhibited in mice fed ethanol diet plus curcumin. Stearic acid, oleic acid and linoleic acid were disease biomarkers and therapical biomarkers. These results reflect the landscape of hepatic metabolism regulation. Our findings illustrate ethanol pathological pathway and metabolic mechanism of curcumin therapy.
... Stearoyl-CoA desaturase-1 (SCD1) is a delta-9 fatty acid desaturase that promotes the synthesis of mono-unsaturated fatty acids and has been found to play an important role in the development of steatosis and liver injury induced by chronic-plus-binge ethanol feeding 77 plays an important role in the control of protein degradation. Chronic-plus-binge ethanol feeding induces a reciprocal regulation of FAT10 and 4-hydroxynonenal (4-HNE) levels in hepatocytes, which stabilizes the oxidatively modified proteins and exacerbates liver injury 91 . ...
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Alcoholic liver disease (ALD), a leading cause of chronic liver injury worldwide, comprises a range of disorders including simple steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Over the last five decades, many animal models that have been useful for the study of ALD pathogenesis have been developed. Recently, a chronic-plus-binge ethanol feeding model was reported. This model induces significant steatosis, hepatic neutrophil infiltration, and liver injury. A clinically relevant model of high-fat diet feeding plus binge ethanol was also developed, which highlights the risk of excessive binge drinking in obese/overweight individuals. All of these models recapitulate some features of the different stages of ALD and have been widely used by many investigators to study the pathogenesis of ALD and test therapeutic drugs/components. However, these models are somewhat variable, depending on mouse genetic background, ethanol dose, and animal facility environment. This review focuses on these models and discusses these variations and some methods to improve the feeding protocol. The pathogenesis, clinical relevance, and translational studies of these models are also discussed.
... Our data corroborate those of Lounis et al. [42], which showed that SCD1 is a key player in the development of AFLD and associated deleterious effects, and suggested SCD1 inhibition as a therapeutic option for the treatment of this hepatic condition. ...
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Ethanol abuse is a serious public health problem that is associated with several stages of alcoholic liver disease (ALD) and a high incidence of morbidity and mortality. Alcoholic fatty liver disease (AFLD), the earliest stage of ALD, is a multifactorial injury that involves oxidative stress and disruptions of lipid metabolism. Although benign and reversible, no pharmacological treatments are available for this condition. In the present study, we induced AFLD in mice with 10% ethanol and a low-protein diet and then orally treated them with a hydroethanolic extract of Baccharis trimera (HEBT; 30 mg kg⁻¹). HEBT reversed ethanol-induced oxidative stress in the liver, reduced lipoperoxidation, normalized GPx, GST, SOD and Cat activity, and GSH and total ROS levels. The reverser effect of HEBT was observed upon ethanol-induced increases in the levels of plasma and hepatic triglycerides, plasma cholesterol, plasma high-density lipoprotein, and plasma and hepatic low-density lipoprotein. Moreover, HEBT increased fecal triglycerides and reduced the histological ethanol-induced lesions in the liver. HEBT also altered the expression of genes that are involved in ethanol metabolism, antioxidant systems, and lipogenesis (i.e., CypE1, Nrf2, and Scd1, respectively). No signs of toxicity were observed in HEBT-treated mice. We propose that HEBT may be a promising pharmacological treatment for AFLD.
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Steatohepatitis, fibrosis, and cirrhosis are common pathological features in the progression of hepatic steatosis. In the current work, we investigated the effect of germinated barely on the structure and function of the liver and its regulatory mechanism on SDC1 gene expression in a steatohepatitis rat model. Forty-eight adult male white Wistar rats were randomly divided into four groups: Group I, control; Group II, rats fed a germinated barley diet; Group III, rats fed a high-fat diet (HFD); and Group IV, rats fed both germinated barley (GB) and a high-fat diet for 14 weeks. Biochemical, histopathological, immunohistochemical, and morphometric studies, as well as qRT-PCR, were used to analyze the effect of germinated barley on steatohepatitis. The rats in Group IV had a lower liver index percentage and improved altered lipid profile and liver function tests compared to those in Group III. Supplementation of GB with a HFD ameliorated the histopathological features in the livers of rats fed a HFD, decreased the percentage of CD68-positive macrophages, and lowered the upregulated expression of SDC1. Supplementation of a HFD with GB prohibited the deterioration of liver function, lipid profile, and alteration of liver structure; it also decreased the associated hepatic inflammation and downregulated SDC1 in liver tissue.
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The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that modulates the metabolic response to drugs and toxic agents. Both PXR activation and deficiency promote hepatic triglyceride accumulation, a hallmark feature of alcoholic liver disease (ALD). However, the molecular mechanism of PXR-mediated activation of ethanol (EtOH)-induced steatosis is unclear. Here, using male wild type (WT) and Pxr-null mice we examined PXR-mediated regulation of chronic EtOH-induced hepatic lipid accumulation and hepatotoxicity. EtOH ingestion for 8 weeks significantly (1.8-fold) upregulated Pxr mRNA levels in WT mice. The EtOH exposure also increased mRNAs encoding hepatic constitutive androstane receptor (3-fold) and its target, Cyp2b10 (220-fold) in a PXR-dependent manner. Furthermore, WT mice had higher serum EtOH levels and developed hepatic steatosis characterized by micro- and macrovesicular lipid accumulation. Consistent with the development of steatosis, lipogenic gene induction was significantly increased in WT mice, including sterol regulatory element-binding protein 1c target gene fatty acid synthase (3.0-fold), early growth response-1 (3.2-fold), and TNFα (3.0-fold), while the expression of peroxisome proliferator-activated receptor α target genes was suppressed. Of note, PXR deficiency suppressed these changes and steatosis. Protein levels, but not mRNAs levels, of EtOH-metabolizing enzymes including alcohol dehydrogenase 1, aldehyde dehydrogenase 1A1 and catalase as well as the microsomal triglyceride transfer protein, involved in regulating lipid output, were higher in Pxr-null than in WT mice. These findings establish that PXR signaling contributes to ALD development and suggest that PXR antagonists may provide a new approach for ALD therapy.
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Alcoholic liver disease (ALD) spans a spectrum of liver pathology, including fatty liver, alcoholic steatohepatitis, and cirrhosis. Accumulating evidence suggests that dietary factors, including dietary fat, as well as alcohol, play critical roles in the pathogenesis of ALD. The protective effects of dietary saturated fat (SF) and deleterious effects of dietary unsaturated fat (USF) on alcohol-induced liver pathology are well recognized and documented in experimental animal models of ALD. Moreover, it has been demonstrated in an epidemiological study of alcoholic cirrhosis that dietary intake of SF was associated with a lower mortality rates, whereas dietary intake of USF was associated with a higher mortality. In addition, oxidized lipids (dietary and in vivo generated) may play a role in liver pathology. The understanding of how dietary fat contributes to the ALD pathogenesis will enhance our knowledge regarding the molecular mechanisms of ALD development and progression, and may result in the development of novel diet-based therapeutic strategies for ALD management. This review explores the relevant scientific literature and provides a current understanding of recent advances regarding the role of dietary lipids in ALD pathogenesis.
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Alcoholic fatty liver disease (AFLD), a potentially pathologic condition, can progress to steatohepatitis, fibrosis, and cirrhosis, leading to an increased probability of hepatic failure and death. Alcohol induces fatty liver by increasing the ratio of reduced form of nicotinamide adenine dinucleotide to oxidized form of nicotinamide adenine dinucleotide in hepatocytes; increasing hepatic sterol regulatory element-binding protein (SREBP)-1, plasminogen activator inhibitor (PAI)-1, and early growth response-1 activity; and decreasing hepatic peroxisome proliferator-activated receptor-α activity. Alcohol activates the innate immune system and induces an imbalance of the immune response, which is followed by activated Kupffer cell-derived tumor necrosis factor (TNF)-α overproduction, which is in turn responsible for the changes in the hepatic SREBP-1 and PAI-1 activity. Alcohol abuse promotes the migration of bone marrow-derived cells (BMDCs) to the liver and then reprograms TNF-α expression from BMDCs. Chronic alcohol intake triggers the sympathetic hyperactivity-activated hepatic stellate cell (HSC) feedback loop that in turn activates the HSCs, resulting in HSC-derived TNF-α overproduction. Carvedilol may block this feedback loop by suppressing sympathetic activity, which attenuates the progression of AFLD. Clinical studies evaluating combination therapy of carvedilol with a TNF-α inhibitor to treat patients with AFLD are warranted to prevent the development of alcoholic liver disease.
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Alcoholic liver disease is a major health problem in the United States and worldwide. Chronic alcohol consumption can cause steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Significant progress has been made to understand key events and molecular players for the onset and progression of alcoholic liver disease from both experimental and clinical alcohol studies. No successful treatments are currently available for treating alcoholic liver disease; therefore, development of novel pathophysiological-targeted therapies is urgently needed. This review summarizes the recent progress on animal models used to study alcoholic liver disease and the detrimental factors that contribute to alcoholic liver disease pathogenesis including miRNAs, S-adenosylmethionine, Zinc deficiency, cytosolic lipin-1β, IRF3-mediated apoptosis, RIP3-mediated necrosis and hepcidin. In addition, we summarize emerging adaptive protective effects induced by alcohol to attenuate alcohol-induced liver pathogenesis including FoxO3, IL-22, autophagy and nuclear lipin-1α.
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Chronic alcohol consumption is a leading cause of chronic liver disease worldwide, leading to cirrhosis and hepatocellular carcinoma. Currently, the most widely used model for alcoholic liver injury is ad libitum feeding with the Lieber-DeCarli liquid diet containing ethanol for 4-6 weeks; however, this model, without the addition of a secondary insult, only induces mild steatosis, slight elevation of serum alanine transaminase (ALT) and little or no inflammation. Here we describe a simple mouse model of alcoholic liver injury by chronic ethanol feeding (10-d ad libitum oral feeding with the Lieber-DeCarli ethanol liquid diet) plus a single binge ethanol feeding. This protocol for chronic-plus-single-binge ethanol feeding synergistically induces liver injury, inflammation and fatty liver, which mimics acute-on-chronic alcoholic liver injury in patients. This feeding protocol can also be extended to chronic feeding for longer periods of time up to 8 weeks plus single or multiple binges. Chronic-binge ethanol feeding leads to high blood alcohol levels; thus, this simple model will be very useful for the study of alcoholic liver disease (ALD) and of other organs damaged by alcohol consumption.
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Stearoyl CoA desaturase 1 (SCD1) catalyzes the rate-limiting step in the production of MUFA that are major components of tissue lipids. Alteration in SCD1 expression changes the fatty acid profile of these lipids and produces diverse effects on cellular function. High SCD1 expression is correlated with metabolic diseases such as obesity and insulin resistance, whereas low levels are protective against these metabolic disturbances. However, SCD1 is also involved in the regulation of inflammation and stress in distinct cell types, including β-cells, adipocytes, macrophages, endothelial cells, and myocytes. Furthermore, complete loss of SCD1 expression has been implicated in liver dysfunction and several inflammatory diseases such as dermatitis, atherosclerosis, and intestinal colitis. Thus, normal cellular function requires the expression of SCD1 to be tightly controlled. This review summarizes the current understanding of the role of SCD1 in modulating inflammation and stress.
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The association between alcohol intake and alcoholic liver disease has been well documented, although cirrhosis of the liver develops in only a small proportion of heavy drinkers. This review focuses on alcoholic hepatitis, a treatable form of alcoholic liver disease. Since up to 40% of patients with severe alcoholic hepatitis die within 6 months after the onset of the clinical syndrome, appropriate diagnosis and treatment are essential.
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This study investigated the mechanism by which chronic ethanol feeding reduces arachidonate and other highly unsaturated fatty acids in pig liver phospholipids. Five micropigs were fed a diet providing 89 kcal/kg body wt for 12 mo, with ethanol and fat as 40 and 34% of energy, respectively. Five control pigs were pairfed corn starch instead of ethanol. The activities of delta 6 and delta 5 desaturases (expressed as microsomal conversion of precursor to product) in liver from ethanol-fed pigs were reduced to less than half that of controls, whereas the activity of delta 9 desaturase was unaffected in the ethanol group. delta 5 Desaturase activity showed positive correlation with the abundance of its products in liver total phospholipids and microsomes in the ethanol group, but not in the controls. Correlation between delta 6 desaturase activity and its products showed similar pattern to that of delta 5 desaturase, but did not reach statistical significance. No difference was observed between the two groups in coenzyme A concentration in the liver. These results suggest that the selective reduction of delta 6 and delta 5 desaturase activities, not the microsomal electron transport system, are directly responsible for the altered profile of liver phospholipids.
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This study was undertaken to elucidate the mechanism underlying the protective effect of a high saturated fat (HSF) diet against the development of alcoholic fatty liver in mice. We tested the effects of a HSF diet on the ethanol-mediated increase in hepatic sterol regulatory element binding protein 1 (SREBP-1) activity. Thirty-two male mice were divided into 4 groups and fed liquid diets consisting of either a high polyunsaturated fat (40% of energy from corn oil) or a HSF (40% of energy from cocoa butter) diet with or without ethanol for 4 wk. In the ethanol-containing diets, ethanol was substituted for an equivalent amount of carbohydrate to provide 27.5% of the total energy. Control mice were pair-fed the same volume of liquid diets as the ethanol-fed mice. The HSF diet suppressed the increase in mature SREBP-1 protein and prevented increased mRNA of the SREBP-1-regulated lipogenic enzymes in the ethanol-fed mice (P < 0.05). Sirtuins 1 (SIRT1), a NAD+-dependent class III histone deacetylase, was upregulated by ethanol administration in mice fed the HSF diet (P < 0.05). The HSF diet blocked histone H3 at lysine 9 (lys9) hyperacetylation and attenuated association of acetylated histone H3-Lys9 with the promoters of mitochondrial glycerol-3-phosphate acyltransferase and stearoyl-CoA desaturase 1 in the livers of the ethanol-fed mice. These results suggest that the protective effects of HSF diet against the development of alcoholic liver steatosis may occur via regulation of the hepatic SIRT1-SREBP-1-histone H3 axis, suppressing the expression of genes encoding lipogenic enzymes and slowing the synthesis of hepatic fatty acids.
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Alcoholic liver disease (ALD) is a complex process that includes a wide spectrum of hepatic lesions, from steatosis to cirrhosis. Cell injury, inflammation, oxidative stress, regeneration and bacterial translocation are key drivers of alcohol-induced liver injury. Alcoholic hepatitis is the most severe form of all the alcohol-induced liver lesions. Animal models of ALD mainly involve mild liver damage (that is, steatosis and moderate inflammation), whereas severe alcoholic hepatitis in humans occurs in the setting of cirrhosis and is associated with severe liver failure. For this reason, translational studies using humans and human samples are crucial for the development of new therapeutic strategies. Although multiple attempts have been made to improve patient outcome, the treatment of alcoholic hepatitis is still based on abstinence from alcohol and brief exposure to corticosteroids. However, nearly 40% of patients with the most severe forms of alcoholic hepatitis will not benefit from treatment. We suggest that future clinical trials need to focus on end points other than mortality. This Review discusses the main pathways associated with the progression of liver disease, as well as potential therapeutic strategies targeting these pathways.
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Levene A P & Goldin R D (2012) Histopathology 61, 141–152 The epidemiology, pathogenesis and histopathology of fatty liver disease Fatty liver disease includes non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD), each of which is increasing in prevalence. Each represents a histological spectrum that extends from isolated steatosis to steatohepatitis and cirrhosis. NAFLD is associated with obesity, diabetes, and insulin resistance, and is considered to be the liver manifestation of the metabolic syndrome. The pathogenesis of NAFLD and ALD involves cytokines, adipokines, oxidative stress, and apoptosis. Histopathology is the gold standard for assessing the severity of liver damage in NAFLD and ALD. We have reviewed the literature, and described and compared the epidemiology, natural disease history, pathogenesis and histopathology of NAFLD and ALD.
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Stearoyl-CoA desaturase1 (SCD1) whole body deficiency protects mice from diet-induced obesity. However the specific mechanism of how SCD1 deficiency protects mice from obesity is not clear yet. To understand the tissue-specific role of SCD1 in energy homeostasis, we investigated the responses of adipocytes, hepatocytes and myotubes to SCD1 inhibition. 3T3-L1 adipocytes treated with a SCD1 inhibitor had decreased expression of lipogenic genes including fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and sterol-regulatory element binding protein 1c (SREBP1c) while the expression of fatty acid oxidative genes including carnitine palmitoyltransferase 1 (CPT1), uncoupling protein 2 (UCP2), and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1-α) remained unaltered. In mouse primary hepatocytes, treatment with the inhibitor reduced the expression of FAS, ACC, and SREBP1c but increased the expression of fatty acid oxidative genes including acyl-CoA oxidase (AOX), CPT1, and PGC1-α. In addition, inhibitor-treated C2C12 myotubes showed decrease in ACC and FAS expression and increase in expression of CPT1, AOX and PGC1-α. AMP-activated protein kinase (AMPK) is known to regulate cellular metabolism in response to available energy and AMPK activation is associated with enhancement of fatty acid oxidation and suppression of lipogenesis. In all tested cell models, AMPK phosphorylation was increased significantly when SCD1 was inhibited. Taken together, our results indicate that inhibition of SCD1 activity has beneficial lipid metabolic effects of decreased lipogenesis and/or increased fatty acid oxidation, which is at least in part due to an increase of AMPK activation.
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Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide and can lead to fibrosis and cirrhosis. The latest surveillance report published by the National Institute on Alcohol Abuse and Alcoholism showed that liver cirrhosis was the 12th leading cause of death in the United States, with a total of 29,925 deaths in 2007, 48% of which were alcohol related. The spectrum of ALD includes simple steatosis, alcoholic hepatitis, fibrosis, cirrhosis, and superimposed hepatocellular carcinoma. Early work on the pathogenesis of the disease focused on ethanol metabolism-associated oxidative stress and glutathione depletion, abnormal methionine metabolism, malnutrition, and production of endotoxins that activate Kupffer cells. We review findings from recent studies that have characterized specific intracellular signaling pathways, transcriptional factors, aspects of innate immunity, chemokines, epigenetic features, microRNAs, and stem cells that are associated with ALD, improving our understanding of its pathogenesis. Despite this progress, no targeted therapies are available. The cornerstone of treatment for alcoholic hepatitis remains as it was 40 years ago: abstinence, nutritional support, and corticosteroids. There is an urgent need to develop new pathophysiology-oriented therapies. Recent translational studies of human samples and animal models have identified promising therapeutic targets.
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Unlabelled: Interleukin-22 (IL-22), a recently identified member of the IL-10 family of cytokines that is produced by Th17 and natural killer cells, plays an important role in controlling bacterial infection, homeostasis, and tissue repair. Here, we tested the effect of IL-22 on alcohol-induced liver injury in a murine model of chronic-binge ethanol feeding. Feeding male C57BL/6 mice with a Lieber-DeCarli diet containing 5% ethanol for 10 days, followed by a single dose of ethanol (5 g/kg body weight) by gavage, induces significant fatty liver and liver injury with peak serum levels of approximately 250 IU/L alanine aminotransferase and 420 IU/L aspartate aminotransferase 9 hours after gavage. Moreover, chronic-binge ethanol administration increases expression of hepatic and serum inflammatory cytokines and hepatic oxidative stress. Using this model, we demonstrate that treatment with IL-22 recombinant protein activates hepatic signal transducer and activator of transcription 3 (STAT3) and ameliorates alcoholic fatty liver, liver injury, and hepatic oxidative stress. Administration with IL-22 adenovirus also prevents alcohol-induced steatosis and liver injury. Deletion of STAT3 in hepatocytes abolishes the hepatoprotection provided by IL-22 in alcoholic liver injury. In addition, IL-22 treatment down-regulates the hepatic expression of fatty acid transport protein, but up-regulates several antioxidant, antiapoptotic, and antimicrobial genes. Finally, expression of IL-22 receptor 1 is up-regulated whereas IL-22 is undetectable in the livers from mice with chronic-binge ethanol feeding or patients with alcoholic hepatitis. Conclusion: Chronic-binge ethanol feeding may be a useful model to study the early stages of alcoholic liver injury. IL-22 treatment could be a potential therapeutic option to ameliorate alcoholic liver disease, due to its antioxidant, antiapoptotic, antisteatotic, proliferative, and antimicrobial effects with the added benefit of potentially few side effects.
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This review aims to address the latest research on hepatic desaturases and metabolic disorders, with focus on stearoyl-CoA desaturase-1 (SCD-1) indices in observational studies. In animal studies, SCD-1 inhibition protects against features of the metabolic syndrome and is associated with improved hepatic insulin resistance and decreased steatosis. In human observational studies, higher estimated hepatic SCD-1 and Δ6-desaturase activities predict the metabolic syndrome, insulin resistance and mortality whereas Δ5-desaturase index is often inversely related. However, because the desaturase activities in the liver and adipose tissue may not be regulated in parallel, it is important to define used lipid fractions when comparing studies. It is also important to take the background diets of the populations into account when comparing studies. Moreover, there may be a divergence in desaturase regulation depending on glycaemic control among individuals. Increased SCD-1 indices reflecting liver desaturase activity have been associated with insulin resistance, fatty liver, the metabolic syndrome and mortality. However, it remains to be determined if high hepatic SCD-1 activity plays a direct role in the development of metabolic disorders or rather is a marker for an unfavourable diet or hepatic insulin resistance.
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De novo lipogenesis (DNL) is a complex yet highly regulated metabolic pathway, and transcription factors such as liver X receptor (LXR), sterol regulatory element-binding protein-1c (SREBP-1c), and carbohydrate response element binding protein (ChREBP) exert significant control over the de novo synthesis of fatty acids. An increase in de novo lipogenesis (DNL) is an important contributor to increased fat mass, while a reduction in lipogenesis may be protective against the development of obesity. In this review, we explore fatty acid synthesis in the context of new insights gleaned from global and tissue-specific gene knockout mouse models of enzymes involved in fatty acid synthesis, namely acetyl-CoA carboxylase, fatty acid synthase, fatty acid elongase 6, and stearoyl-CoA desaturase 1. A disruption in fatty acid synthesis, induced by the deficiency of any one of these enzymes, affects lipid metabolism and in some cases may protect against obesity in a tissue and gene-specific manner, as discussed in detail in this review.
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To investigate the relationships of serum fatty acid (FA) composition and estimated desaturase activities with the liver fat marker alanine aminotransferase (ALT). 546 Swedish elderly men of a population-based cohort participated in this cross-sectional study. FA composition was assessed in serum cholesterol esters to determine dietary fat quality (e.g. linoleic) and desaturation products (e.g. dihomo-gamma-linolenic acid). Desaturase indices, including stearoyl coenzymeA desaturase-1 (SCD-1), were calculated by FA product-to-precursor ratios. In linear regression analyses adjusting for lifestyle, abdominal obesity and insulin sensitivity, the dietary biomarker linoleic acid (n-6), but not n-3 FAs, was inversely related to ALT. Desaturation products including palmitoleic, oleic, gamma-linolenic and dihomo-gamma-linolenic acids, and Delta6-desaturase and SCD-1 indices were directly related to ALT (all p<0.05). After further adjustment for factors previously linked to fatty liver (i.e. serum lipids, adiponectin concentrations), SCD-1 index (p=0.004) and insulin resistance (p<0.0001) were independent determinants of ALT activity, whereas waist circumference, triglycerides, non-esterified FA and adiponectin were not. A low dietary intake of linoleic acid and elevated SCD-1 index may contribute to higher ALT activity in elderly men, even independently of obesity and insulin resistance.
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Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries and is considered the hepatic manifestation of metabolic syndrome. The hallmark of NAFLD is hepatic neutral lipid accumulation, mainly triacylglycerol, in the absence of significant ethanol consumption, viral infection or other specific etiologies. Hepatic lipid accumulation results from an imbalance between lipid availability (from circulating lipid uptake or de novo lipogenesis) and lipid disposal (via free fatty acid oxidation or triglyceride-rich lipoprotein secretion) and eventually triggers lipoperoxidative stress and hepatic injury. Each of these steps is altered in NAFLD, although to a different extent. Regulation of these pathways is complex and involves nuclear receptors, membrane transport proteins and cellular enzymes. We will review available data on different steps of hepatic lipid metabolism in NAFLD and recent advances in understanding molecular mechanisms underlying hepatic fat accumulation in these subjects.
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The rates of ethanol oxidation in various species are linked to the rates of general metabolism, and more specifically that of O2 utilization by the liver. After chronic ethanol administration, increased oxidation of ethanol is accompanied by increased total hepatic O2 utilization, as studied in the whole animal, the perfused liver, and isolated liver slices. The correlation is particularly striking in the spontaneously hypertensive rat. This linkage makes the liver of the chronically ethanol-consuming rat abnormally vulnerable to hypoxic damage. Exposure to 5% oxygen atmosphere for 6 hours produced major elevations of SGOT and SOCT activities and marked centrilobular necrosis, in alcohol-treated animals but not in controls. The same differential susceptibility was found to acute anemia produced by bleeding. The possible relation of these findings to alcoholic liver damage in humans is discussed.
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Until two decades ago, dietary deficiencies were considered to be the only reason for alcoholics to develop liver disease. As the overall nutrition of the population improved, more emphasis was placed on secondary malnutrition and direct hepatotoxic effects of ethanol were established. Ethanol is hepatotoxic through redox changes produced by the NADH generated in its oxidation via the alcohol dehydrogenase pathway, which in turn affects the metabolism of lipids, carbohydrates, proteins, and purines. Ethanol is also oxidized in liver microsomes by an ethanol-inducible cytochrome P-450 (P-450IIE1) that contributes to ethanol metabolism and tolerance, and activates xenobiotics to toxic radicals thereby explaining increased vulnerability of the heavy drinker to industrial solvents, anesthetic agents, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens, and even nutritional factors such as vitamin A. In addition, ethanol depresses hepatic levels of vitamin A, even when administered with diets containing large amounts of the vitamin, reflecting, in part, accelerated microsomal degradation through newly discovered microsomal pathways of retinol metabolism, inducible by either ethanol or drug administration. The hepatic depletion of vitamin A is strikingly exacerbated when ethanol and other drugs were given together, mimicking a common clinical occurrence. Microsomal induction also results in increased production of acetaldehyde. Acetaldehyde, in turn, causes injury through the formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair, and alterations in microtubules, plasma membranes and mitochondria with a striking impairment of oxygen utilization. Acetaldehyde also causes glutathione depletion and lipid peroxidation, and stimulates hepatic collagen production by the vitamin A storing cells (lipocytes) and myofibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS)
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Nine patients with severe alcoholic fatty livers were studied to evaluate the effects of aqueous testosterone and norethandrolone on the rate of fat removal from the liver. Serial liver biopsies showed that the addition of either of these anabolic steroids to a diet high in calories and protein reversed hepatic steatosis at a rate three to five times faster than that observed with diet alone. The relationship of this therapeutic effect to their actions on serum lipoproteins is discussed, but as yet no definite conclusions can be drawn.
Article
Male Sprague-Dawley rats were fed, ad libitum for 30 days, a fat-free (FF) liquid diet containing 34% of the calories as ethanol or a control FF diet in which alcohol was replaced by an isocaloric amount of dextrins. The cytosolic fatty acid synthetase and the microsomal stearoyl-CoA desaturase activities in the livers of rats fed the alcohol diet were about half of those observed in the livers of control rats. The conclusion is that chronic ethanol consumption depresses the activities of these lipogenic enzymes in the liver.
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258 alcohol-abusing men, free from cirrhosis on primary liver biopsy, were followed for 10-13 years during which cirrhosis developed in 38, corresponding to a rate of 2% per year. The likelihood of cirrhosis developing proved to be independent of duration of abuse and of daily consumption before the primary biopsy. This indicates that the effect of alcohol abuse is not cumulative over time, but rather establishes conditions for the development of cirrhosis. The rate of cirrhosis increased stepwise with degree of steatosis in the primary biopsy, and in those with alcoholic hepatitis was nine times higher than in those with no steatosis. This finding, together with the results on alcohol abuse, indicates that steatosis and alcoholic hepatitis, despite their reversibility, are causally associated with cirrhosis rather than epiphenomena of alcohol abuse. In the alcohol-abusing man, a liver biopsy provides more information than alcoholic history about the likelihood of future cirrhosis.
Article
"Pure" alcoholic fatty liver has been widely assumed to be "benign" with very low risk of progression to cirrhosis. Studies thus far have included either patients with coexisting recognised precursor lesions of cirrhosis or have been restricted to short-term histological follow-up. We have followed 88 patients, first seen between 1978 and 1985, with a histological diagnosis of pure alcoholic fatty liver and no evidence of fibrosis or alcoholic hepatitis, for a median of 10.5 years, to determine any factors predictive of disease progression. Of the 88, at follow-up nine had developed cirrhosis and a further seven fibrosis. Eight of nine patients with cirrhosis had continuing alcohol consumption of more than 40 units per week at follow-up; in the other patients, consumption was unknown. Independent histological predictors of progression on index biopsy were: presence of mixed macro/microvesicular fat, and presence of giant mitochondria. We can no longer regard alcoholic fatty liver as benign. In the presence of continuing high alcohol consumption the above histological features identified those at high risk (47-61%) of disease progression. Therefore, patients with these features should be counselled intensively regarding their alcohol consumption.
Article
The metabolism of the essential fatty acids [1-14C]20:4n-6, [1-14C]20:5n-3 and [1-14C]22:6n-3 was studied in rat hepatocytes fed ethanol in two different diets. Using a diet with a low lipid content ethanol (1) reduced the elongation of eicosapentaenoic acid, (2) reduced the esterification of docosahexaenoic acid (DHA) in phospholipids (PL), (3) increased the oxidation of DHA, (4) increased the ratio of esterification of DHA in phosphatidylethanolamine (PE) compared to phosphatidylcholine (PC) (PE/PC ratio), (5) altered the formation of PL molecular species, and (6) induced a decrease in the endogenous content of the hepatocytes of arachidonic acid and linoleic acid and an increase in oleic acid, 20:3n-9 and DHA. Using a high lipid diet, only the above-mentioned effect (4) was induced by ethanol, not the effects (1)-(3) and (5)-(6).
Article
In experimental rat liver perfusion we observed net production of free acetate accompanied by accelerated ketogenesis with long-chain fatty acids. Mitochondrial acetyl-CoA hydrolase, responsible for the production of free acetate, was found to be inhibited by the free form of CoA in a competitive manner and activated by reduced nicotinamide adenine dinucleotide (NADH). The conditions under which the ketogenesis was accelerated favored activation of the hydrolase by dropping free CoA and elevating NADH levels. Free acetate was barely metabolized in the liver because of low affinity, high K(m), of acetyl coenzyme A (acetyl-CoA) synthetase for acetate. Therefore, infused ethanol was oxidized only to acetate, which was entirely excreted into the perfusate. The acetyl-CoA synthetase in the heart mitochondria was much lower in K(m) than it was in the liver, thus the heart mitochondria was capable of oxidizing free acetate as fast as other respiratory substrates, such as succinate. These results indicate that rat liver produces free acetate as a byproduct of ketogenesis and may supply free acetate, as in the case of ketone bodies, to extrahepatic tissues as fuel.
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The constellation of histopathologic lesions that characterize alcoholic and nonalcoholic steatohepatitis has been well described and has served as the basis for clinical diagnosis, natural history studies, and experimental models for analyses of etiopathogenesis. The lesions common to both entities include, to varying degrees, steatosis, liver cell ballooning, lobular inflammation with a notable component of polymorphonuclear leukocytes, and a characteristic form of fibrosis that is initially located in the perisinusoidal regions of acinar zone 3. Cirrhosis with or without steatosis or steatohepatitis may occur in both entities. Mallory's hyaline is common but not necessary; megamitochondria and varying amounts of iron may be observed in either process. Hepatocellular carcinoma is a recognized complication of both processes, albeit with greater frequency in the former. Alcoholic hepatitis may present with more severe clinical and histologic manifestations than the nonalcoholic counterpart, including significant morbidity and mortality. The perivenular lesions collectively referred to as sclerosing hyaline necrosis are markers of severity, and are not common in nonalcoholics. In many instances, however, the microscopic lesions of these two processes are similar, likely as a reflection of common pathogenetic pathways, and the distinction between the two is ultimately clinically derived.
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Stearoyl-CoA desaturase (SCD) is a central lipogenic enzyme catalyzing the synthesis of monounsaturated fatty acids, mainly oleate (C18:1) and palmitoleate (C16:1), which are components of membrane phospholipids, triglycerides, wax esters, and cholesterol esters. Several SCD isoforms (SCD1-3) exist in the mouse. Here we show that mice with a targeted disruption of the SCD1 isoform have reduced body adiposity, increased insulin sensitivity, and are resistant to diet-induced weight gain. The protection from obesity involves increased energy expenditure and increased oxygen consumption. Compared with the wild-type mice the SCD1-/- mice have increased levels of plasma ketone bodies but reduced levels of plasma insulin and leptin. In the SCD1-/- mice, the expression of several genes of lipid oxidation are up-regulated, whereas lipid synthesis genes are down-regulated. These observations suggest that a consequence of SCD1 deficiency is an activation of lipid oxidation in addition to reduced triglyceride synthesis and storage.
Article
Our previous work has shown that ethanol induces the fatty acid synthesis pathway by activation of sterol regulatory element-binding protein 1 (SREBP-1). In the present study, we studied the mechanisms of this activation by identifying a new target of ethanol, AMP-activated protein kinase (AMPK). The effects of ethanol on AMPK, acetyl-CoA carboxylase (ACC), and SREBP-1 were assessed in rat hepatic cells and in the livers of ethanol-fed mice. In rat hepatoma H4IIEC3 or McA-RH 7777 cell lines, ethanol-induced transcription of an SREBP-regulated promoter was suppressed by the presence of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) or metformin, 2 known AMPK activators. Consistent with this, over expression of a constitutively active form of AMPK blocked the effect of ethanol, whereas coexpression of a dominant-negative form of AMPK augmented the effect. Moreover, activation of AMPK by metformin or AICAR largely blocked the ability of ethanol to increase levels of mature SREBP-1 protein. These findings suggest that the effect of ethanol on SREBP-regulated promoter activation was partially mediated through AMPK inhibition. We further demonstrated that AMPK was inhibited by ethanol in hepatic cells. In parallel, ethanol increased the activity of ACC and suppressed the rate of palmitic acid oxidation. Finally, feeding mice a low-fat diet with ethanol resulted in significantly reduced hepatic AMPK activity, increased ACC activity, and enhanced malonyl CoA content. Taken together, our findings suggest that AMPK may play a key role in regulating the effects of ethanol on SREBP-1 activation, fatty acid metabolism, and development of alcoholic fatty liver.
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In this article, subjects diagnosed with alcoholic liver disease are shown to have lower concentrations of several polyunsaturated fatty acids (PUFAs), including 18:2n6, 18:3n6, 20:3n6, 18:3n3, 22:5n3, and 22:6n3, but not 20:4n6 and 22:4n6, nor 22:5n6, in the total lipid extracts of their livers compared with findings for specimens obtained from patients diagnosed with primary biliary cirrhosis and from control subjects. Findings of studies in animals have demonstrated that prolonged alcohol consumption reduces liver polyunsaturate content. However, the effect of ethanol on the elongation/desaturation of essential fatty acids is complex, as in vitro study results indicate that the direction of the effect of alcohol may be related to the dose of alcohol. Findings of studies in hepatocyte cell culture indicate that ethanol increased delta-5 and delta-6 desaturase activities throughout a broad concentration range. In contrast, lower liver desaturase activity has been reported in animals consuming high concentrations of alcohol (36%-40% energy) over a period of several months. Findings from in vivo isotope tracers studies in nonhuman primates and felines indicate that prolonged periods of moderate (mean consumption 2.6 g kg(-1) d(-1) and 1.2 g kg(-1) d(-1), respectively) alcohol consumption had no effect on the uptake of either linoleic (18:2n6) or alpha-linolenic (18:3n3) acids into the plasma and lead to an increased incorporation of these deuterated precursors into 20:4n6 and 22:6n3. Thus, this likely reflects a stimulated, rather than an inhibited, production of long-chain PUFAs. In numerous studies in various species, investigators have documented that alcohol consumption can increase the level of lipid peroxidation in tissues, and sustained periods of ethanol-induced peroxidation can deplete tissues of PUFAs. A hypothesis to rationalize the long-term effects of alcohol consumption on liver PUFA concentration that takes into consideration the effect of ethanol on essential fatty acid metabolism is presented.
Article
Both dietary fatty acids and alcohol play an important role in the pathogenesis of alcoholic liver disease. Findings of studies in rats show a steatogenic role for dietary fat. A role for polyunsaturated fatty acids in alcoholic liver disease is supported by results of studies, which show that pathologic changes occur only in rats fed ethanol with polyunsaturated fatty acids. The mechanisms through which the fatty acids promote alcoholic liver disease include enhanced oxidative stress, production of endotoxin, and increased expression of proinflammatory cytokines.
Article
Alcohol abuse is one of the major causes of liver fibrosis worldwide. Although the pathogenesis of liver fibrosis is a very complex phenomenon involving different molecular and biological mechanisms, several lines of evidence established that the first ethanol metabolite, acetaldehyde, plays a key role in the onset and maintenance of the fibrogenetic process. This review briefly summarizes the molecular mechanisms underlying acetaldehyde pro-fibrogenic effects. Liver fibrosis represents a general wound-healing response to a variety of insults. Although mortality due to alcohol abuse has been constantly decreasing in the past 20 years in Southern Europe and North America, in several Eastern-European countries and Great Britain Alcoholic Liver Disease (ALD) shows a sharply increasing trend [Bosetti, C., Levi, F., Lucchini, F., Zatonski, W.A., Negri, E., La, V.C., 2007. Worldwide mortality from cirrhosis: an update to 2002. J. Hepatol. 46, 827-839]. ALD has a complex pathogenesis, in which acetaldehyde (AcCHO), the major ethanol metabolite, plays a central role. Ethanol is mainly metabolized in the liver by two oxidative pathways. In the first one ethanol is oxidized to acetaldehyde by the cytoplasmic alcohol dehydrogenase enzyme (ADH), acetaldehyde is then oxidized to acetic acid by the mitochondrial acetaldehyde dehydrogenase (ALDH). The second pathway is inducible and involves the microsomal ethanol-oxidizing system (MEOS), in which the oxidation of ethanol to acetaldehyde and acetic acid also leads to generation of reactive oxygen species (ROS). Chronic ethanol consumption significantly inhibits mitochondrial ALDH activity while the rate of ethanol oxidation to acetaldehyde is even enhanced, resulting in a striking increase of tissue and plasma acetaldehyde levels [Lieber, C.S., 1997. Ethanol metabolism, cirrhosis and alcoholism. Clin. Chim. Acta 257, 59-84]. This review will focus on the molecular mechanisms by which acetaldehyde promote liver fibrosis.
Practice Guideline Committee of the American Association for the Study of Liver D, Practice Parameters Committee of the American College of G, Alcoholic liver disease
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