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Association of chemokines and NASH. In adipose tissue of the obese, bone-marrow-derived monocytes are recruited from the bloodstream, predominantly via MCP-1-CCR2 signaling. The RANTES-CCR5 pathway also plays an important role in monocyte recruitment in adipose tissue. Infiltrated macrophages in obese adipose tissue undergo a phenotypic switch from alternative M2 macrophages to classical M1 macrophages. The latter secrete pro-inflammatory cytokines, which result in insulin resistance, adipokine dysfunction, and excess lipid accumulation in the liver. In the fatty liver, the recruitment and activation of immune cells, including Kupffer cells, contribute to hepatic inflammation, which is involved in hepatic stellate cell activation.
Source publication
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders worldwide. It is associated with clinical states such as obesity, insulin resistance, and type 2 diabetes, and covers a wide range of liver changes, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular car...
Contexts in source publication
Context 1
... other chemokines involved in obesity may contribute to macrophage recruitment and insulin resistance. In previous work, we demonstrated that CCR5-deficient mice are protected from insulin resistance and hepatic fatty acid infiltration, through the regulation of macrophage recruitment and the response of M1/M2 macrophage polarization to inflammation (Figure 2) [57]. ...
Context 2
... other chemokines involved in obesity may contribute to macrophage recruitment and insulin resistance. In previous work, we demonstrated that CCR5-deficient mice are protected from insulin resistance and hepatic fatty acid infiltration, through the regulation of macrophage recruitment and the response of M1/M2 macrophage polarization to inflammation (Figure 2) [57]. Association of chemokines and NASH. ...
Context 3
... expression in hepatocytes is increased in animals fed a high-fat diet and leads to the hepatic recruitment of CCR2 + myeloid cells that promote hepatic steatosis [50]. The MCP-1-CCR2 pathway is also up-regulated in the livers of animals with NASH and is thus critical to Figure 2. Association of chemokines and NASH. ...
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Introduction:
Nonalcoholic steatohepatitis (NASH) associated or not with cirrhosis is the third leading indication for liver transplantation (LT) around the world. After transplants, NASH has a high prevalence and occurs as both recurrent and de novo manifestations. De novo NASH can also occur in allografts of patients transplanted for non-NASH liv...
Citations
... This polyvalence in determining rather different pathologies is attributable to the fact that insulin exerts physiological effects on lipid and protein metabolism and participates with its anabolic function in the division and proliferation of the cell without neglecting the fact that its receptors are distributed in various organs and tissues of the body [41]. Although IR is typically a male condition, the study of gender-specific differences has become important since the protective role of estrogens, which reduce the risk of this disorder among women, was discovered [42][43][44]. Table 3. Associated health conditions of insulin resistance. ...
... This polyvalence in determining rather different pathologies is attributable to the fact that insulin exerts physiological effects on lipid and protein metabolism and participates with its anabolic function in the division and proliferation of the cell without neglecting the fact that its receptors are distributed in various organs and tissues of the body [41]. Although IR is typically a male condition, the study of gender-specific differences has become important since the protective role of estrogens, which reduce the risk of this disorder among women, was discovered [42][43][44]. ...
Insulin resistance is the main mechanism in a whole series of pathological conditions, which are not only of metabolic interest but also of a systemic type. This phenomenon means that the body’s cells become less sensitive to the hormone insulin, leading to higher levels of insulin in the blood. Insulin resistance is a phenomenon that can be found in both men and women and in particular, in the latter, it is found mainly after menopause. Premenopause, hormonal fluctuations during the menstrual cycle, and the presence of estrogen can affect insulin sensitivity. Androgens, such as testosterone, are typically higher in men and can contribute to insulin resistance. In both sexes, different human body types affect the distribution and location of body fat, also influencing the development of diabetes and cardiovascular disease. Insulin resistance is also associated with some neurological and neurogenerative disorders, polycystic ovary syndrome, atherosclerosis, and some of the main neoplastic pathologies. A healthy lifestyle, including regular physical activity, a balanced diet, and self-maintenance, can help to prevent the onset of insulin resistance, regardless of gender, although the different habits between men and women greatly affect the implementation of preventative guidelines that help in fighting the manifestations of this metabolic disorder. This review may help to shed light on gender differences in metabolic diseases by placing a necessary focus on personalized medical management and by inspiring differentiated therapeutic approaches.
... Normally, insulin encourages the uptake of glucose and the synthesis of fatty acids from nonlipid molecules, which is known as lipogenesis. Insulin stimulates glycolysis by activating glucokinase, together with hepatic pyruvate kinase, acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase, sterol regulatory element-binding protein 1c (SREBP-1c), and Spot 14, which leads to FA synthesis [64]. In general, the resistance of insulin decreases the hormone's capacity to diminish glucose production; however, at the same time, it can support lipogenesis [65]. ...
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases. Its incidence is progressively rising and it is possibly becoming a worldwide epidemic. NAFLD encompasses a spectrum of diseases accounting for the chronic accumulation of fat within the hepatocytes due to various causes, excluding excessive alcohol consumption. In this study, we aimed to focus on finding evidence regarding the implications of oxidative stress and inflammatory processes that form the multifaceted pathophysiological tableau in relation to thrombotic events that co-occur in NAFLD and associated chronic liver diseases. Recent evidence on the pathophysiology of NAFLD suggests that a complex pattern of multidirectional components, such as prooxidative, proinflammatory, and prothrombotic components, better explains the multiple factors that promote the mechanisms underlying the fatty acid excess and subsequent processes. As there is extensive evidence on the multi-component nature of NAFLD pathophysiology, further studies could address the complex interactions that underlie the development and progression of the disease. Therefore, this study aimed to describe possible pathophysiological mechanisms connecting the molecular impairments with the various clinical manifestations, focusing especially on the interactions among oxidative stress, inflammation, and coagulation dysfunctions. Thus, we described the possible bidirectional modulation among coagulation homeostasis, oxidative stress, and inflammation that occurs in the various stages of NAFLD.
... It represents a set of pathological conditions that range from simple hepatic steatosis (SS) or non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH) and cirrhosis [2]. Primary NAFLD is now acknowledged as the hepatic manifestation of metabolic syndrome (MetS) [3,4]. Processes that are involved in the onset of SS and its transition to NASH remain not fully explored. ...
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have been linked to changes in amino acid (AA) levels. The objective of the current study was to examine the relationship between MRI parameters that reflect inflammation and fibrosis and plasma AA concentrations in NAFLD patients. Plasma AA levels of 97 NAFLD patients from the MAST4HEALTH study were quantified with liquid chromatography. Medical, anthropometric and lifestyle characteristics were collected and biochemical parameters, as well as inflammatory and oxidative stress biomarkers, were measured. In total, subjects with a higher MRI-proton density fat fraction (MRI-PDFF) exhibited higher plasma AA levels compared to subjects with lower PDFF. The concentrations of BCAAs (p-Value: 0.03), AAAs (p-Value: 0.039), L-valine (p-Value: 0.029), L-tyrosine (p-Value: 0.039) and L-isoleucine (p-Value: 0.032) were found to be significantly higher in the higher PDFF group compared to lower group. Plasma AA levels varied according to MRI-PDFF. Significant associations were also demonstrated between AAs and MRI-PDFF and MRI-cT1, showing the potential utility of circulating AAs as diagnostic markers of NAFLD.
... Through intrahepatic lipotoxicity, NAFLD can progress from simple steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, hepatic decompensation, and hepatocellular carcinoma [4]. Insulin resistance promotes the development and progression of NAFLD [5]. On the other hand, NAFLD worsens insulin resistance and increases the risk of incident diabetes mellitus [6], resulting in a self-perpetuating cycle between NAFLD and insulin resistance. ...
Background
Accumulating evidence suggests a potential relationship between non-alcoholic fatty liver disease (NAFLD) and fatty pancreas, as both conditions are associated with fat deposition in the liver and pancreas, respectively. The meta-analysis aimed to investigate the bidirectional association between NAFLD and fatty pancreas, as well as their respective effects on disease severity.
Methods
A systematic search of the EMBASE and MEDLINE databases, from inception to August 2022, was conducted to identify observational studies examining the association between NAFLD and fatty pancreas, as well as their impact on disease severity. The pooled odds ratio (OR) with a 95% confidence interval (CI) was estimated using a random-effects model.
Results
Our analysis included 26 case-control or cross-sectional studies, comprising 67,803 participants. We observed a significant association between NAFLD and an increased odds of having fatty pancreas (OR, 6.18; 95% CI, 4.49–8.51; I2 = 92%). Similarly, fatty pancreas was significantly associated with an increased odds of having NAFLD (OR, 9.56; 95% CI, 5.09–17.95; I2 = 83%). Furthermore, the presence of fatty pancreas was associated with a 1.75-fold increased risk of severe NAFLD based on ultrasonographic classification (95% CI, 1.46–2.10; I2 = 0%). Among NAFLD patients, the coexistence of fatty pancreas was associated with a trend towards increased odds of having non-alcoholic steatohepatitis (OR, 3.52; 95% CI, 0.65–18.93; I2 = 82%) and advanced fibrosis (OR, 2.47; 95% CI, 0.52–11.80; I2 = 76%).
Conclusion
This meta-analysis discloses a bidirectional association between NAFLD and fatty pancreas, emphasizing the importance of understanding the intricate relationship between these two conditions.
... With regard to (1) NAFLD/NASH, ectopic fat accumulation in the liver has been shown to be associated with enhancement of insulin resistance in the liver. [31][32][33][34] Excessive fat accumulation in the liver also causes activation of macrophages and result in further enhancement of insulin resistance in the liver. 3 35 With regard to (2) alcoholic liver disease, alcohol intake has been shown to be associated with enhancement of insulin resistance in the liver as well as in peripheral tissues. ...
Objective
We aimed to clarify the relationship between serum alanine transaminase (ALT) levels and incidence of new-onset diabetes in a Japanese general population.
Setting
Population-based retrospective cohort study using annual health check-up data for residents of Iki City, Nagasaki Prefecture, Japan.
Participants
A total of 5330 Japanese individuals (≥30 years old) without diabetes at baseline were analysed.
Primary and secondary outcome measures
Serum ALT levels were determined using an enzymatic method and were classified into gender-specific quartile groups as follows: group 1 (3–16 U/L in men and 3–13 U/L in women), group 2 (17–21 U/L in men and 14–16 U/L in women), group 3 (22–29 U/L in men and 17–22 U/L in women) and group 4 (30–428 U/L in men and 23–268 U/L in women). The study outcome was the incidence of diabetes (fasting glucose ≥7.0 mmol/L, non-fasting glucose ≥11.1 mmol/L, glycated haemoglobin ≥6.5% or use of glucose-lowering therapies).
Results
After an average follow-up period of 5.0 years, 279 individuals developed diabetes. The incidence rate of diabetes increased with elevation of serum ALT levels (0.7% per 100 person-years in group 1, 0.9% in group 2, 0.9% in group 3 and 1.7% in group 4) (p<0.001 for trend). This association was significant after adjustment for other risk factors including age, sex, obesity, hypertension, dyslipidaemia, smoking, current daily alcohol intake and regular exercise (p<0.001 for trend). Comparable associations were observed between men and women (p=0.459 for interaction).
Conclusion
Serum ALT levels were associated with future development of diabetes in the general Japanese population.
... The prevalence of NAFLD causes big concern as it affects, by current statistics, > 25% of the general population [3], > 50% of people with type 2 diabetes mellitus (T2DM), and > 80% of people with obesity [4,5]. Being reversible, NAFLD is responsive to recommended lifestyle interventions such as dietary changes and physical exercise [6], except for its latest stage, i.e. non-alcoholic steatohepatitis (NASH) that is associated with cirrhosis, and hepatocellular carcinoma (HCC), and ultimately requires liver transplantation [1]. NAFLD is also considered the hepatic manifestation of the metabolic syndrome (see Fig. 1) and has been categorized as a "cardiometabolic" disease, since recent studies have demonstrated that NAFLD mortality is more commonly related to cardiovascular disease than to liver-related complications [7]. ...
Background and aims:
The worldwide prevalence of Non-alcoholic Fatty Liver Disease (NAFLD) raises concerns about associated risk factors, such as obesity and type 2 Diabetes Mellitus, for leading causes of disability and death. Besides Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS), functional imaging with Positron Emission Tomography (PET) could contribute to a deeper understanding of the pathophysiology of NAFLD. Here we describe a novel approach using the PET tracer [18F]FTHA, which is an analog of long-chain free fatty acids (FFA) and is taken up by tissues to enter mitochondria or to be incorporated into complex lipids for further export as very-low-density lipoprotein (VLDL).
Methods:
Male Sprague Dawley rats, after 6 weeks on a high-fat diet (HFD), were used as a model of diet induced NAFLD, while a standard diet (SD) served as a control group. Liver fat was estimated by MR spectroscopy at a 9.4 T system for phenotyping. To measure hepatic FFA uptake, rats underwent 60 min dynamic [18F]FTHA-PET scans after unrestricted access to food (HFD: n = 6; SD: n = 6) or overnight (≤16h) fasting (HFD: n = 6; SD: n = 5). FFA removal was assessed from incorporated 18F-residual in de novo synthesized VLDL out of plasma.
Results:
MRS of the liver confirmed the presence of NAFLD (>5.6% fat). Under non-fasting conditions, hepatic [18F]FTHA uptake was significantly increased in NAFLD: SUVmean (p = 0.03) within [0; 60] min interval, SUVmean (p = 0.01) and SUVmax (p = 0.03) within [30; 60] min interval. SUVs for hepatic uptake under fasting conditions were not significantly different between the groups. Analysis of FFA removal demonstrated elevated values of 18F-residue in the VLDL plasma fraction of the healthy group compared to the NAFLD (p = 0.0569).
Conclusion:
Our novel approach for assessing FFA metabolism using [18F]FTHA demonstrated differences in the hepatic FFA uptake and FFA incorporation into VLDL between healthy and NAFLD rats. [18F]FTHA-PET could be used to study metabolic disturbances involved in the progression of NAFLD.
... Our longitudinal study documenting complications from NAFLD provides epidemiological evidence to support an association between fatty liver diseases and DM or potential cardiovascular disease risks in PWH. Studies have shown that insulin resistance, which is closely related to metabolic abnormalities including obesity, hypertension, and dyslipidemia, is more prevalent in those with NAFLD, which subsequently increases DM risk [20]. PWH have a higher prevalence of these conditions partly due to exposure to ART [21,22]; other risk factors such as smoking, alcohol consumption, and viral coinfections may also play a role. ...
Background:
We investigated the association of non-alcoholic fatty liver disease (NAFLD) plus or minus a concurrent diagnosis of non-alcoholic steatohepatitis (NASH) with incident diabetes mellitus (DM) and the risk factors associated with NAFLD or NASH development.
Methods:
This prospective study analyzed people with HIV (PWH) aged ≥18 years without excessive alcohol consumption or hepatitis co-infections. NAFLD was defined as controlled attenuation parameter (CAP) ≥248 dB/m, whereas NASH with significant disease activity and liver fibrosis was defined as FibroScan-AST (FAST) score ≥0.67. Cox proportional hazard regression was used to investigate the association of NAFLD with or without NASH with new-onset DM.
Results:
Of 847 PWH, the median age at baseline was 45 (IQR 38-51) years (43% female). Baseline NAFLD was associated with 2.8-fold higher risk of new-onset DM after adjusting for age, sex, family history of DM, ART duration, smoking, statin use and stavudine/didanosine/zidovudine exposure, and time-updated BMI, hypertension, and dyslipidemia. Combined NAFLD and NASH at baseline had 3.1-fold higher new-onset DM risk. In separate analyses, baseline DM did not predict progression to NAFLD or NASH, but TAF use was associated with an increased risk of NAFLD (HR: 2.01, 95% CI 1.02, 4.02) or NASH development (HR: 2.31, 95%CI 1.12, 5.11).
Conclusions:
In this longitudinal study, NAFLD alone or combined with NASH strongly predicts new-onset DM development. These highlight the need for systematic risk assessments and management of NAFLD/NASH, as it may contribute to the development of metabolic complications such as DM and subsequent cardiovascular diseases in PWH.
... This illness encompasses simple steatosis (benign fatty infiltration), non-alcoholic steatohepatitis (NASH) (fatty infiltration with inflammation), fibrosis, and cirrhosis, which can develop into hepatocellular cancer [1][2][3]. NAFLD is linked to insulin resistance and genetic vulnerability [4], and because of the rising incidence of obesity and obesity-related metabolic syndrome, NAFLD has become the primary cause of chronic liver disease in industrialized nations and the third cause of liver transplantation [5][6][7][8]. Therefore, NAFLD is a significant public health issue [9] but presently has no approved pharmacotherapy. ...
Excess hepatic lipid accumulation is the hallmark of non-alcoholic fatty liver disease (NAFLD), for which no medication is currently approved. However, glucagon-like peptide-1 receptor agonists (GLP-1RAs), already approved for treating type 2 diabetes, have lately emerged as possible treatments. Herein we aim to investigate how the GLP-1RA exendin-4 (Ex-4) affects the microRNA (miRNAs) expression profile using an in vitro model of steatosis. Total RNA, including miRNAs, was isolated from control, steatotic, and Ex-4-treated steatotic cells and used for probing a panel of 799 highly curated miRNAs using NanoString technology. Enrichment pathway analysis was used to find the signaling pathways and cellular functions associated with the differentially expressed miRNAs. Our data shows that Ex-4 reversed the expression of a set of miRNAs. Functional enrichment analysis highlighted many relevant signaling pathways and cellular functions enriched in the differentially expressed miRNAs, including hepatic fibrosis, insulin receptor, PPAR, Wnt/β-Catenin, VEGF, and mTOR receptor signaling pathways, fibrosis of the liver, cirrhosis of the liver, proliferation of hepatic stellate cells, diabetes mellitus, glucose metabolism disorder and proliferation of liver cells. Our findings suggest that miRNAs may play essential roles in the processes driving steatosis reduction in response to GLP-1R agonists, which warrants further functional investigation.
... NAFLD such as insulin resistance, in ammation, obesity and type 2 diabetes are metabolic syndromes [6, 7,8]. Therefore, it is important to treat metabolic diseases that are closely related to non-alcoholic fatty liver disease, as well as NAFLD itself [2]. ...
... Recent studies have shown that, farther to environmental factors, genetics also play a role in the development of non-alcoholic fatty liver disease [6]. Genes related to insulin resistance including those coding adiponectin, resistin leptin, may affect the spread of non-alcoholic fatty liver disease [7]. There is progressive evidence, which shows the fact that the correlation of single nucleotide polymorphisms (SNPs) of the ADIPOQ gene with the serum level of adiponectin in blood serum has been established. ...
Background
Adiponectin hormone is effective in reducing liver inflammation. In this study, the relationship between polymorphisms of the adiponectin gene with adiponectin level biochemical variables and NAFLD has been investigated.
Methods and Results
The case-control study was performed on 80 individuals with NAFLD and 80 healthy individuals. Determination of polymorphisms of rs266729, rs1501299 and rs17300539 from the ADIPOQ gene was performed by PCR- RFLP method. The level of adiponectin and insulin hormones was also measured by ELISA kit. Findings showed that serum triglyceride level, fasting blood sugar, Aspartate Aminotransferase (AST) Alanine Aminotransferase (ALT) and diastolic blood pressure are higher in patients than in healthy individuals. Adiponectin levels and High-density lipoprotein cholesterol (HDL-C) in patients were lower than healthy individuals and body mass index (BMI) was higher in patients (P < 0.05). None of the SNPs were associated with insulin resistance. The results of the investigation of rs17300539 and rs266729 showed that there is no significant difference in the frequencies of alleles and genotypes between the case and control groups. rs1501299 review results showed that there is a significant difference between the frequency of G allele and genotype in healthy and patient groups(P < 0.05). In case (individuals with NAFLD) group of 17300539, BMI was higher in GA carriers than in GG genotype carriers(P < 0.05). There was a relationship between rs17300539 and rs266729 polymorphisms and AST (P < 0.05).
Conclusion
It seems that the G allele of rs17300539 in the adiponectin gene is effective in reducing the complications of NAFLD. The rs1501299 polymorphism is associated with NAFLD.
... 73 NAFLD results from ectopic fat deposition in the liver, leading to liver dysfunction from lipo-toxicity. 74 Chronic steatosis produces cytokines, immune cell recruitment, and cellular damage resulting in non-alcoholic steatohepatitis (NASH) and advanced cirrhosis, promoting atherosclerosis, and increased cardiovascular disease. 57,74 Identification and management of liver disease in patients with PCOS are crucial as they tend to present with more severe and aggressive liver disease coexisting with other metabolic abnormalities. ...
... 74 Chronic steatosis produces cytokines, immune cell recruitment, and cellular damage resulting in non-alcoholic steatohepatitis (NASH) and advanced cirrhosis, promoting atherosclerosis, and increased cardiovascular disease. 57,74 Identification and management of liver disease in patients with PCOS are crucial as they tend to present with more severe and aggressive liver disease coexisting with other metabolic abnormalities. 75,76 However, no therapeutic intervention is currently defined as an optimal to target and decrease the lipotoxic effect of fatty accumulation in the liver. ...
Polycystic ovary syndrome (PCOS) is a complex endocrinopathy affecting many women of reproductive age. Although its physiology is poorly understood, hyper-androgenemia and insulin resistance play a pivotal role in this complex syndrome, predisposing patients to a variety of cardiovascular and metabolic modalities. Current therapeutic options, including lifestyle modifications and medications, often do not satisfactorily improve clinical outcomes. SGLT2 inhibitors (SGLT-2i) are a novel option which can potentially improve many hormonal and metabolic parameters for patients with PCOS, though the net cardiovascular effects remain under investigation in this population of patients with PCOS. Overall, the use of SGLT-2i may be associated with beneficial somatometric, metabolic and hormonal outcomes of PCOS. To date, all available studies have recorded body mass index, waist and hip circumference, and fat mass reductions, improved insulin and androgen levels, and reduced blood pressure. The aim of the present review is to summarise PCOS-related manifestations and mechanisms leading to cardiovascular disease, to explore the cardiometabolic impact of SGLT2i on PCOS, and to critically analyse the cardiometabolic and hormonal outcomes of the recent studies on the use of SGLT2i in women with PCOS.
