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Publications (172)
Clinical and preclinical studies established that supplementing diets with ω3 polyunsaturated fatty acids (PUFA) can reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH) but molecular underpinnings of this action were elusive. Herein, we used multi‐omic network analysis that unveiled critical molecular pathways involved in ω3 PUFA effe...
Background
Nonalcoholic fatty liver disease (NAFLD) is a global health problem. Identification of factors contributing to the onset and progression of NAFLD have the potential to direct novel strategies to combat NAFLD.
Methods
We examined the time course of western diet (WD)-induced NAFLD and its progression to nonalcoholic steatohepatitis (NASH)...
Background
Nonalcoholic fatty liver disease (NAFLD) is a global health problem. Identifying early gene indicators contributing to the onset and progression of NAFLD has the potential to develop novel targets for early therapeutic intervention. We report on the early and late transcriptomic signatures of western diet (WD)-induced nonalcoholic steato...
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic fatty liver disease worldwide, particularly in obese and type 2 diabetic individuals. Currently, there are no therapies for NAFLD that have been approved by the US Food and Drug Administration. Herein, we examine the rationale for using ω3 polyunsaturated fatty acids (PUFAs) in NAF...
Nonalcoholic steatohepatitis (NASH) is currently the only prevalent metabolic disease with no FDA-approved treatment strategy. Supplementation of ω3 polyunsaturated fatty acids (PUFA) represent a promising treatment as it can attenuate fibrosis and inflammation, but the mechanisms are poorly defined. We employed a causal inference approach for mult...
We previously reported xanthohumol (XN), and its synthetic derivative tetrahydro-XN (TXN), attenuates high-fat diet (HFD)-induced obesity and metabolic syndrome in C57Bl/6J mice. The objective of the current study was to determine the effect of XN and TXN on lipid accumulation in the liver. Non-supplemented mice were unable to adapt their caloric i...
Background: While oxylipins have been linked to coronary artery disease (CAD), little is known about their diagnostic and prognostic potential.
Objective: We tested whether plasma concentration of specific oxylipins may discriminate among number of diseased coronary arteries and predict median 5-year outcomes in symptomatic adults.
Methods: Using a...
We previously reported xanthohumol (XN), and its synthetic derivative tetrahydro-XN (TXN) attenuates high-fat diet (HFD) induced obesity and metabolic syndrome in C57BL/6J mice. The objective of the current study was to determine the effect of XN and TXN on lipid accumulation in the liver. Non-supplemented mice were unable to adapt their caloric in...
Western diet (WD) is one of the major culprits of metabolic disease including type 2 diabetes (T2D) with gut microbiota playing an important role in modulating effects of the diet. Herein, we use a data-driven approach (Transkingdom Network analysis) to model host-microbiome interactions under WD to infer which members of microbiota contribute to t...
This experiment compared performance and physiological responses of the offspring from cows supplemented with Ca salts of soybean oil (CSSO) or prilled saturated fat (CON) during late-gestation. Non-lactating, pregnant, multiparous Angus × Hereford cows (n = 104) that conceived during the same fixed-time artificial insemination protocol were assign...
This experiment compared plasma fatty acid (FA) profile of forage-fed beef cows receiving a molasses-based supplement enriched with Ca salts of soybean oil [CSSO; 24.7% of dry matter (DM)] via a self-fed low-moisture block (LMB) or hand-fed granular concentrate daily (CONC). Thirty-six nonlactating, nonpregnant, multiparous beef cows were blocked b...
Nonalcoholic fatty liver disease (NAFLD) is a major public health problem worldwide. NAFLD ranges in severity from benign steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and primary hepatocellular cancer (HCC). Obesity and type 2 diabetes mellitus (T2DM) are strongly associated with NAFLD, and the western diet (WD) is a major contribut...
Mice are a commonly-used model to investigate aging-related bone loss but, in contrast to humans, mice exhibit cancellous bone loss prior to skeletal maturity. The mechanisms mediating premature bone loss are not well established. However, our previous work in female mice suggests housing temperature is a critical factor. Premature cancellous bone...
This study evaluated the effects of supplementing Ca salts of soybean oil (CSSO) to beef steers at 2 mo of age via creep-feeding, and/or during a 40-d preconditioning period on performance and carcass development responses. A total of 64 steers were enrolled in this study over 2 yr (32 steers/yr), with 4 periods each year: creep-feeding (CF; d 0 to...
Background
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, particularly in obese and type 2 diabetic individuals. NAFLD ranges in severity from benign steatosis to nonalcoholic steatohepatitis (NASH); and NASH can progress to cirrhosis, primary hepatocellular carcinoma (HCC) and liver failure. As such, N...
Hepatosteatosis and fibrosis in RD- and WD-fed female Ldlr
-/- mice.
Livers of a control and a WD-fed mouse (WD38) were fixed in buffered formalin, sectioned and stained with hematoxylin and eosin and photographed at 200x. Liver from the control group (RD46) shows no signs of hepatosteatosis (H & E) or fibrosis (Sirius Red). Liver from the western...
Hepatosteatosis in liver of a WD-fed female Ldlr
-/- mouse.
Liver of a WD-fed mouse (WD38) was fixed in buffered formalin, sectioned and stained with hematoxylin and eosin and photographed at 400x. Regions representing microsteatosis, macrosteatosis and inflammation, i.e., granulocytes, are marked.
(TIF)
Principal component analysis (PCA) of lipid changes in the RD46 versus WD38 and WD46 groups.
Data included in this analysis included only lipids quantified by LC/MS that were significantly affected by the WD. Liver lipidomic profiles differ depending on the diet and the duration of the diet. PCA was conducted after log transformation on all statist...
Western diet effects on hepatic expression of enzymes linked to cholesterol metabolism.
Transcript abundance was quantified as described in the Materials and Methods section. Results are expressed as mRNA abundance, Fold Change; mean ± SEM, N = 7–8 samples, *, FDR <0.05 versus the RD46 group. Hmg CoA Red: HMG CoA reductase; Hmg CoA Syn 1: Hmg CoA s...
Primer pairs for qRTPCR.
(XLSX)
Heat map comparing the oxylipin composition in female Ldlr-/- WD fed mice after 38 and 46 weeks with the RD group.
For each group the average value from 7–8 biological replicates was used. A logarithm data transformation and auto scaling (mean-centered divided by the standard deviation of each variable) were performed in MetaboAnalyst 4.0.in order...
Oxylipin standards used for LC/MS analysis.
(XLSX)
Purpose of review:
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic fatty liver disease worldwide. The incidence of NAFLD parallels the prevalence of obesity. Moreover, NAFLD can progress to nonalcoholic steatohepatitis (NASH), cirrhosis and primary hepatocellular cancer (HCC). As such, NAFLD has become a major public health con...
Two experiments investigated the effects of supplementing Ca salts of soybean oil (CSSO) during early gestation on reproductive function and pregnancy rates to artificial insemination (AI) in Bos taurus beef cows. In Exp. 1, 771 suckled, lactating, multiparous Angus cows were divided into 22 groups of approximately 35 cows/group, and timed-insemina...
Obese and type 2 diabetic (T2DM) patients have a high prevalence of nonalcoholic fatty liver disease (NAFLD). NAFLD is a continuum of chronic liver diseases ranging from benign hepatosteatosis to nonalcoholic steatohepatitis (NASH), cirrhosis and primary hepatocellular cancer (HCC). Because of its strong association with the obesity epidemic, NAFLD...
Background
Nonalcoholic fatty liver disease (NAFLD) is a major public health concern in western societies. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, is characterized by hepatic steatosis, inflammation, oxidative stress and fibrosis. NASH is a risk factor for cirrhosis and hepatocellular carcinoma. NASH is predicted to be t...
Features which differ significantly between the WDD versus WDO groups.
(DOCX)
Top 20 correlations between plasma TLR2 agonists and hepatic features: Blockage and Remission Arms1.
(DOCX)
Top 20 Features correlating with hepatic collagen 1A1 expression: Remission Arm.
(DOCX)
Relative abundance of hepatic transcripts linked to inflammation [A] and fibrosis [B]: Hepatic mRNA abundance was quantified using qRTPCR arrays as described in Materials and Methods. The reference gene was Hsp90. Results are represented as mRNA Abundance, Relative to Hsp90 (reference gene) for the RD group only. N = 5; mean ± SD.
(TIF)
Top 20 Features correlating with hepatic collagen 1A1 expression: Blockage Arm.
(DOCX)
Diet effects on hepatic transcripts encoding Mcp1, TLR4, TNFα Diet effNox2.
A-E: Hepatic mRNA abundance was quantified as described in Materials and Methods using in-house PCR primers. Results are represented as mRNA Abundance-Fold Change; N = 4–7; mean ± SD; *, p<0.05 versus the RD group; #, p<0.05 versus the WDO group; one-way ANOVA. F: Hepatic m...
Features which differ significantly between the WDO versus RD groups.
(DOCX)
Features which differ significantly between the WDChO versus WDChD groups.
(DOCX)
Top 20 Features Correlating with Hepatic Osteopontin Expression: Blockage Arm.
(DOCX)
Top 20 features correlating with hepatic Osteopontin expression: Remission Arm.
(DOCX)
Nonalcoholic fatty liver disease (NAFLD) is a major public health concern. NASH, the progressive form of NAFLD, is characterized by hepatosteatosis, inflammation, oxidative stress and fibrosis. NASH is a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. We previously established that DHA attenuated the onset of western diet (WD...
Background
Nonalcoholic fatty liver disease (NAFLD) is a major public health burden in western societies. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is characterized by hepatosteatosis, inflammation, oxidative stress, and hepatic damage that can progress to fibrosis and cirrhosis; risk factors for hepatocellular carcinoma....
Effect of the NP and WD on hepatic gene expression-Study1.
Mice were fed the Chow or WD diets as described in Materials and Methods. RNA was extracted and the abundance of mRNA transcripts encoding proteins involved in inflammation [A], oxidative stress [B] and fibrosis and ECM remodeling [C] were quantified. Results are presented as mRNA Abundance...
Effect of diet on hepatic fatty acid composition-Study 1.
Hepatic lipids were extracted, saponified, converted to fatty acid methyl esters and quantified by gas chromatography as described in Material and Methods. [A]: Hepatic fatty acid content, results are expressed as nmol/mg protein; [B]: Sum of fatty acids in specific classes; results are expr...
Significant features associated with NASH in Ldlr-/- mice as determined by ANOVA-Tukey HSD.
(DOCX)
Nonalcoholic fatty liver disease (NAFLD) has increased in parallel with central obesity, and its prevalence is anticipated to increase as the obesity epidemic remains unabated. NAFLD is now the most common cause of chronic liver disease in developed countries and is defined as excessive lipid accumulation in the liver, that is, hepatosteatosis. NAF...
Docosahexaenoic acid (22:6ω3; DHA), but not eicosapentaenoic acid (20:5ω3; EPA), attenuates western diet (WD)-induced hepatic fibrosis in a Ldlr-/- mouse model of nonalcoholic steatohepatitis (NASH). We examined the molecular basis for the differential effect of dietary EPA and DHA on WD-induced hepatic fibrosis. DHA was more effective than EPA at...
The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased in parallel with central obesity and is now the most common chronic liver disease in developed countries. NAFLD is defined as excessive accumulation of lipid in the liver, i.e. hepatosteatosis. The severity of NAFLD ranges from simple fatty liver (steatosis) to non-alcoholic...
The objective of this experiment was to determine if frequency of protein supplementation impacts physiological responses associated with reproduction in beef cows. Fourteen non-pregnant, non-lactating beef cows were ranked by age and BW, and allocated to 3 groups. Groups were assigned to a 3 × 3 Latin square design, containing 3 periods of 21 d an...
Nonalcoholic fatty liver disease (NAFLD) is a major public health concern in the obese and type 2 diabetic populations. The high fat lard diet (HFD) induces obesity and fatty liver in C57BL/6J mice and suppresses expression of the PPAR-target gene, fatty acid elongase-5 (Elovl5). Elovl5 plays a key role in MUFA and PUFA synthesis. Increasing hepati...
Non‐alcoholic fatty liver disease (NAFLD) is prevalent in >80% of obese adults and >60% of type 2 diabetic patients. NAFLD can progress to non‐alcoholic steatohepatitis (NASH) which is characterized by hepatosteatosis, inflammation, oxidative stress & fibrosis. Current clinical recommendations for NASH include weight loss coupled with therapies to...
The objective of this experiment was to compare fatty acid (FA) concentrations in plasma and reproductive tissues, as well as hormones and expression of genes associated with pregnancy establishment in beef cows supplemented or not with Ca salts of soybean oil (CSSO) beginning after timed-AI. Ninety non-lactating multiparous Nelore (Bos indicus) co...
Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease and a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. Previously, we reported that dietary docosahexaenoic acid (DHA, 22:6,n-3) was more effective than eicosapentaenoic acid (EPA, 20:5,n-3) at reversing western diet (WD) induced NASH...
To test the hypothesis that embryogenesis depends upon α-tocopherol (E) to protect embryo polyunsaturated fatty acids (PUFAs) from lipid peroxidation, new methodologies were applied to measure α-tocopherol and fatty acids in extracts from saponified zebrafish embryos. A solid phase extraction method was developed to separate the analyte classes, us...
Non‐alcoholic steatohepatitis (NASH) is a progressive form of fatty liver disease that is characterized by hepatic inflammation, oxidative stress and fibrosis. The capacity of eicosapentaenoic acid (20:5ω3; EPA) and docosahexaenoic acid (22:6ω3; DHA) to attenuate diet‐induced NASH was examined in Ldlr−/− mice fed a western diet (WD) for 16 weeks. T...
Fatty liver develops in obese individuals because of an imbalance in hepatic triglyceride (TG) synthesis, secretion, hydrolysis and fatty acid oxidation (FAO). High fat diets induce obesity and fatty liver in C57BL/6J mice and lower hepatic C20–22 PUFA and fatty acid elongase‐5 (Elovl5), a key enzyme involved in PUFA synthesis. The role Elovl5 play...
Fatty acid regulation of hepatic gene transcription was first reported in the early 1990s. Several transcription factors have been identified as targets of fatty acid regulation. This regulation is achieved by direct fatty acid binding to the transcription factor or by indirect mechanisms where fatty acids regulate signaling pathways controlling th...
The incidence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased in parallel with the incidence of obesity. While both NAFLD and NASH are characterized by hepatosteatosis, NASH is characterized by hepatic damage, inflammation, oxidative stress, and fibrosis. We previously reported that feeding Ldlr(-/-...
Elevated hepatic expression of fatty acid elongase-5 (Elovl5) induces FoxO1 phosphorylation, lowers FoxO1 nuclear content and suppresses expression of genes involved in gluconeogenesis. In this report we define the molecular and metabolic basis of Elovl5 control of FoxO1 phosphorylation. Adenoviral-mediated (Ad-Elovl5) induction of hepatic Elovl5 i...
Epidemiological studies on Greenland Inuits in the 1970s and subsequent human studies have established an inverse relationship between the ingestion of omega-3 fatty acids [C20-22 omega-3 polyunsaturated fatty acids (PUFA)], blood levels of C20-22 omega-3 PUFA and mortality associated with cardiovascular disease [CVD]. C20-22 omega-3 PUFA have plei...
The frequency of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased in parallel with obesity in the United States. NASH is progressive and characterized by hepatic damage, inflammation, fibrosis, and oxidative stress. Because C20-22 (n-3) PUFA are established regulators of lipid metabolism and inflammatio...
The incidence of NAFLD and non‐alcoholic steatohepatitis (NASH) has increased in parallel with obesity. While both are characterized by excessive hepatic lipid accumulation, NASH is defined as hepatic inflammation with hepatocellular damage. Our goal was to examine the effect of C20–22 ω3 PUFA on diet induced NASH in LDLR−/− C57BL/6J mice. Mice con...
Elevated fatty acid elongase‐5 (Elovl5) activity in livers of high fat diet induced obese‐ diabetic C57BL/6J mice corrects fasting hyperglycemia by suppressing gluconeogenesis (GNG) through the regulation of Akt2 and FoxO1 phosphorylation status. This report examines Elovl5 regulated signaling mechanisms controlling Akt2 & FoxO1 phosphorylation. El...
α-Tocopherol is a required, lipid-soluble antioxidant that protects PUFA. We hypothesized that α-tocopherol deficiency in zebrafish compromises PUFA status. Zebrafish were fed for 1 y either an α-tocopherol-sufficient (E+; 500 mg α-tocopherol/kg) or -deficient (E-; 1.1 mg α-tocopherol/kg) diet containing α-linolenic (ALA) and linoleic (LA) acids bu...
We examined the impact of α‐tocopherol (E) deficiency on polyunsaturated fatty acid (PUFA) status in zebrafish, which were fed defined diets with α‐linolenic (ALA) and linoleic (LA) acid, but without arachidonic (ARA) or docosahexeanoic (DHA) acids; diets were either E sufficient (E+) or deficient (E−). Analysis of fish PUFA contents showed that th...
To discuss transcriptional mechanisms regulating hepatic lipid metabolism.
Humans who are obese or have diabetes (NIDDM) or metabolic syndrome (MetS) have low blood and tissue levels of C20-22 polyunsaturated fatty acids (PUFAs). Although the impact of low C20-22 PUFAs on disease progression in humans is not fully understood, studies with mice have...
Acetyl CoA carboxylase (ACC1 and ACC2) generates malonyl CoA, a substrate for de novo lipogenesis (DNL) and an inhibitor of mitochondrial fatty acid β-oxidation (FAO). Malonyl CoA is also a substrate for microsomal fatty acid elongation, an important pathway for saturated (SFA), mono- (MUFA) and polyunsaturated fatty acid (PUFA) synthesis. Despite...
Elevated hepatic fatty acid elongase-5 (Elovl5) activity lowers blood glucose in fasted chow-fed C57BL/6J mice. As high-fat diets induce hyperglycemia and suppress hepatic Elovl5 activity, we tested the hypothesis that elevated hepatic Elovl5 expression attenuates hyperglycemia in high-fat-diet-induced obese mice. Increasing hepatic Elovl5 activity...
Enhanced production of monounsaturated fatty acids (FA) derived from carbohydrate-enriched diets has been implicated in the development of obesity and insulin resistance. The FA elongases Elovl-5 and Elovl-6 are regulated by nutrient and hormone status, and have been shown using intact yeast and mammalian microsome fractions to be involved in the s...
Cancellous bone decreases and bone marrow fat content increases with age. Osteoblasts and adipocytes are derived from a common precursor, and growth hormone (GH), a key hormone in integration of energy metabolism, regulates the differentiation and function of both cell lineages. Since an age-related decline in GH is associated with bone loss, we in...
The results of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort study revealed a strong association between dyslipidemia and the development of diabetic retinopathy. However, there are no experimental data on retinal fatty acid metabolism in diabetes. This study determined retinal-specific...
Very long chain fatty acids confer functional diversity on cells by variations in their chain length and degree of unsaturation. Microsomal fatty acid elongation represents the major pathway for determining the chain length of saturated, monounsaturated, and polyunsaturated fatty acids in cellular lipids. The overall reaction for fatty acid elongat...
Increased basal and loss of glucose-stimulated insulin secretion (GSIS) are hallmarks of beta-cell dysfunction associated with type 2 diabetes. It has been proposed that elevated glucose promotes insulin secretory defects by activating sterol regulatory element binding protein (SREBP)-1c, lipogenic gene expression, and neutral lipid storage. Activa...
Hepatic fatty acid elongase-5 (Elovl-5) plays an important role in long chain monounsaturated and polyunsaturated fatty acid synthesis. Elovl-5 activity is regulated during development, by diet, hormones, and drugs, and in chronic disease. This report examines the impact of elevated Elovl-5 activity on hepatic function. Adenovirus-mediated inductio...
The liver plays a central role in whole body lipid metabolism and adapts rapidly to changes in dietary fat composition. This adaption involves changes in the expression of genes involved in glycolysis, de-novo lipogenesis, fatty acid elongation, desaturation and oxidation. This review brings together metabolic and molecular studies that help explai...
The type and quantity of dietary fat ingested contributes to the onset and progression of chronic diseases, like diabetes and atherosclerosis. The liver plays a central role in whole body lipid metabolism and responds rapidly to changes in dietary fat composition. Polyunsaturated fatty acids (PUFA) play a key role in membrane composition and functi...
Docosahexaenoic acid (DHA(22:6,n3)) is the principal n3 polyunsaturated fatty acid (PUFA) in the retina. The authors previously demonstrated that DHA(22:6,n3) inhibited cytokine-induced adhesion molecule expression in primary human retinal vascular endothelial (hRVE) cells, the target tissue affected by diabetic retinopathy. Despite the importance...
Fatty acid elongases and desaturases play an important role in hepatic and whole body lipid composition. We examined the role that key transcription factors played in the control of hepatic elongase and desaturase expression. Studies with peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice establish that PPARalpha was requir...
Carbohydrate regulatory element-binding protein (ChREBP), MAX-like factor X (MLX), and hepatic nuclear factor-4α (HNF-4α)
are key transcription factors involved in the glucose-mediated induction of hepatic L-type pyruvate kinase (L-PK) gene transcription.
n-3 polyunsaturated fatty acids (PUFA) and WY14643 (peroxisome proliferator-activated receptor...