Abstract 15783: Reduction in Hepatic Tristetraprolin Increases Oxidative Metabolism and Protects Against High-Fat Diet Induced Diabetes

Introduction: Type II diabetes mellitus (T2DM) is a growing health problem affecting over 29 million Americans and individuals with T2DM have increased mortality after myocardial infarction and stroke. Thus, it is imperative to find novel treatments for diabetes to offset the increased risk of cardiovascular disease (CVD) related mortality. Tristetraprolin (TTP) is an mRNA binding protein first identified as an insulin responsive gene. It binds to AU-rich elements (AREs) in the 3’ untranslated region (UTR) of certain transcripts and promotes their degradation. Reduced TTP expression has been observed in human patients with obesity and insulin resistance, and computational analysis suggests that TTP may bind to and degrade the mRNA of key enzymes involved in glucose oxidation. Thus, we hypothesized that downregulation of TTP would increase glucose oxidation and protect against T2DM. Results: We found hepatic expression of TTP to be decreased in diabetic mice. Using an in silico analysis to identify mRNAs that are targeted by TTP and play a role in glucose metabolism, we identified the pyruvate dehydrogenase-E2 subunit (PDH-E2) to contain several conserved TTP binding sites in its 3’ UTR. PDH-E2 expression was significantly increased (mRNA > 1.4-fold; protein > 2-fold) in hepatocytes isolated from liver-specific TTP knockout (KO) mice. Furthermore, measurement of PDH-E2 mRNA stability showed that PDH-E2 mRNA is significantly stabilized with TTP deletion, indicating that TTP regulates PDH-E2 mRNA. We then assessed whether the regulation of PDH-E2 by TTP alters glucose metabolism. Using Seahorse, we found a 1.7-fold increase in oxidative metabolism in TTP KO cells fed with glucose and pyruvate. This increase was reversed with siRNA mediated downregulation of PDH-E2. Systemically, liver-specific TTP KO mice fed a high-fat diet had significantly lower blood glucose levels after glucose tolerance tests and insulin tolerance tests. Conclusion: Our results suggest that a decrease in TTP protects against the development of T2DM by increasing PDH-E2 expression and subsequent glucose oxidation in the liver. Together, these data provide a novel, potential therapeutic target for T2DM, a significant modifiable risk factor contributing to CVD mortality.

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Vitamin A status affects weight gain and hepatic glucose metabolism in rats fed a high-fat diet

Biochemistry and Cell Biology ◽

10.1139/bcb-2018-0284 ◽

2019 ◽

Vol 97 (5) ◽

pp. 545-553 ◽

Cited By ~ 2

Author(s):

Heqian Kuang ◽

Cheng-hsin Wei ◽

Tiannan Wang ◽

Jennifer Eastep ◽

Yang Li ◽

...

Keyword(s):

Glucose Metabolism ◽

Vitamin A ◽

Insulin Receptor ◽

High Fat Diet ◽

Glycogen Synthase ◽

Mitogen Activated Protein Kinase ◽

High Fat ◽

Expression Levels ◽

Hepatic Expression ◽

Hepatic Glucose

Whether vitamin A (VA) has a role in the development of metabolic abnormalities associated with intake of a high-fat diet (HFD) is unclear. Sprague–Dawley rats after weaning were fed an isocaloric VA sufficient HFD (VAS-HFD) or a VA deficient HFD (VAD-HFD) for 8 weeks. Body mass, food intake, liver and adipose tissue mass, and the hepatic expression levels of key proteins for metabolism were determined. VAD-HFD rats had lower body, liver, and epididymal fat mass than VAS-HFD rats. VAD-HFD rats had lower hepatic protein expression levels of cytochrome P450 26A1, glucokinase, and phosphoenolpyruvate carboxykinase than VAS-HFD rats. VAD-HFD rats had higher protein levels of glycogen synthase kinase (GSK)-3α and lower levels of GSK-3β, but not glycogen synthase, than VAS-HFD rats. VAD-HFD rats had higher hepatic levels of insulin receptor substrate-1 (IRS-1), insulin receptor β-subunit, mitogen-activated protein kinase proteins, and peroxisome proliferator-activated receptor-gamma coactivator 1α mRNA, and lower level of IRS-2 protein than VAS-HFD rats. These results indicate that in a HFD setting, VA deficiency attenuated HFD-induced obesity, and VA status altered the expression levels of proteins required for glucose metabolism and insulin signaling. We conclude that VA status contributes to the regulation of hepatic glucose and lipid metabolism in a HFD setting, and may regulate hepatic carbohydrate metabolism.

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Cardiac Transcriptome Analysis Reveals Nr4a1 Mediated Glucose Metabolism Dysregulation in Response to High-Fat Diet

Genes ◽

10.3390/genes11070720 ◽

2020 ◽

Vol 11 (7) ◽

pp. 720

Author(s):

Lihui Men ◽

Wenting Hui ◽

Xin Guan ◽

Tongtong Song ◽

Xuan Wang ◽

...

Keyword(s):

Glucose Metabolism ◽

Transcriptome Analysis ◽

High Fat Diet ◽

Critical Role ◽

Enrichment Analysis ◽

Pathway Enrichment Analysis ◽

High Fat ◽

Altered Expression ◽

Increased Risk ◽

H9c2 Cardiomyocytes

Obesity is associated with an increased risk of developing cardiovascular disease (CVD), with limited alterations in cardiac genomic characteristics known. Cardiac transcriptome analysis was conducted to profile gene signatures in high-fat diet (HFD)-induced obese mice. A total of 184 differentially expressed genes (DEGs) were identified between groups. Based on the gene ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs, the critical role of closely interlocked glucose metabolism was determined in HFD-induced cardiac remodeling DEGs, including Nr4a1, Fgf21, Slc2a3, Pck1, Gck, Hmgcs2, and Bpgm. Subsequently, the expression levels of these DEGs were evaluated in both the myocardium and palmitic acid (PA)-stimulated H9c2 cardiomyocytes using qPCR. Nr4a1 was highlighted according to its overexpression resulting from the HFD. Additionally, inhibition of Nr4a1 by siRNA reversed the PA-induced altered expression of glucose metabolism-related DEGs and hexokinase 2 (HK2), the rate-limiting enzyme in glycolysis, thus indicating that Nr4a1 could modulate glucose metabolism homeostasis by regulating the expression of key enzymes in glycolysis, which may subsequently influence cardiac function in obesity. Overall, we provide a comprehensive understanding of the myocardium transcript molecular framework influenced by HFD and propose Nr4a1 as a key glucose metabolism target in obesity-induced CVD.

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Effect of a high-fat diet on the hepatic expression of nuclear receptors and their target genes: relevance to drug disposition

British Journal Of Nutrition ◽

10.1017/s0007114514003717 ◽

2015 ◽

Vol 113 (3) ◽

pp. 507-516 ◽

Cited By ~ 25

Author(s):

Ragia H. Ghoneim ◽

Emilienne T. Ngo Sock ◽

Jean-Marc Lavoie ◽

Micheline Piquette-Miller

Keyword(s):

Nuclear Receptors ◽

High Fat Diet ◽

Target Genes ◽

Drug Disposition ◽

Fold Increase ◽

High Fat ◽

Expression Levels ◽

Hepatic Expression ◽

The Impact ◽

Fat Feeding

More than 1·4 billion individuals are overweight or obese worldwide. While complications often require therapeutic intervention, data regarding the impact of obesity on drug disposition are scarce. As the influence of diet-induced obesity on drug transport and metabolic pathways is currently unclear, the objective of the present study was to investigate the effect of high fat feeding for 13 weeks in female Sprague–Dawley rats on the hepatic expression of the nuclear receptors pregnane X receptor (PXR), constitutive androstane receptor (CAR), liver X receptor (LXR) and farnesoid X receptor (FXR) and several of their target genes. We hypothesised that high fat feeding would alter the gene expression of major hepatic transporters through a dysregulation of the expression of the nuclear receptors. The results demonstrated that, along with a significant increase in body fat and weight, a high-fat diet (HFD) induced a significant 2-fold increase in the expression of PXR as well as a 2-, 5- and 2·5-fold increase in the hepatic expression of the PXR target genes Abcc2, Abcb1a and Cyp3a2, respectively (P< 0·05). The expression levels of FXR were significantly increased in rats fed a HFD in addition to the increase in the expression levels of FXR target genes Abcb11 and Abcb4. The expression levels of both LXRα and LXRβ were slightly but significantly increased in rats fed a HFD, and the expression levels of their target genes Abca1 and Abcg5, but not Abcg8, were significantly increased. The expression of the nuclear receptor CAR was not significantly altered between the groups. This suggests that a HFD may induce changes in the hepatobiliary transport and metabolism of endogenous and exogenous compounds.

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Non-Fasting Factor VII Coagulant Activity (FVII:C) Increased by High-Fat Diet

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642518 ◽

1994 ◽

Vol 71 (06) ◽

pp. 755-758 ◽

Cited By ~ 46

Author(s):

E M Bladbjerg ◽

P Marckmann ◽

B Sandström ◽

J Jespersen

Keyword(s):

High Fat Diet ◽

Fat Content ◽

Factor Vii ◽

Amidolytic Activity ◽

High Fat ◽

Low Fat Diet ◽

Increased Risk ◽

Coagulant Activity ◽

High Fat Diets ◽

Fat Diets

SummaryPreliminary observations have suggested that non-fasting factor VII coagulant activity (FVII:C) may be related to the dietary fat content. To confirm this, we performed a randomised cross-over study. Seventeen young volunteers were served 2 controlled isoenergetic diets differing in fat content (20% or 50% of energy). The 2 diets were served on 2 consecutive days. Blood samples were collected at 8.00 h, 16.30 h and 19.30 h, and analysed for triglycerides, FVII coagulant activity using human (FVII:C) or bovine thromboplastin (FVII:Bt), and FVII amidolytic activity (FVIPAm). The ratio FVII:Bt/FVII:Am (a measure of FVII activation) increased from fasting levels on both diets, but most markedly on the high-fat diet. In contrast, FVII: Am (a measure of FVII protein) tended to decrease from fasting levels on both diets. FVII:C rose from fasting levels on the high-fat diet, but not on the low-fat diet. The findings suggest that high-fat diets increase non-fasting FVII:C, and consequently may be associated with increased risk of thrombosis.

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Disturbances in the glucose metabolism in the brain: the role of stress and high-fat diet

10.26226/morressier.5b681761b56e9b005965c76f ◽

2018 ◽

Author(s):

Katarzyna Glombik

Keyword(s):

Glucose Metabolism ◽

High Fat Diet ◽

High Fat ◽

The Brain

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Effects of Antarctic krill oil on lipid and glucose metabolism in C57BL/6J mice fed with high fat diet

Lipids in Health and Disease ◽

10.1186/s12944-017-0601-8 ◽

2017 ◽

Vol 16 (1) ◽

Cited By ~ 9

Author(s):

Dewei Sun ◽

Liang Zhang ◽

Hongjian Chen ◽

Rong Feng ◽

Peirang Cao ◽

...

Keyword(s):

Glucose Metabolism ◽

High Fat Diet ◽

Antarctic Krill ◽

Krill Oil ◽

High Fat ◽

Antarctic Krill Oil

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NT-PGC-1α Activation Attenuates High-Fat Diet–Induced Obesity by Enhancing Brown Fat Thermogenesis and Adipose Tissue Oxidative Metabolism

Diabetes ◽

10.2337/db13-1837 ◽

2014 ◽

Vol 63 (11) ◽

pp. 3615-3625 ◽

Cited By ~ 19

Author(s):

Hee-Jin Jun ◽

Yagini Joshi ◽

Yuvraj Patil ◽

Robert C. Noland ◽

Ji Suk Chang

Keyword(s):

Adipose Tissue ◽

Oxidative Metabolism ◽

High Fat Diet ◽

Brown Fat ◽

High Fat ◽

Diet Induced Obesity

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Abstract 476: Shear Stress-induced Atherosclerotic Plaque Regression is Reversed by Regulation of Macrophage Mobility via Matrix Metalloproteinase Inhibition

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a476 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Stefania Simeone ◽

Talin Ebrahimian ◽

Veronique Michaud ◽

Stephanie Lehoux

Keyword(s):

Shear Stress ◽

High Fat Diet ◽

Fold Increase ◽

Atherosclerotic Plaques ◽

High Shear ◽

High Fat ◽

Gelatinase Activity ◽

Mmp Inhibitor ◽

Post Surgery ◽

Plaque Regression

Atherosclerotic plaques form in regions of low blood flow, whereas vessels exposed to high shear stress remain lesion-free. We hypothesized that exposing established atherosclerotic plaques to elevated shear stress leads to lesion regression by facilitating inflammatory cell movement within the plaque. We developed a model of arteriovenous fistula (AVF) in mice, where the right carotid artery is anastomosed into the jugular vein. LDLR-/- mice were placed on a high-fat diet. Control mice were sacrificed at week 12, which coincided with sham and AVF surgery. Sham and AVF mice were kept on a high-fat diet for a further 4 weeks. This procedure increases the shear stress in the brachiocephalic artery (BCA) and leads to a 51% plaque regression in AVF. All groups had comparable lipid levels. However, BCA plaque macrophage, smooth muscle cell and collagen content was halved in AVF. We observed greater gelatinase activity in plaques of AVF mice, suggesting a role for matrix metalloproteinases (MMPs) in plaque regression. MMP-9 and MMP-3 expression was increased in AVF plaques whereas MMP-2 and MMP-14 expression was decreased (p<0.05). A separate group of mice was therefore treated post-surgery with an MMP inhibitor, doxycycline, or with a TIMP-1 over-expressing plasmid. Both prevented the reduction in plaque size in the AVF group. To better define the mechanism of plaque regression in the AVF, we devised an endothelial cell (EC)-macrophage co-culture system where the ECs were exposed to high, low or no shear stress, and macrophages exposed to the EC effluent. There was a 2.5 fold increase in the migration of macrophages exposed to high shear effluent vs. low shear (p<0.05). This coincided with a 3-fold increase in the number of macrophages expressing activated β1 integrin in the high shear conditions. Uptake of apoptotic cells by macrophages was also 25% higher in the high shear vs. static (p<0.05). When repeated using the MMP inhibitor, GM6001, the high shear increase in migration was blocked in the presence of MMP inhibition; however, it had no effect on cell phagocytosis. Our findings suggest that shear stress acting on ECs may influence the cells within the plaque by increasing MMP activity allowing for better macrophage motility, an important feature of regressing plaques.

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