scholarly journals Peroxisome Proliferator-Activated Receptors and Hepatitis C Virus-Induced Insulin Resistance

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-6 ◽  
Author(s):  
Francesco Negro
Keyword(s):  
Insulin Resistance ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Insulin Signalling ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Insulin Resistant ◽  
Peroxisome Proliferator Activated Receptors ◽  
Chronic Hepatitis C Patients

Insulin resistance and type 2 diabetes are associated with hepatitis C virus infection. A wealth of clinical and experimental data suggests that the virus is directly interfering with the insulin signalling in hepatocytes. In the case of at least one viral genotype (the type 3a), insulin resistance seems to be directly mediated by the downregulation of the peroxisome proliferator-activated receptorγ. Whether and how this interaction may be manipulated pharmacologically, in order to improve the responsiveness to antivirals of insulin resistant chronic hepatitis C, patients remain to be fully explored.

scholarly journals Peroxisome proliferator-activated receptors and hepatitis C virus

2011 ◽  
Vol 4 (6) ◽  
pp. 419-431 ◽  
Author(s):  
M. Eslam ◽  
M. A. Khattab ◽  
S. A. Harrison
Keyword(s):  
Insulin Resistance ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatic Steatosis ◽  
Adverse Outcomes ◽  
Peroxisome Proliferator ◽  
Nuclear Factors ◽  
Peroxisome Proliferator Activated Receptors ◽  
The Relationship

The prevalence of type 2 diabetes mellitus and insulin resistance are higher among people chronically infected with hepatitis C (CHC) when compared with the general population and people with other causes of chronic liver disease. Both insulin resistance and diabetes are associated with adverse outcomes across all stages of CHC, including the liver transplant population. CHC is also associated with the development of hepatic steatosis, a common histological feature present in approximately 55% (32–81%) of cases. There is a complex interrelationship between insulin resistance and hepatic steatosis and both are postulated to aggravate each other. The peroxisome proliferator-activated receptors (PPARs) are nuclear factors involved in the regulation of glucose, lipid homeostasis, inflammatory response, cell differentiation, and cell cycle. The relationship between hepatitis C virus replication and PPARs has been the focus of recent study. Given the availability of potent agonists, PPARs may represent a novel pharmacological target in the treatment of CHC.

scholarly journals Gynura divaricata ameliorates hepatic insulin resistance by modulating insulin signalling, maintaining glycolipid homeostasis and reducing inflammation in type 2 diabetic mice

2019 ◽  
Vol 8 (6) ◽  
pp. 928-938 ◽  
Author(s):  
Xuan Dong ◽  
Shu-Xiang Zhao ◽  
Bing-Qing Xu ◽  
Yu-Qing Zhang
Keyword(s):  
Insulin Resistance ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Molecular Mechanisms ◽  
Insulin Signalling ◽  
Fasting Blood Glucose ◽  
Hepatic Insulin Resistance ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Insulin Signalling Pathway

Abstract Diabetes mellitus, one of the fastest growing epidemics worldwide, has become a serious health problem in modern society. Gynura divaricata (GD), an edible medicinal plant, has been shown to have hypoglycaemic effects. The molecular mechanisms by which GD improves hepatic insulin resistance (IR) in mice with type 2 diabetes (T2D) remain largely unknown. The aerial parts of GD were prepared in a lyophilized powder, which was added into the diet of T2D mice for 4 weeks. GD could result in an obvious decrease in fasting blood glucose and insulin levels in T2D mice. Meanwhile, the underlying mechanisms involved in the insulin-signalling pathway, glucose metabolism, lipid metabolism and inflammatory reaction in the liver tissue were also investigated by western blot, which indicated that GD further ameliorated hepatic IR by activating the PI3K/p-AKT pathway, decreasing the levels of hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase and increasing the levels of glucokinase and peroxisome proliferator-activated receptor-γ in the livers of T2D mice. GD has the potential to alleviate both hyperglycaemia and hepatic IR in T2D mice. Therefore, GD might be a promising functional food or medicine for T2D treatment.

scholarly journals Diet Modifies Pioglitazone’s Influence on Hepatic PPARγ-Regulated Mitochondrial Gene Expression

PPAR Research ◽  
2020 ◽  
Vol 2020 ◽  
pp. 1-20
Author(s):  
Sakil Kulkarni ◽  
Jiansheng Huang ◽  
Eric Tycksen ◽  
Paul F. Cliften ◽  
David A. Rudnick
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Transcriptional Regulation ◽  
Mitochondrial Gene ◽  
Peroxisome Proliferator ◽  
Large Set ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Insulin Resistant

Pioglitazone (Pio) is a thiazolidinedione (TZD) insulin-sensitizing drug whose effects result predominantly from its modulation of the transcriptional activity of peroxisome proliferator-activated-receptor-gamma (PPARγ). Pio is used to treat human insulin-resistant diabetes and also frequently considered for treatment of nonalcoholic steatohepatitis (NASH). In both settings, Pio’s beneficial effects are believed to result primarily from its actions on adipose PPARγ activity, which improves insulin sensitivity and reduces the delivery of fatty acids to the liver. Nevertheless, a recent clinical trial showed variable efficacy of Pio in human NASH. Hepatocytes also express PPARγ, and such expression increases with insulin resistance and in nonalcoholic fatty liver disease (NAFLD). Furthermore, mice that overexpress hepatocellular PPARγ and Pio-treated mice with extrahepatic PPARγ gene disruption develop features of NAFLD. Thus, Pio’s direct impact on hepatocellular gene expression might also be a determinant of this drug’s ultimate influence on insulin resistance and NAFLD. Previous studies have characterized Pio’s PPARγ-dependent effects on hepatic expression of specific adipogenic, lipogenic, and other metabolic genes. However, such transcriptional regulation has not been comprehensively assessed. The studies reported here address that consideration by genome-wide comparisons of Pio’s hepatic transcriptional effects in wildtype (WT) and liver-specific PPARγ-knockout (KO) mice given either control or high-fat (HFD) diets. The results identify a large set of hepatic genes for which Pio’s liver PPARγ-dependent transcriptional effects are concordant with its effects on RXR-DNA binding in WT mice. These data also show that HFD modifies Pio’s influence on a subset of such transcriptional regulation. Finally, our findings reveal a broader influence of Pio on PPARγ-dependent hepatic expression of nuclear genes encoding mitochondrial proteins than previously recognized. Taken together, these studies provide new insights about the tissue-specific mechanisms by which Pio affects hepatic gene expression and the broad scope of this drug’s influence on such regulation.

scholarly journals Peroxisome Proliferator-Activated Receptor γ and Adipose Tissue—Understanding Obesity-Related Changes in Regulation of Lipid and Glucose Metabolism

2006 ◽  
Vol 92 (2) ◽  
pp. 386-395 ◽  
Author(s):  
Arya M. Sharma ◽  
Bart Staels
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Endocrine Function ◽  
Low Grade ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Abstract Context: Adipose tissue is a metabolically dynamic organ, serving as a buffer to control fatty acid flux and a regulator of endocrine function. In obese subjects, and those with type 2 diabetes or the metabolic syndrome, adipose tissue function is altered (i.e. adipocytes display morphological differences alongside aberrant endocrine and metabolic function and low-grade inflammation). Evidence Acquisition: Articles on the role of peroxisome proliferator-activated receptor γ (PPARγ) in adipose tissue of healthy individuals and those with obesity, metabolic syndrome, or type 2 diabetes were sourced using MEDLINE (1990–2006). Evidence Synthesis: Articles were assessed to provide a comprehensive overview of how PPARγ-activating ligands improve adipose tissue function, and how this links to improvements in insulin resistance and the progression to type 2 diabetes and atherosclerosis. Conclusions: PPARγ is highly expressed in adipose tissue, where its activation with thiazolidinediones alters fat topography and adipocyte phenotype and up-regulates genes involved in fatty acid metabolism and triglyceride storage. Furthermore, PPARγ activation is associated with potentially beneficial effects on the expression and secretion of a range of factors, including adiponectin, resistin, IL-6, TNFα, plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, and angiotensinogen, as well as a reduction in plasma nonesterified fatty acid supply. The effects of PPARγ also extend to macrophages, where they suppress production of inflammatory mediators. As such, PPARγ activation appears to have a beneficial effect on the relationship between the macrophage and adipocyte that is distorted in obesity. Thus, PPARγ-activating ligands improve adipose tissue function and may have a role in preventing progression of insulin resistance to diabetes and endothelial dysfunction to atherosclerosis.

Impact of α-lipoic acid on liver peroxisome proliferator-activated receptor-α, vascular remodeling, and oxidative stress in insulin-resistant rats

2011 ◽  
Vol 89 (10) ◽  
pp. 743-751 ◽  
Author(s):  
Adil El Midaoui ◽  
Calin Lungu ◽  
Hui Wang ◽  
Lingyun Wu ◽  
Caroline Robillard ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipoic Acid ◽  
Tap Water ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
Cross Sectional ◽  
Peroxisome Proliferator Activated Receptor ◽  
Insulin Resistant ◽  
Plasma Ffa ◽  
The Impact

This study sought to determine the impact of α-lipoic acid (LA) on superoxide anion (O2•–) production and peroxisome proliferator-activated receptor-α (PPARα) expression in liver tissue, plasma free fatty acids (FFA), and aortic remodeling in a rat model of insulin resistance. Sprague–Dawley rats (50–75 g) were given either tap water or a drinking solution containing 10% D-glucose for 14 weeks, combined with a diet with or without LA supplement. O2•– production was measured by lucigenin chemiluminescence, and PPAR-α expression by Western blotting. Cross-sectional area (CSA) of the aortic media and lumen and number of smooth muscle cells (SMC) were determined histologically. Glucose increased systolic blood pressure (SBP), plasma levels of glucose and insulin, and insulin resistance (HOMA index). All of these effects were attenuated by LA. Whereas glucose had no effect on liver PPAR-α protein level, it decreased plasma FFA. LA decreased the aortic and liver O2•– production, body weight, and plasma FFA levels in control and glucose-treated rats. Liver PPAR-α protein levels were increased by LA, and negatively correlated with plasma FFA. Medial CSA was reduced in all glucose-treated rats, and positively correlated with plasma FFA but not with SBP or aortic O2•– production. Glucose also reduced aortic lumen area, so that the media-to-lumen ratio remained unchanged. The ability of LA to lower plasma FFA appears to be mediated, in part, by increased hepatic PPAR-α expression, which may positively affect insulin resistance. Glucose-fed rats may serve as a unique model of aortic atrophic remodeling in hypertension and early metabolic syndrome.

scholarly journals Oxidative Stress Attenuates Lipid Synthesis and Increases Mitochondrial Fatty Acid Oxidation in Hepatoma Cells Infected with Hepatitis C Virus

2015 ◽  
Vol 291 (4) ◽  
pp. 1974-1990 ◽  
Author(s):  
Donna N. Douglas ◽  
Christopher Hao Pu ◽  
Jamie T. Lewis ◽  
Rakesh Bhat ◽  
Anwar Anwar-Mohamed ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Growth Arrest ◽  
Lipid Synthesis ◽  
Reactive Oxygen ◽  
Hcv Infection ◽  
Peroxisome Proliferator ◽  
Oxygen Species ◽  
Peroxisome Proliferator Activated Receptor

Cytopathic effects are currently believed to contribute to hepatitis C virus (HCV)-induced liver injury and are readily observed in Huh7.5 cells infected with the JFH-1 HCV strain, manifesting as apoptosis highly correlated with growth arrest. Reactive oxygen species, which are induced by HCV infection, have recently emerged as activators of AMP-activated protein kinase. The net effect is ATP conservation via on/off switching of metabolic pathways that produce/consume ATP. Depending on the scenario, this can have either pro-survival or pro-apoptotic effects. We demonstrate reactive oxygen species-mediated activation of AMP-activated kinase in Huh7.5 cells during HCV (JFH-1)-induced growth arrest. Metabolic labeling experiments provided direct evidence that lipid synthesis is attenuated, and β-oxidation is enhanced in these cells. A striking increase in nuclear peroxisome proliferator-activated receptor α, which plays a dominant role in the expression of β-oxidation genes after ligand-induced activation, was also observed, and we provide evidence that peroxisome proliferator-activated receptor α is constitutively activated in these cells. The combination of attenuated lipid synthesis and enhanced β-oxidation is not conducive to lipid accumulation, yet cellular lipids still accumulated during this stage of infection. Notably, the serum in the culture media was the only available source for polyunsaturated fatty acids, which were elevated (2-fold) in the infected cells, implicating altered lipid import/export pathways in these cells. This study also provided the first in vivo evidence for enhanced β-oxidation during HCV infection because HCV-infected SCID/Alb-uPA mice accumulated higher plasma ketones while fasting than did control mice. Overall, this study highlights the reprogramming of hepatocellular lipid metabolism and bioenergetics during HCV infection, which are predicted to impact both the HCV life cycle and pathogenesis.

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