PPARγ is essential for protection against nonalcoholic steatohepatitis

Wu, Chung Wah; Chu, Ellie S.M.; Lam, C N Y; Cheng, Alfred S.L.; Lee, C W; Wong, Vincent Wai‐Sun; Sung, Joseph J.Y.; Yu, Jun

doi:10.1038/gt.2010.41

Cited by 74 publications

(61 citation statements)

References 31 publications

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“…PPARα‐ as well as PPARγ‐deficient mice are more sensitive to the development of steatohepatitis under an MCD than wild‐type mice 21, 22. Using selective PPAR agonists, it was reported that Wy‐14,643 (a PPARα agonist), GW501516 (a PPARδ agonist), and PPARγ activation by pioglitazone prevent and/or reverse MCD‐induced steatohepatitis 21, 22, 23, 24, 25. In the foz/foz model, a protective effect on steatohepatitis was observed with PPARα agonist treatment 15…”

Section: Discussionmentioning

confidence: 99%

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Wettstein

Luccarini

Poekes

et al. 2017

Hepatology Communications

114

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IVA337 is a pan‐peroxisome proliferator‐activated receptor (PPAR) agonist with moderate and well‐balanced activity on the three PPAR isoforms (α, γ, δ). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet‐induced obesity model (high‐fat/high‐sucrose diet); a methionine‐ and choline‐deficient diet; the foz/foz model; the CCl4‐induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl4 model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of β‐oxidation‐related and fatty acid desaturation‐related genes in both the methionine‐ and choline‐deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARα, PPARδ, or PPARγ agonists. Conclusion: The therapeutic potential of IVA337 for the treatment of patients with NASH is supported by our data. (Hepatology Communications 2017;1:524–537)

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Section: Discussionmentioning

confidence: 99%

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Wettstein

Luccarini

Poekes

et al. 2017

Hepatology Communications

114

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“…In contrast to the liver, luteolin treatment in the HFDfed mice elevated lipogenesis through increasing PPARg protein expression in adipose tissue. Wu et al (33) reported overexpression of PPARg delivered by adenovirusPPARg attenuated steatohepatitis by redistribution of FA from liver to adipose tissue by enhancing expression of FA uptake genes and lipogenic genes in adipose tissue. Luteolin significantly reduced the plasma FFA level with a simultaneous increase in adipocyte FA uptake gene (Cd36, Ffar3, Fabp4, and Lpl) expressions, leading to the reduction of hepatic lipotoxicity via the increased FFA flux to the liver.…”

Section: Discussionmentioning

confidence: 99%

Luteolin Attenuates Hepatic Steatosis and Insulin Resistance Through the Interplay Between the Liver and Adipose Tissue in Mice with Diet-Induced Obesity

et al. 2014

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The flavonoid luteolin has various pharmacological activities. However, few studies exist on the in vivo mechanism underlying the actions of luteolin in hepatic steatosis and obesity. The aim of the current study was to elucidate the action of luteolin on obesity and its comorbidity by analyzing its transcriptional and metabolic responses, in particular the luteolin-mediated cross-talk between liver and adipose tissue in diet-induced obese mice. C57BL/6J mice were fed a normal, high-fat, and high-fat + 0.005% (weight for weight) luteolin diet for 16 weeks. In high fatfed mice, luteolin improved hepatic steatosis by suppressing hepatic lipogenesis and lipid absorption. In adipose tissue, luteolin increased PPARg protein expression to attenuate hepatic lipotoxicity, which may be linked to the improvement in circulating fatty acid (FA) levels by enhancing FA uptake genes and lipogenic genes and proteins in adipose tissue. Interestingly, luteolin also upregulated the expression of genes controlling lipolysis and the tricarboxylic acid (TCA) cycle prior to lipid droplet formation, thereby reducing adiposity. Moreover, luteolin improved hepatic insulin sensitivity by suppressing SREBP1 expression that modulates Irs2 expression through its negative feedback and gluconeogenesis. Luteolin ameliorates the deleterious effects of diet-induced obesity and its comorbidity via the interplay between liver and adipose tissue.Obesity is characterized by excessive fat accumulation and is associated with metabolic complications such as adiposity, dyslipidemia, insulin resistance, and steatohepatitis. The liver is one of the major organs responsible for metabolizing fats from the diet. Dysregulation of lipid metabolism in the liver induces abnormal accumulation of lipids and the subsequent formation of lipid droplets (LDs), known as hepatic steatosis. Hepatic steatosis is common in obese individuals and is strongly linked to insulin resistance (1,2). Adipose tissue is also a critical component of metabolic control and is an endocrine organ that secretes a number of adipokines known to mediate lipid metabolism, inflammation, and insulin sensitivity (3). Although the complex relationship between adiposity and hepatic steatosis has not been completely elucidated, dysregulation of lipid metabolism in the liver and adipose tissue may be involved in the pathogenesis of adiposity as well as its associated metabolic complications. One hypothesis for the explanation of a link between visceral adiposity and hepatic steatosis and insulin resistance is the "portal hypothesis," which proposes that a high rate of lipolysis of the visceral adipose tissue can lead to an increased delivery of free fatty acids (FFAs) to the liver via the portal vein, and that chronic exposure of the liver to elevated FFAs can promote hepatic steatosis and hepatic insulin resistance (4,5). However, it is still unclear how visceral adiposity is associated with hepatic steatosis and insulin resistance, in particular at the level of transcriptional changes that occur in ...

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“…So far, activating agonists of PPARs such as Wy-14,643 and rosiglitazone have been tested for their effectiveness in diminishing the symptoms of NASH (12,39). However, the trials have not yet been successful, because the clinically applied PPAR agonists, rosiglitazone and pioglitazone, have several side effects such as edema, increased adiposity, liver toxicity, myocardial infarction, and heart failure (30,31).…”

Section: Fig 2 (Continued)mentioning

confidence: 99%

RORα Decreases Oxidative Stress Through the Induction of SOD2 and GPx1 Expression and Thereby Protects Against Nonalcoholic Steatohepatitis in Mice

Han

Kim

et al. 2014

Antioxidants & Redox Signaling

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Aims: Increased hepatic oxidative stress and inflammation is the main cause of exacerbating nonalcoholic steatohepatitis (NASH). Retinoic acid-related orphan receptor a (RORa) regulates diverse target genes associated with lipid metabolism, and its expression level is low in the liver of patients with NASH. Here, we investigated the role of RORa in regulating hepatic oxidative stress and inflammation. Results: First, cholesterol sulfate (CS), an agonist of RORa, lowered oxidative stress that was induced by 1.5 mM oleic acid in the primary cultures of hepatocytes. Second, exogenously introduced RORa or CS treatment induced the mRNA level of antioxidant enzymes, superoxide dismutase 2 (SOD2) and glutathione peroxidase 1 (GPx1), through the RORa response elements located in the upstream promoters of Sod2 and Gpx1. Third, RORa significantly decreased reactive oxygen species levels and mRNA levels of tumor necrosis factor a (TNFa) and interleukin-1b that were induced by lipopolysaccharide or TNFa in Kupffer cells. Finally, the administration of JC1-40 decreased the signs of liver injury, lipid peroxidation, and inflammation in the MCD diet-induced NASH mice. Innovation and Conclusion: We showed for the first time that RORa and its ligands protect NASH in mice by reducing hepatic oxidative stress and inflammation. Further, the molecular mechanism of the protective function of RORa against oxidative stress in the liver was revealed. These findings may offer a rationale for developing therapeutic strategies against NASH using RORa ligands.

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PPARγ is essential for protection against nonalcoholic steatohepatitis

Cited by 74 publications

References 31 publications

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Luteolin Attenuates Hepatic Steatosis and Insulin Resistance Through the Interplay Between the Liver and Adipose Tissue in Mice with Diet-Induced Obesity

RORα Decreases Oxidative Stress Through the Induction of SOD2 and GPx1 Expression and Thereby Protects Against Nonalcoholic Steatohepatitis in Mice

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