Activation of peroxisome proliferator activated receptor alpha ameliorates ethanol mediated liver fibrosis in mice

Nan, Yuemin; Kong, Lingbo; Ren, Wei-Guang; Wang, Rongqi; Du, Jinghua; Li, Wencong; Zhao, Suxian; Zhang, Yuguo; Wu, Wenjuan; Di, Hai-Ling; Li, Ya; Yu, Jun

doi:10.1186/1476-511x-12-11

Cited by 44 publications

(34 citation statements)

References 40 publications

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“…This is especially attractive since fibrate drugs have been used in humans to treat hyperlipidemia for over 80 years. A recent report showed that PPARα agonist WY14643 alleviated liver injury caused by alcohol ingestion combined with carbon tetrachloride intraperitoneal injection in mice (Nan et al, 2013), in which carbon tetrachloride may be the major contributor for the observed severe liver injury including fibrosis. Our study suggests that PPARα agonists or other treatments with the capability to enhance mitochondria metabolic pathways may ameliorate alcoholic liver injury.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Fatty Acid and Bile Acid Metabolism By Peroxisome Proliferator-Activated ReceptorαProtects Against Alcoholic Liver Disease

Tyburski

Wang

et al. 2014

Alcohol Clin Exp Res

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Background Chronic alcohol intake affects liver function and causes hepatic pathological changes. It has been shown that peroxisome proliferator-activated receptor α (PPARα)-null mice developed more pronounced hepatic changes than wild type (WT) mice after chronic exposure to a diet containing 4% alcohol. The remarkable similarity between the histopathology of ALD in Ppara-null model and in humans, and the fact that PPARα expression and activity in human liver are less than one-tenth of those in WT mouse liver make Ppara-null a good system to investigate ALD. Methods In this study, the Ppara-null model was used to elucidate the dynamic regulation of PPARα activity during chronic alcohol intake. Hepatic transcriptomic and metabolomic analyses were used to examine alterations of gene expression and metabolites associated with pathological changes. The changes triggered by alcohol consumption on gene expression and metabolites in Ppara-null mice were compared with those in wild-type mice. Results The results showed that in the presence of PPARα, three major metabolic pathways in mitochondria, namely the fatty acid β-oxidation, the tricarboxylic acid cycle (TCA) and the electron transfer chain, were induced in response to two-month alcohol feeding, while these responses were greatly reduced in the absence of PPARα. In line with the transcriptional modulations of these metabolic pathways, lipidomic profiling showed consistent accumulation of triglycerides in Ppara-null mice, a robust increase of hepatic cholic acid and its derivatives, and a strong induction of fibrogenesis genes exclusively in alcohol-fed Ppara-null mice. Conclusions These observations indicate that PPARα plays a protective role to enhance mitochondrial function in response to chronic alcohol consumption by adaptive transcriptional activation and suggest that activation of this nuclear receptor may be of therapeutic value in the treatment of ALD.

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Section: Discussionmentioning

confidence: 99%

Modulation of Fatty Acid and Bile Acid Metabolism By Peroxisome Proliferator-Activated ReceptorαProtects Against Alcoholic Liver Disease

Tyburski

Wang

et al. 2014

Alcohol Clin Exp Res

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“…Liquid diets have extensively been used in rodents to produce ethanol dependence and physiological changes associated with chronic ethanol use (Gilpin et al, 2008; Macey et al, 1996; Nan et al, 2013; Umathe, Bhutada, Dixit, & Shende, 2008; Verleye, Heulard, & Gillardin, 2009; Zhang et al, 2013). Mice were single-housed with a nestlet, and provided for one week with a basic diet consisting of the chocolate flavored high protein nutritional drink, Boost ® (Nestlé Health Science, Switzerland), supplemented with 3g/L vitamin mixture (MP Biomedicals, LLC, Solon, OH) and 5g/L mineral mix (ICN Biomedicals, Inc., Aurora, OH) (Gilpin et al, 2008; Verleye et al, 2009).…”

Section: Methodsmentioning

confidence: 99%

“…After an habituation period to the liquid diet, mice were divided into two groups based on age, sex, and weight. The first group received the basic diet containing 4% vol/vol ethanol for six weeks (Nan et al, 2013; Verleye et al, 2009; Zhang et al, 2013). The second, yoked-control, group continued to receive the basic diet supplemented with an iso-coloric amount of sucrose in order to account for the increased calories associated with ethanol consumption.…”

Section: Methodsmentioning

confidence: 99%

Assessment of affective and somatic signs of ethanol withdrawal in C57BL/6J mice using a short-term ethanol treatment

Perez

Biasi

2015

Alcohol

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Alcohol is one of the most prevalent addictive substances in the world. Withdrawal symptoms result from abrupt cessation of alcohol consumption in habitual drinkers. The emergence of both affective and physical symptoms produces a state that promotes relapse. Mice provide a preclinical model that could be used to study alcohol dependence and withdrawal while controlling for both genetic and environmental variables. The use of a liquid ethanol diet offers a reliable method for the induction of alcohol dependence in mice, but this approach is impractical when conducting high throughput pharmacological screens or when comparing multiple strains of genetically engineered mice. The goal of this study was to compare withdrawal associated behaviors in mice chronically treated with a liquid ethanol diet vs. mice treated with a short-term ethanol treatment that consisted of daily ethanol injections containing the alcohol dehydrogenase inhibitor, 4-methylpyrazole. Twenty-four hours after ethanol treatment, mice were tested in the open field arena, the elevated plus maze, the marble burying test or for changes in somatic signs during spontaneous ethanol withdrawal. Anxiety-like and compulsive-like behavior, as well as physical signs, were all significantly elevated in mice undergoing withdrawal, regardless of the route of ethanol administration. Therefore, a short-term ethanol treatment can be utilized as a screening tool for testing genetic and pharmacological agents before investing in a more time consuming ethanol treatment.

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“…However, nuclear receptors are also important in ASH, CASH, and TASH. PPAR [227], PXR [228], CAR [229], LXR [230], and FXR [231] are implicated in the pathogenesis or therapy of alcoholic liver disease. Nuclear receptor activation may also be involved in the steatohepatitis associated with atypical antipsychotic medications [232].…”

Section: Nuclear Receptors In Ash Cash and Tashmentioning

confidence: 99%

Nuclear receptors and nonalcoholic fatty liver disease

Cave

Clair

Hardesty

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

232

204

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Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic side effects. The impact of nuclear receptor crosstalk in NAFLD is likely to be profound, but requires further elucidation. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

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Activation of peroxisome proliferator activated receptor alpha ameliorates ethanol mediated liver fibrosis in mice

Cited by 44 publications

References 40 publications

Modulation of Fatty Acid and Bile Acid Metabolism By Peroxisome Proliferator-Activated ReceptorαProtects Against Alcoholic Liver Disease

Modulation of Fatty Acid and Bile Acid Metabolism By Peroxisome Proliferator-Activated ReceptorαProtects Against Alcoholic Liver Disease

Assessment of affective and somatic signs of ethanol withdrawal in C57BL/6J mice using a short-term ethanol treatment

Nuclear receptors and nonalcoholic fatty liver disease

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