Abstract
The development of alcoholic fatty liver is associated with reduced adipocyte-derived adiponectin levels, decreased hepatic adiponectin receptors, and deranged hepatic adiponectin signaling in animals. Peroxisomal proliferator-activated receptor-gamma (PPAR-gamma) plays a key role in the regulation of adiponectin in adipose tissue. The aim of the present study was to test the ability of rosiglitazone, a known PPAR-gamma agonist, to reverse the inhibitory effects of ethanol on adiponectin expression and its hepatic signaling, and to attenuate alcoholic liver steatosis in mice. Mice were fed modified Lieber-DeCarli ethanol-containing liquid diets for 4 wk or pair-fed control diets. Four groups of mice were given a dose of either 3 or 10 mg.kg body wt(-1).day(-1) of rosiglitazone with or without ethanol in their diets for the last 2 wk of the feeding study. Coadministration of rosiglitazone and ethanol increased the expression and circulating levels of adiponectin and enhanced the expression of hepatic adiponectin receptors (AdipoRs) in mice. These increases correlated closely with the activation of a hepatic sirtuin 1 (SIRT1)-AMP-activated kinase (AMPK) signaling system. In concordance with stimulated SIRT1-AMPK signaling, rosiglitazone administration enhanced expression of fatty acid oxidation enzymes, normalized lipin 1 expression, and blocked elevated expression of genes encoding lipogenic enzymes which, in turn, led to increased fatty acid oxidation, reduced lipogenesis, and alleviation of steatosis in the livers of ethanol-fed mice. Enhanced hepatic adiponectin-SIRT1-AMPK signaling contributes, at least in part, to the protective action of rosiglitazone against alcoholic fatty liver in mice.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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AMP-Activated Protein Kinases / genetics
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AMP-Activated Protein Kinases / metabolism*
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Acetyl-CoA Carboxylase / metabolism
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Acetylation / drug effects
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Adiponectin / pharmacology
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Adiponectin / physiology*
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Animals
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Cell Line, Tumor
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Ethanol / pharmacology
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Fatty Liver, Alcoholic / blood
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Fatty Liver, Alcoholic / metabolism
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Fatty Liver, Alcoholic / pathology
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Fatty Liver, Alcoholic / prevention & control*
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Gene Expression / drug effects
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Gene Expression / genetics
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Histones / metabolism
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Intra-Abdominal Fat / drug effects
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Intra-Abdominal Fat / metabolism
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Ion Channels / genetics
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Lipid Metabolism / drug effects
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Lipid Metabolism / genetics
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Liver / drug effects
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Liver / metabolism
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Liver / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mitochondrial Proteins / genetics
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Models, Biological
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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PPAR gamma / genetics
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Phosphatidate Phosphatase
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RNA, Small Interfering / genetics
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Rats
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Receptors, Adiponectin / genetics
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Retinoid X Receptor alpha / genetics
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Rosiglitazone
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Sirtuin 1 / genetics
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Sirtuin 1 / metabolism*
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Thiazolidinediones / pharmacology
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Thiazolidinediones / therapeutic use*
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transaminases / blood
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Transcription Factors
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Triglycerides / blood
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Triglycerides / metabolism
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Tumor Necrosis Factor-alpha / genetics
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Uncoupling Protein 2
Substances
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Adiponectin
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Histones
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Ion Channels
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Mitochondrial Proteins
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Nuclear Proteins
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PPAR gamma
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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RNA, Small Interfering
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Receptors, Adiponectin
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Retinoid X Receptor alpha
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Thiazolidinediones
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Trans-Activators
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Transcription Factors
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Triglycerides
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Tumor Necrosis Factor-alpha
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Uncoupling Protein 2
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Rosiglitazone
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Ethanol
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Transaminases
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AMP-Activated Protein Kinases
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Lpin1 protein, mouse
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Phosphatidate Phosphatase
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Sirt1 protein, mouse
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Sirtuin 1
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Acetyl-CoA Carboxylase