Pioglitazone prevents alcohol-induced fatty liver in rats through up-regulation of c-Met

Gastroenterology. 2004 Mar;126(3):873-85. doi: 10.1053/j.gastro.2003.12.008.

Abstract

Background & aims: Treatment of steatosis is important in preventing development of fibrosis in alcoholic liver diseases. This study aimed to examine if pioglitazone, an antidiabetic reagent serving as a ligand of peroxisome proliferator-activated receptor gamma (PPAR gamma), could prevent alcoholic fatty liver.

Methods: Rats fed with an ethanol-containing liquid diet were given the reagent at 10 mg/kg per day intragastrically for 6 weeks. Hepatic genes involved in actions of the reagent were mined by transcriptome analyses, and their changes were confirmed by real-time polymerase chain reaction and Western blotting analyses. The direct effects of pioglitazone on primary-cultured hepatocytes were also assessed in vitro.

Results: Pioglitazone significantly attenuated steatosis and lipid peroxidation elicited by chronic ethanol exposure without altering insulin resistance. Mechanisms for improving effects of the reagent appeared to involve restoration of the ethanol-induced down-regulation of c-Met and up-regulation of stearoyl-CoA desaturase (SCD). Such effects of pioglitazone on the c-Met signaling pathway resulted from its tyrosine phosphorylation and resultant up-regulation of the apolipoprotein B (apoB)-mediated lipid mobilization from hepatocytes through very low-density lipoprotein (VLDL) as well as down-regulation of sterol regulatory element binding protein (SREBP) -1c and SCD levels and a decrease in triglyceride synthesis in the liver.

Conclusions: Pioglitazone activates c-Met and VLDL-dependent lipid retrieval and suppresses triglyceride synthesis and thereby serves as a potentially useful stratagem to attenuate ethanol-induced hepatic steatosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking
  • Animals
  • Apolipoproteins B / metabolism
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cells, Cultured
  • DNA / biosynthesis
  • DNA-Binding Proteins / metabolism
  • Fatty Liver, Alcoholic / prevention & control*
  • Gene Expression Profiling
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Isoenzymes / metabolism
  • Lipid Peroxidation / drug effects
  • Liver / metabolism
  • Male
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation / drug effects
  • Pioglitazone
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Stearoyl-CoA Desaturase / metabolism
  • Sterol Regulatory Element Binding Protein 1
  • Thiazolidinediones / pharmacology*
  • Time Factors
  • Transcription Factors*
  • Tyrosine / metabolism
  • Up-Regulation

Substances

  • Apolipoproteins B
  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Isoenzymes
  • Srebf1 protein, rat
  • Sterol Regulatory Element Binding Protein 1
  • Thiazolidinediones
  • Transcription Factors
  • Tyrosine
  • DNA
  • Stearoyl-CoA Desaturase
  • Proto-Oncogene Proteins c-met
  • Pioglitazone