Pioglitazone Prevents Alcohol-Induced Fatty Liver in Rats Through Upregulation of c-Met

Kengo Tomita, Toshifumi Azuma, Naoto Kitamura, Jiro Nishida, Gen Tamiya, Akira Oka, Sayaka Inokuchi, Takeshi Nishimura, Makoto Suematsu, Hiromasa Ishii

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104 Citations (Scopus)

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 (PPARγ) 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 strata-gem to attenuate ethanol-induced hepatic steatosis.

Original languageEnglish
Pages (from-to)873-885
Number of pages13
JournalGastroenterology
Volume126
Issue number3
DOIs
Publication statusPublished - 2004 Mar

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Tomita, K., Azuma, T., Kitamura, N., Nishida, J., Tamiya, G., Oka, A., Inokuchi, S., Nishimura, T., Suematsu, M., & Ishii, H. (2004). Pioglitazone Prevents Alcohol-Induced Fatty Liver in Rats Through Upregulation of c-Met. Gastroenterology, 126(3), 873-885. https://doi.org/10.1053/j.gastro.2003.12.008