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

Research output: Contribution to journalArticle

103 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

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pioglitazone
Fatty Liver
Up-Regulation
Alcohols
Ethanol
Stearoyl-CoA Desaturase
VLDL Lipoproteins
Hepatocytes
Liver
Triglycerides
Down-Regulation
Alcoholic Fatty Liver
Lipid Mobilization
Sterol Regulatory Element Binding Protein 1
Alcoholic Liver Diseases
PPAR gamma
Apolipoproteins B
Gene Expression Profiling
Hypoglycemic Agents
Lipid Peroxidation

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Tomita, K., Azuma, T., Kitamura, N., Nishida, J., Tamiya, G., Oka, A., ... 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

Pioglitazone Prevents Alcohol-Induced Fatty Liver in Rats Through Upregulation of c-Met. / Tomita, Kengo; Azuma, Toshifumi; Kitamura, Naoto; Nishida, Jiro; Tamiya, Gen; Oka, Akira; Inokuchi, Sayaka; Nishimura, Takeshi; Suematsu, Makoto; Ishii, Hiromasa.

In: Gastroenterology, Vol. 126, No. 3, 03.2004, p. 873-885.

Research output: Contribution to journalArticle

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, vol. 126, no. 3, pp. 873-885. https://doi.org/10.1053/j.gastro.2003.12.008
Tomita, Kengo ; Azuma, Toshifumi ; Kitamura, Naoto ; Nishida, Jiro ; Tamiya, Gen ; Oka, Akira ; Inokuchi, Sayaka ; Nishimura, Takeshi ; Suematsu, Makoto ; Ishii, Hiromasa. / Pioglitazone Prevents Alcohol-Induced Fatty Liver in Rats Through Upregulation of c-Met. In: Gastroenterology. 2004 ; Vol. 126, No. 3. pp. 873-885.
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AU - Nishida, Jiro

AU - Tamiya, Gen

AU - Oka, Akira

AU - Inokuchi, Sayaka

AU - Nishimura, Takeshi

AU - Suematsu, Makoto

AU - Ishii, Hiromasa

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