Pioglitazone prevents alcohol-induced fatty liver in rats through up-regulation of c-Met.
OBJECTIVE
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.
Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Kengo
K
Tomita
Toshifumi
T
Azuma
Naoto
N
Kitamura
Jiro
J
Nishida
Gen
G
Tamiya
Akira
A
Oka
Sayaka
S
Inokuchi
Takeshi
T
Nishimura
Makoto
M
Suematsu
Hiromasa
H
Ishii
D000428:Alcohol Drinking; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D005235:Fatty Liver, Alcoholic / Q000517:prevention & control*; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D014157:Transcription Factors; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation
D001055:Apolipoproteins B; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D007527:Isoenzymes; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D045162:Thiazolidinediones; D014157:Transcription Factors; D014443:Tyrosine; D004247:DNA; D013230:Stearoyl-CoA Desaturase; D019859:Proto-Oncogene Proteins c-met; D000077205:Pioglitazone