Decreased microsomal triglyceride transfer protein activity contributes to initiation of alcoholic liver steatosis in rats.
OBJECTIVE
To elucidate the role of microsomal triglyceride transfer protein (MTP) in the pathogenesis of alcoholic fatty liver, the effects of ethanol on MTP activity and gene expression were investigated.


RESULTS
Male Sprague-Dawley rats fed an ethanol-containing liquid diet for 37 days, respectively, showed 2.9- and 4.9-fold increases in hepatic cholesterol and triglyceride content in comparison with rats fed an isocaloric ethanol-free diet (P<0.01). Furthermore, a significant decrease in MTP activity and mRNA expression (by 27 and 58%, respectively) was observed after ethanol administration. Intravenous injection of human recombinant hepatocyte growth factor (hrHGF) on each of the last 7 days markedly suppressed ethanol-induced lipid accumulation in the liver. This inhibition of fatty change by hrHGF was accompanied by recovery of MTP activity and gene expression. No inhibitory effect of hrHGF on ethanol-induced acyl-CoA synthetase activation was observed. Experiments using human hepatoma-derived HepG2 cells indicated a direct positive effect of hrHGF on MTP gene expression as well as apolipoprotein B secretion.


CONCLUSIONS
These results suggest that reduced MTP activity is crucial to development of alcoholic fatty liver, while promotion of MTP activity by HGF might serve as a therapeutic measure against alcoholic liver steatosis.
Sugimoto
Taizo
T
Department of Internal Medicine and Molecular Science, B5, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Yamashita
Shizuya
S
Ishigami
Masato
M
Sakai
Naohiko
N
Hirano
Ken-ichi
K
Tahara
Minoru
M
Matsumoto
Kunio
K
Nakamura
Toshikazu
T
Matsuzawa
Yuji
Y
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D006528:Carcinoma, Hepatocellular; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism; D003066:Coenzyme A Ligases / Q000235:genetics; D000431:Ethanol / Q000494:pharmacology; D005235:Fatty Liver, Alcoholic / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D001055:Apolipoproteins B; D002352:Carrier Proteins; D002492:Central Nervous System Depressants; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D000431:Ethanol; D017228:Hepatocyte Growth Factor; D002784:Cholesterol; D003066:Coenzyme A Ligases; C561832:Acsl1 protein, rat