Ethanol induces fatty acid synthesis pathways by activation of sterol regulatory element-binding protein (SREBP).
Alcoholic fatty liver is the earliest and most common response of the liver to alcohol and may be a precursor of more severe forms of liver injury. The mechanism by which ethanol causes fatty liver and liver injury is complex. We found that in both rat H4IIEC3 and McA-RH7777 hepatoma cell lines, ethanol induced transcription of a sterol regulatory element-binding protein (SREBP)-regulated promoter via increased levels of mature SREBP-1 protein. This effect of ethanol was blocked by addition of sterols. This effect is likely mediated by acetaldehyde, because the effect was only seen in cell lines expressing alcohol dehydrogenase, and inhibition of ethanol oxidation by 4-methylpyrazole blocked the effect in the hepatoma cells. Furthermore, the aldehyde dehydrogenase inhibitor cyanamide enhanced the effect of ethanol in the hepatoma cells. Consistent with these in vitro findings, feeding mice a low fat diet with ethanol for 4 weeks resulted in a significant increase in steady-state levels of the mature (active) form of SREBP-1. Activation of SREBP-1 by ethanol feeding was associated with increased expression of hepatic lipogenic genes as well as the accumulation of triglyceride in the livers. These finding suggest that metabolism of ethanol increased hepatic lipogenesis by activating SREBP-1 and that this effect of ethanol may contribute to the development of alcoholic fatty liver.
You
Min
M
Department of Medicine, Indiana University School of Medicine and Richard Roudebush Veteran's Affairs Medical Center, Indianapolis, Indiana 46202, USA. miyou@iupui.edu
Fischer
Monika
M
Deeg
Mark A
MA
Crabb
David W
DW
D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D022762:CCAAT-Enhancer-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D005227:Fatty Acids / Q000096:biosynthesis*; D015151:Immunoblotting; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020033:Protein Isoforms; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism; D014407:Tumor Cells, Cultured
D022762:CCAAT-Enhancer-Binding Proteins; D002492:Central Nervous System Depressants; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D020033:Protein Isoforms; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; D000431:Ethanol; D000426:Alcohol Dehydrogenase