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J. Biol. Chem., Vol. 277, Issue 32, 29342-29347, August 9, 2002
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From the Departments of Medicine, Indiana University School of
Medicine and Richard Roudebush Veteran's Affairs Medical Center,
Indianapolis, Indiana 46202
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.
Ethanol Induces Fatty Acid Synthesis Pathways by Activation of
Sterol Regulatory Element-binding Protein (SREBP)*
,
*
This work was supported by Grant AA06463 from the National
Institute on Alcohol Abuse and Alcoholism (to D. W. C.) and Grant AA07611 from the Alcohol Research Center.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Veterans
Administration Research 151, Third Floor D-3035, 1481 West Tenth St., Indianapolis, IN 46202. Tel.: 317-554-0000 (ext. 4544); Fax:
317-554-0116; E-mail: miyou@iupui.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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