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Suppression of Extracellular Signal‐regulated Kinase‐1/2 Causes Fat Accumulation in Hepatocytes: A Potential Mechanism in Alcoholic Fatty Liver Disease (ALD)
Author(s) -
Wang Zhigang,
Yao Tong,
Song Zhenyuan
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1000.1
Subject(s) - mapk/erk pathway , steatosis , triglyceride , endocrinology , medicine , chemistry , diacylglycerol kinase , fatty liver , kinase , cholesterol , biochemistry , protein kinase c , disease
Although much progress has been made, the underlying mechanism in alcohol‐induced hepatic steatosis is still obscure. In this study, we examined the effect of alcohol exposure on MEK/ERK1/2 activation and its potential involvement in the development of hepatic steatosis. In animal studies, male C57BL/6 mice were pair‐fed with liquid diets containing either ethanol or an isocaloric maltose‐dextrin mixture for four weeks. In the in vitro investigations, HepG2 cells were utilized. Our results showed that chronic alcohol feeding resulted in increased triglyceride accumulation in the liver and liver injury in mice. These observations were concomitant with decreased S‐adenosylmethionine/S‐adenosylhomocysteine ratio and suppressed ERK 1/2 activation in the liver. Using HepG2 cells, we found that ERK inhibition by U0126 elevated intracellular triglyceride contents, and this was associated with increased gene expression of diacylglycerol acyltransferase‐2 (DGAT2). In contrast, epidermal growth factor, a major activator of ERK1/2, reduced triglyceride synthesis. Furthermore, N‐acetyl‐S‐farnesyl‐L‐cysteine (AFC), a methyltrasferase inhibitor, elevated triglyceride synthesis, which is associated with ERK ½ inhibition and enhanced DGAT2 expression. Taken together, our findings suggest that suppression of ERK‐1/2 activation may play a mechanistic role in the development of ALD. Supported by the National Institutes of Health grants K01 AA015344 and R01 AA017442 (Z Song).