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Involvement and Mechanism of DGAT2 Upregulation in the Pathogenesis of Alcoholic Fatty Liver Disease

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posted on 25.07.2012, 00:00 by Zhigang Wang, Tong Yao, Zhenyuan Song
The mechanisms involved in the development of alcoholic liver disease (ALD) are not well-established. We investigated the involvement of acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2) upregulation in mediating hepatic fat accumulation induced by chronic alcohol consumption. Chronic alcohol feeding caused fatty liver and increased hepatic DGAT2 gene and protein expression, concomitant with a significant suppression of hepatic MEK/ERK1/2 activation. In vitro studies demonstrated that specific inhibitors of the MEK/ERK1/2 pathway increased DGAT2 gene expression and triglyceride (TG) contents in HepG2 cells, while epidermal growth factor, a strong ERK1/2 activator, had the opposite effect. Moreover, chronic alcohol feeding decreased hepatic S-adenosylmethionine (SAM): S-adenosylhomocysteine (SAH) ratio, an indicator of disrupted transmethylation reactions. Mechanistic investigations revealed that N-acetyl-S-farnesyl-L-cysteine, a potent inhibitor of isoprenylcysteine carboxyl methyltransferase, suppressed ERK1/2 activation, followed by an enhanced DGAT2 expression and an elevated TG content in HepG2 cells. Lastly, we demonstrated that the beneficial effects of betaine supplementation in ALD were associated with improved SAM/SAH ratio, alleviated ERK1/2 inhibition, and attenuated DGAT2 upregulation. In conclusion, our data suggest that upregulation of DGAT2 plays an important role in the pathogenesis of ALD, and that abnormal methionine metabolism contributes, at least partially, to DGAT2 upregulation via suppression of MEK/ERK1/2 activation.


Supported by the National Institutes of Health grants K01 AA015344 and R01 AA017442 (Z Song).


Publisher Statement

This research was originally published in Journal of Lipid Research. Zhigang Wang, Tong Yao, Zhenyuan Song. Involvement and Mechanism of DGAT2 Upregulation in the Pathogenesis of Alcoholic Fatty Liver Disease. Journal of Lipid Research. 2010. 11:3158-3165. © the American Society for Biochemistry and Molecular Biology. DOI: 10.1194/jlr.M007948


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