Involvement and mechanism of DGAT2 upregulation in the pathogenesis of alcoholic fatty liver disease

Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, USA.
The Journal of Lipid Research (Impact Factor: 4.42). 11/2010; 51(11):3158-65. DOI: 10.1194/jlr.M007948
Source: PubMed


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 MAPK/ERK kinase/extracellular regulated kinase 1/2 (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, whereas 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.

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    • "iet showed a remarkable suppression of hepatic ERK1 / 2 activation ( Wang et al . , 2010a ) . On the opposite side , an increase in the level of phosphorylated ERK1 / 2 improved liver steatosis ( Aghazadeh and Yazdanparast , 2010 ) . Chronic alcohol also caused a signif - icant suppression of hepatic ERK1 / 2 activation and triggered fatty liver ( Wang et al . , 2010b ) . We hypothesize that one of the MEK / ERK targets could be C / EBPa or C / EBPb . ERK can phosphorylate C / EBPa at Ser 21 ( Ross et al . , 2004 ) . Moreover , phosphorylation of C / EBPb at Thr235 by ERK2 is a key determinant of its capacity for transactivation ( Nakajima et al . , 1993 ) . Based on these studies , we suggest that p"
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