title: Involvement and mechanism of DGAT2 upregulation in the pathogenesis of alcoholic fatty liver disease.
abstract: 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.
authors.affiliation: Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Wang
authors.forename: Tong
authors.initials: T
authors.lastname: Yao
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Song
mesh_terms: D000438:Alcohols / Q000494:pharmacology; D000818:Animals; D001622:Betaine / Q000494:pharmacology; D051048:Diacylglycerol O-Acyltransferase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005235:Fatty Liver, Alcoholic / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D008715:Methionine / Q000378:metabolism; D008780:Methyltransferases / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000438:Alcohols; D004791:Enzyme Inhibitors; D014280:Triglycerides; D001622:Betaine; D008715:Methionine; D008780:Methyltransferases; C516957:DGAT2 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3