title: Evidence for regulated monoacylglycerol acyltransferase expression and activity in human liver.
abstract: Intrahepatic lipid accumulation is extremely common in obese subjects and is associated with the development of insulin resistance and diabetes. Hepatic diacylglycerol and triacylglycerol synthesis predominantly occurs through acylation of glycerol-3-phosphate. However, an alternative pathway for synthesizing diacylglycerol from monoacylglycerol acyltransferases (MGAT) could also contribute to hepatic glyceride pools. MGAT activity and the expression of the three genes encoding MGAT enzymes (MOGAT1, MOGAT2, and MOGAT3) were determined in liver biopsies from obese human subjects before and after gastric bypass surgery. MOGAT expression was also assessed in liver of subjects with nonalcoholic fatty liver disease (NAFLD) or control livers. All MOGAT genes were expressed in liver, and hepatic MGAT activity was readily detectable in liver lysates. The hepatic expression of MOGAT3 was highly correlated with MGAT activity, whereas MOGAT1 and MOGAT2 expression was not, and knockdown of MOGAT3 expression attenuated MGAT activity in a liver-derived cell line. Marked weight loss following gastric bypass surgery was associated with a significant reduction in MOGAT2 and MOGAT3 expression, which were also overexpressed in NAFLD subjects. These data suggest that the MGAT pathway is active and dynamically regulated in human liver and could be an important target for pharmacologic intervention for the treatment of obesity-related insulin resistance and NAFLD.
authors.affiliation: Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Hall
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Global Research and Development, Groton, CT.
authors.forename: Kou
authors.initials: K
authors.lastname: Kou
authors.affiliation: Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
authors.forename: Zhouji
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
authors.forename: Terri A
authors.initials: TA
authors.lastname: Pietka
authors.affiliation: Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
authors.forename: Mrudula
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Korenblat
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Global Research and Development, Groton, CT.
authors.forename: Kyuha
authors.initials: K
authors.lastname: Lee
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Global Research and Development, Groton, CT.
authors.forename: Kay
authors.initials: K
authors.lastname: Ahn
authors.affiliation: Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
authors.forename: Elisa
authors.initials: E
authors.lastname: Fabbrini
authors.affiliation: Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
authors.forename: Samuel
authors.initials: S
authors.lastname: Klein
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Global Research and Development, Groton, CT.
authors.forename: Bryan
authors.initials: B
authors.lastname: Goodwin
authors.affiliation: Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO;. Electronic address: bfinck@dom.wustl.edu.
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
mesh_terms: D000217:Acyltransferases / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D051048:Diacylglycerol O-Acyltransferase / Q000378:metabolism; D005234:Fatty Liver / Q000201:enzymology / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D056945:Hep G2 Cells; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000201:enzymology / Q000473:pathology; D055815:Young Adult
chemical_list: D000217:Acyltransferases; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase; C021802:2-acylglycerol O-acyltransferase