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.
Highlights
Intrahepatic lipid accumulation is extremely common in obese subjects and is associated with the development of insulin resistance and diabetes
Human MOGAT1, MOGAT2, and MOGAT3 mRNAs were all highly expressed in pooled liver RNA, and MOGAT2 and MOGAT3 mRNAs were highly expressed in small intestinal RNA (Fig. 2)
MGAT3 protein was detected in liver and intestinal extracts (Fig. 2), indicating that this monoacylglycerol acyltransferases (MGAT) family protein is expressed at detectable levels in human liver
Summary
In Cohort 1, liver biopsies were obtained from 43 women and 11 men [body mass index (BMI) of 57.4 ± 11.9 kg/m2] during GBS, and MOGAT expression and MGAT activity were determined as described below. Blood samples were obtained before beginning the tracer infusion to determine background plasma glucose tracer-to-tracee ratio (TTR), and every 10 min during the final 30 min of the infusion period to determine insulin concentrations and glucose kinetics. 0.0004 0.0005 0.0011 0.0019 0.0025 0.0013 0.0006 0.0034 0.2625 0.7120 0.5489 were placed on ice, and plasma was separated by using refrigerated centrifugation within 30 min of collection and stored at Ϫ80°C until final analyses were performed In this cohort, liver biopsies were obtained twice, by needle biopsy during GBS and percutaneously one year after surgery during the infusion study. To obtain tissue from non-NAFLD livers, hepatic biopsies from cadaveric donors were obtained at time of transplant All subjects gave their written, informed consent before participating in this study, which was approved by the Human Research Protection Office of Washington University School of Medicine, St. Louis, MO. The primers used in these analyses can be found in supplementary Table I
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