Evidence for regulated monoacylglycerol acyltransferase expression and activity in human liver

Abstract

Obesity is associated with nonalcoholic fatty liver disease (NAFLD), which represents a spectrum of liver abnormalities that are characterized by an increase in intrahepatic triacylglycerol (TAG) content (i.e., steatosis) with or without infl ammation and fi brosis (i.e., steatohepatitis). The presence of steatosis is an important marker of metabolic dysfunction and correlates closely with multiorgan insulin resistance and dyslipidemia ( 1 ), which are key risk factors for diabetes and coronary artery disease. However, the mechanisms responsible for the link between increased intrahepatic TAG content and metabolic disease are not clear.It has been hypothesized that the hepatocellular accumulation of specifi c lipid intermediates, including diacylglycerol (DAG), acyl-CoA, and ceramide, in people with NAFLD is the molecular mechanism driving insulin resistance ( 2, 3 ). Accordingly, an understanding of the metabolic interrelationships among hepatic glycerolipid synthesis and lipid intermediates has important physiological and clinical implications. There are two pathways for diacylglycerol synthesis. In the liver, most DAG and TAG are synthesized from the sequential acylation of glycerol-3-phosphate. However, these lipids can also be synthesized from monoacylglycerol through the monoacylglycerol acyltransferase (MGAT) pathway ( Fig. 1 ) ( 4, 5 ). The MGAT and glycerol-3-phosphate pathways are convergent and each results in the synthesis of DAG, which is then acylated to form TAG by the DAG acyltransferase (DGAT) enzymes ( Fig. 1 ). The MGAT pathway is an important TAG 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 signifi cant 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 ...

Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis

“…The finding that MGAT1 mRNA levels were increased in the PNPLA3 I148M transgenic mice is consistent with this possibility. Humans with NAFLD have recently been reported to have increased hepatic MGAT activity (51) Levels of mRNA encoding the lipid droplet-associated protein CIDEC, which were increased in the livers of PNPLA3 I148M transgenic mice, are also upregulated in other mouse models of fatty liver disease (52,53). Expression CIDEC is associated with an increase in the size of cytosolic lipid droplets in various cell types (53).…”

Inhibiting Monoacylglycerol Acyltransferase 1 Ameliorates Hepatic Metabolic Abnormalities but Not Inflammation and Injury in Mice

“…MGAT activity in human liver is substantial (10), and MGAT expression is strikingly increased in NAFLD (10 -13). Previous work using antisense oligonucleotides (ASOs) and RNAi approaches have shown that short term hepatic suppression of Mogat1 led to a significant improvement in hepatic insulin signaling and whole-body glucose homeostasis (12,13).…”

Characterization of a Novel Intestinal Glycerol-3-phosphate Acyltransferase Pathway and Its Role in Lipid Homeostasis

“…Reactions were initiated by incubating microsomal proteins with 4 M [ 14 C]decanoyl-CoA (PerkinElmer Life Sciences) in the presence or absence (control) of 35 M 2-oleoylglycerol in 50 mM HEPES (pH 7.4), 10 mM MgCl 2 , 0.001% Triton X-100, and 2.5% v/v acetone. A non-selective lipase inhibitor MAFP (methyl arachidonyl fluorophosphates) was added to block the hydrolysis of both product and substrate as previously described (24). After 30 min reactions were terminated by adding 50 l of 1% phosphoric acid.…”