The function of MGAT1 in alcohol-induced hepatic steatosis and treatment of hepatic steatosis via MGAT1 enzyme inhibition

Abstract

Alcohol is the major cause of hepatic steatosis, and continuous consumption can lead to hepatic fibrosis, cirrhosis, and superimposed hepatocellular carcinoma. Hepatic steatosis is especially associated with metabolic diseases such as diabetes, and it is clearly present at the start of liver diseases. However, it is unclear how the alcohol is involved in fatty liver formation. Here, I evaluate the relationships between NAD+/NADH ratio, sirtuin1 (SIRT1) and peroxisome proliferator-activated receptor γ (PPARγ), to understand the mechanism of alcoholic fatty liver. In the course of ethanol consumption, NAD+ was converted into NADH by alcohol dehydrogenase and aldehyde dehydrogenase, and subsequently SIRT1 level, which is regulated by NAD+, decreased. Decreased SIRT1 activates PPARγ, a key transcription factor involved in lipogenesis, by increasing its acetylation. Activated PPARγ increased the expression of monoacylglycerol O-acyltransferase 1 (MGAT1) gene, known to have an important role in triacylglycerol synthesis, and PPARγ accelerated alcoholic hepatic steatosis. Moreover, MGAT1 knock-down significantly attenuated the alcohol-induced hepatic lipid accumulation. This result suggests that PPARγ and its target gene, MGAT1, have an important role in alcohol-induced fatty liver as well as non-alcoholic fatty liver.

To develop MGAT inhibitor, I set up a new screening method using Ellman’s reagent, and performed the 1st screening using 2300 FDA-approved drugs. From these, 36 chemicals were shown to repress MGAT activity, and based on the structures of these chemicals, 300 additional chemicals with similar structures were screened. The final candidates came down to 20 substances. Of these, B1758 was administrated to ob/ob mice for 2 wk, showing a significant decrease in hepatic TG content and liver weight, suggesting that B1758 successfully suppresses hepatic steatosis. Taken together, the development of MGAT inhibitor may be a useful strategy to treat fatty liver disease, which, if untreated, may induce chronic liver disease such as liver cirrhosis.