May 2012

Cutting the fat: potential new drug target for treating lipid accumulation in fatty liver

JLR news

 

Obese people often have significant lipid accumulation in the liver, which is associated with the development of insulin resistance and diabetes. One form of lipid that may accumulate, diacylglycerol, is predominately synthesized through an acylation pathway. But it has been hypothesized that an alternative pathway of synthesizing diacylglycerol from monoacylglycerol, utilizing a class of enzymes known as monoacylglycerol acyltransferases (MGATs), may contribute to these accumulating amounts of lipids in the liver.

In an article titled “Evidence for regulated monoacylglycerol acyltransferase expression and activity in human liver” by Angela M. Hall at the Center for Human Nutrition at Washington University at St. Louis and colleagues, MGAT activity and the expression of three genes known to encode MGATs (MOGAT1, MOGAT2 and MOGAT3) were examined from liver biopsy samples obtained from obese study participants before and after they underwent gastric bypass surgery (1). The results of this study are published in the May issue of the Journal of Lipid Research.

journal_news_JLR_figure_v2 
Two convergent pathways for triacylglycerol biosynthesis. The stepwise acylation of glycerol through the two pathways for triacylglycerol synthesis are shown. Abbreviations: fatty acid (FA), glycerol-3-phosphate (G-3-P), G-3-P acyltransferase (GPAT), lysophosphatidic acid (LPA), acylglycerol-3-phosphate acyltransferase (AGPAT), phosphatidic acid (PA), monoacylglycerol (MAG), MAG acyltransferase (MGAT), diacylglycerol (DAG), DAG acyltransferase (DGAT), and triacylglycerol (TAG).
































All three MOGAT genes were shown to be readily expressed in the liver. However, only MOGAT3’s expression correlated with MGAT activity, while the expression of the other two genes were not. MOGAT expression also was compared in patients before and a year after gastric bypass surgery: Expression of MOGAT2 and MOGAT3 were significantly lower after surgery than before.

These results were compared with MOGAT expression in people with nonalcoholic fatty liver disease, who had significantly higher MOGAT2 and MOGAT3 expression when stacked up against control participants. Their data suggest that when a person has fatty liver disease MOGAT2 and MOGAT3 expression is upregulated. But when a patient experiences marked weight loss, the body corrects this increased expression to effectively lower it. This up- and downregulation appears to be dynamic, so the increased or decreased activity of these MGATS are expected to depend on an individual’s health status.

Taken together, the research presented in this study indicates drugs that specifically target MOGAT3 have the potential to provide therapeutic treatment for obese people with insulin resistance, diabetes and other lipid abnormalities related to fatty liver. Targeting this one gene could head off or prevent lipid accumulation in the liver altogether.

REFERENCE
  1. 1. Hall, A.N. J. Lipid Research (2012) doi: 10.1194/jlr.P025536.

Mary L. Chang (mchang@asbmb.org) is managing editor of the Journal of Lipid Research and coordinating journal manager of Molecular and Cellular Proteomics.


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