Humanized Monoacylglycerol Acyltransferase 2 Mice Develop Non‐alcoholic Steatohepatitis and Fibrosis that Responds to Treatment with Elafibranor

Abstract

The number of individuals with non-alcoholic fatty liver disease (NAFLD) is at epidemic levels worldwide. Although thought of as benign, NAFLD can progress to more severe forms of the disease that include non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. Presently no therapies exist that can treat NAFLD and/or NASH even though this area of drug discovery has been highly active. The accumulation of triglycerides and fatty acids in the liver are linked to the initiation and progression of NAFLD. Intestinal monoacylglycerol acyltransferase 2 (MGAT2) catalyzes the resynthesis of triglycerides from dietary triglyceride-derived monoacylglycerol and fatty acids. Mice lacking mMGAT2 are resistant to obesity-dependent hepatic steatosis, a phenotype that is partially restored by expressing hMGAT2 in the intestine, suggesting that inhibiting human MGAT2 activity may be a viable option for treating NAFLD. Here, we generated transgenic hMgat2+/+ mice and characterized their responses to being fed different metabolic diets in order to test whether this cohort could be used as a model to test drug efficacy. hMgat2+/+ mice fed a steatotic diet acquired NAFLD and had elevated levels of several inflammatory cytokines in the liver, indicating the presence of ongoing NASH. Hydroxyproline and galectin-3 levels were highly elevated, and correlated with the degree of fibrosis seen by histology. hMgat2+/+ mice fed a high fat diet became obese, were glucose intolerant, and acquired insulin resistance, suggesting the onset of diabetes. The majority of phenotypes observed with both diets were attenuated by treatment with the PPARa/d agonist, elafibranor. Thus, hMgat2+/+ mice may be an excellent “humanized” model that can be used for testing drug efficacy targeting systemic hMGAT2 activity, and undoubtedly be invaluable in furthering our understanding of how hMGAT2 activity affects overall triglyceride metabolism.