Humanized Monoacylglycerol Acyltransferase 2 mice Become Obese and develop Metabolic Dysfunction-Associated Steatotic Liver Disease when fed a High Fat Diet

Objective: Elevated monoacylglycerol acyltransferase 2 (hMOGAT2) expression is seen in individuals having obesity and mice lacking mMGAT2 activity are resistant to diet-induced obesity. Whether hMOGAT2 inhibitors have therapeutic value in treating obesity requires the use of physiologically relevant pre-clinical models to test for drug efficacy. Methods: Here we characterized how humanized hMOGAT2 mice globally expressing hMOGAT2 responded metabolically to being fed a high fat diet. Results: hMOGAT2 and mMgat2 mice fed a high fat diet became obese, glucose-intolerant, and insulin resistant. Blood triglycerides and cholesterol levels were markedly elevated, as were liver triglycerides. Histological staining revealed the presence of metabolic dysfunction-associated steatotic liver disease (MASLD) and the beginning stages of metabolic dysfunction-associated steatohepatitis (MASH). Liver and adipose pAKTSer473 levels were decreased indicating defects in insulin signaling leading to pre-diabetes. Liver gluconeogenesis and de novo lipogenesis were likely increased based on the elevated gene expressions of Srebp2, Fasn, Pck1, and G6pc. TGF-β1-driven hepatic stellate cell activation led to extracellular matrix formation and increased pJNK-pSMAD2 and pJAK2-pSTAT5 signaling, contributing to hepatocyte apoptosis. Liver IL-4 and IL-13 levels were elevated further driving collagen deposition and the transition from MASLD to MASH. Conclusions: Results showing that humanized hMOGAT2 mice respond like mMgat2 mice lend support for their use as an in vivo preclinical efficacy model for testing hMOGAT2 inhibitors and for studying hMOGAT2 activity in the context of obesity