Diacylglycerol acyltransferase 1/2 inhibition induces dysregulation of fatty acid metabolism and leads to intestinal barrier failure and diarrhea in mice

The intestinal metabolism and transport of triacylglycerol (TAG) play a critical role in dietary TAG absorption, and defects in the process are associated with congenital diarrhea. The final reaction in TAG synthesis is catalyzed by diacylglycerol Acyltransferase (DGAT1 and DGAT2), which uses activated fatty acids (FA) as substrates. Loss-of-function mutations in DGAT1 cause watery diarrhea in humans, but mechanisms underlying the relationship between altered DGAT activity and diarrhea remain largely unclear. Here, the effects of DGAT1 and DGAT2 inhibition, alone or in combination, on dietary TAG absorption and diarrhea in mice were investigated by using a selective DGAT1 inhibitor (PF-04620110) and DGAT2 inhibitor (PF-06424439). Simultaneous administration of a single dosing of these inhibitors drastically decreased intestinal TAG secretion into the blood circulatory system and TAG accumulation in the duodenum at 60 min after lipid gavage. Under 60% high-fat diet (HFD) feeding, their repeated simultaneous administration for 2 days induced severe watery diarrhea and occasionally led to death. The diarrhea was accompanied by enhanced fecal FA excretion, intestinal injury and barrier failure. DGAT1 or DGAT2 inhibition alone did not induce the phenotypic changes observed in DGAT1/2 inhibitor-treated mice. The results demonstrate that DGAT1/2 inhibition alters TAG absorption and results in watery diarrhea in mice. DGAT1/2 inhibition-induced diarrhea may be caused by intestinal barrier dysfunction due to dysregulation of the cytotoxic FA metabolism. These findings suggest that DGAT-mediated intestinal TAG synthesis is a vital step for maintaining intestinal barrier integrity under HFD feeding.