Melatonin regulates accumulation of lipids in the liver via the IP3R on the mitochondria-associated membranes (MAMs)

Nonalcoholic fatty liver disease (NAFLD) is a common metabolic disease of the liver that can progress to hepatitis, cirrhosis, and even cancer in extreme cases. In this study, we investigated the effect of Melatonin (Mel) on lipid accumulation and explored the molecular mechanism behind it. Mel treatment reduced lipid accumulation and enhanced autophagy in oleic acid (OA) + palmitic acid (PA)-induced cells. Notably, Mel could regulate the inositol 1,4,5-triphosphate receptor (IP3R) pathway in OA + PA-induced cells and form hydrogen bonds with the IP3R protein. Interestingly, when cells were transfected with siRNA-IP3R, the regulatory effects of Mel on lipid accumulation and autophagy were lost in OA + PA-induced cells. We found that this might be due to Mel-regulated IP3R acting on the AMPK/mTOR pathway rather than on Bcl-2 and Beclin1. More importantly, we found that Mel could reduce the increase in MAMs caused by OA + PA-induced cells. And the integrity of MAMs could influence the role of Mel in regulating IP3R, as well as the regulation of lipid accumulation and autophagy by Mel. In summary, this study revealed that Mel has the function of ameliorating lipid accumulation by regulating the expression of IP3R on MAMs. This is because Mel-regulated IP3R can induce autophagy and alleviate lipid accumulation. This provides a new theoretical basis for Mel to regulate lipid accumulation.