Regulatory role of sirtuin-1 by targeting MDM2 to mitochondria-associated membranes formation in the treatment of NAFLD

Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder characterized by excessive fat accumulation in the liver. Aberrant enrichment of mitochondria-associated membranes (MAMs) plays a significant role in promoting the overproduction of reactive oxygen species (ROS). However, the precise role of MAMs in NAFLD and the potential targets regulating MAMs formation remain unclear.This study demonstrated that SIRT1 inhibits abnormal MAM enrichment in the livers of NAFLD mice and PA-incubated hepatocytes. Moreover, the protective effects of SIRT1 against NAFLD caused by excessive caloric intake are closely associated with its ability to block MAMs-induced mitochondrial Ca²⁺ overload. This regulation alleviates Ca²⁺ dysregulation and subsequently inhibits ROS overproduction-mediated mitochondrial dysfunction. Transcriptomic analysis confirmed that mouse double minute 2 homolog (MDM2) may acts as a downstream target of activated SIRT1 in regulating MAMs formation and thereby protecting against the development of NAFLD. Taken together, this reseach revealed that SIRT1 activation inhibits the aberrant formation of MAMs caused by excessive calorie intake. This effect is linked to the suppression of MDM2 expression and disruption of its interaction of MDM2 with resident MAMs Ca2 + channels by SIRT1, ultimately alleviating mitochondrial Ca²⁺ overload induced mitochondria oxidative stress.