Dimethyl fumarate improves non-alcoholic fatty liver disease by regulating SIRT1 signal to inhibit MAMs over-enrichment.

Non-alcoholic fatty liver disease (NAFLD) is a complex metabolic disorder of the liver with an increasing global prevalence. Despite significant advancements in understanding NAFLD, effective therapeutic strategies remain limited. Mitochondria-associated membranes (MAMs) are specialized domains of the endoplasmic reticulum (ER) that closely interact with mitochondria and play a crucial role in regulating Ca2+ homeostasis. Our previous research demonstrated that dimethyl fumarate (DMF) alleviates NAFLD by modulating hepatic Ca2+ homeostasis. However, the precise mechanisms remain unclear. In this study, we found that DMF significantly alleviated lipid accumulation in NAFLD mice by inhibiting excessive MAMs enrichment. Mechanistically, DMF improved mitochondrial function by reducing mitochondrial Ca2+ overload and oxidative stress caused by MAMs over-enrichment. Furthermore, our results demonstrated that protective effects of DMF against NAFLD are dependent on Sirtuin-1 (SIRT1) regulation. Inhibition of SIRT1 markedly reversed the ability of DMF to suppress MAMs over-enrichment in both in vitro and in vivo models. Moreover, the beneficial effects of DMF on oxidative stress, mitochondrial dysfunction, and hepatic steatosis were abrogated by co-administration of EX527, a selective SIRT1 inhibitor. In summary, our findings demonstrate that DMF alleviates mitochondrial Ca2+ dysregulation caused by aberrant MAMs enrichment, thereby reducing oxidative stress and mitochondrial dysfunction, ultimately inhibiting lipid accumulation in hepatocytes. These results provide new insights into the therapeutic potential of DMF for NAFLD treatment.