Irisin Alleviates Impaired Mitochondrial Fusion via Enhancing PKA/SIRT3/mTOR Pathway in Hepatic Steatosis

Hepatic steatosis, a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), arises from disrupted lipid homeostasis. Mitochondrial dysfunction, particularly imbalances in mitochondrial fusion and fission, plays a crucial role in MASLD progression. Irisin, an exercise-induced myokine, is involved in lipid metabolism, though its precise mechanisms of action remain unclear. An irisin-Fc fusion protein was prophylactically administered to mice with high-fat diet (HFD)-induced MASLD for 12 weeks. Liver tissues were analyzed using oil red O staining and hepatic and serum lipid profiling to evaluate irisin's therapeutic efficacy. Expression levels of proteins involved in fatty acid metabolism and mitochondrial dynamics were assessed. In palmitate (PA)-treated HepG2 cells, mitochondrial morphology was analyzed, and fatty acid uptake was determined through colocalization of fluorescently labeled PA with mitochondria. PKA activity and SIRT3 expression were validated using a PKA agonist/inhibitor and SIRT3 overexpression or knockdown via plasmid transfection and siRNA. Irisin significantly reduced lipid accumulation in HFD-induced MASLD mouse models and PA-treated HepG2 cells. These effects were associated with enhanced mitochondrial fusion, indicated by increased expression of mitofusin 2 and optic atrophy type 1 and reduced excessive fission, evidenced by decreased activation of dynamin-related protein 1. These changes were mediated partly through PKA/SIRT3/mTOR pathway activation, which facilitated mitochondrial fatty acid uptake and β-oxidation while inhibiting lipogenesis. Our results demonstrate the protective role of irisin in alleviating hepatic steatosis by regulating mitochondrial dynamics. These findings provide valuable evidence of the antisteatogenic mechanisms of irisin and its therapeutic potential for MASLD management.