Muscle-derived ANXA2 promotes hepatic steatosis by activating SREBP1c-mediated de novo lipogenesis

Hepatic steatosis, a hallmark of many liver diseases, is primarily driven by metabolic dysfunction; however, the extrahepatic regulatory mechanisms remain poorly understood. This study aimed to investigate muscle-liver crosstalk and to identify the underlying mechanisms of hepatic steatosis in patients with muscular dystrophy.

We used mouse models of muscular dystrophy, fibroadipogenic progenitor (FAP)-specific annexin A2 (ANXA2) knockout mice, and muscle biopsy samples from patients with muscular dystrophy. The correlation between serum ANXA2 levels and lipid accumulation was evaluated in both human patients and mouse models of muscular dystrophy. RNA sequencing, mass spectrometry, and peptide library analyses were performed to investigate the mechanisms underlying hepatic steatosis associated with muscular dystrophy.

We identified hepatic steatosis and hyperlipidemia in both patients and mouse models of muscular dystrophy. Using multiomic analyses, we found that muscle-resident FAPs secrete ANXA2, which functions as a key myokine driving hepatic steatosis. Muscle-specific overexpression of ANXA2 and manipulation of primary cells further confirmed this finding. In vivo FAP-specific ANXA2 ablation significantly alleviated systemic metabolic disturbances and hepatic steatosis in muscular dystrophy mouse models and high-fat diet-treated mice. Mechanistically, ANXA2 secreted by FAPs acts on hepatocyte-specific ANXA2R, promoting liver de novo lipogenesis through activation of the sterol regulatory element-binding protein 1c (SREBP1c) signaling pathway. Moreover, neutralizing ANXA2 suppressed hepatic steatosis and insulin resistance in mice. Collectively, our results demonstrate that ANXA2 derived from muscle FAPs promotes hepatic steatosis by activating SREBP1c-mediated de novo lipogenesis.

Our findings identify the ANXA2-SREBP1c axis as a novel mechanism underlying muscle-liver metabolic crosstalk, and suggest that ANXA2 may represent a potential therapeutic target for hepatic steatosis in metabolic dysfunction-associated steatotic liver disease.