Hepatic GAL1 deficiency alleviates steatosis via WWP2-mediated PARP1 degradation and activation of the SIRT1-CPT1A pathway.

BACKGROUND

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver disease worldwide and is closely associated with obesity, diabetes, and other metabolic disorders. Because MASLD progression poses serious health risks, elucidating the underlying mechanisms is essential to guide early intervention and therapeutic strategies.

METHODS

Proteomic analysis was used to identity high-fat diet (HFD)-induced proteins in mouse liver. Galectin-1 (GAL1) expression was assessed via immunohistochemistry in human liver tissues. Liver-specific GAL1-deficient mice were generated using adeno-associated virus. Mice were fed either a chow diet or an HFD. Functional studies were performed in cell lines using western blotting, RT-qPCR, immunofluorescence, co-immunoprecipitation, mass spectrometry, and molecular docking analysis.

RESULTS

GAL1 expression was elevated in liver tissues from patients with MASLD and in mouse models. Liver-specific GAL1 knockdown alleviated hepatic steatosis and enhanced fatty acid oxidation (FAO). Mechanistically, GAL1 competitively bound to the BRCT domain of poly (ADP-ribose) polymerase 1 (PARP1), thereby interfering with its interaction with the WW domain -containing E3 ubiquitin protein ligase 2 (WWP2). Hepatic GAL1 knockdown promoted the PARP1 -WWP2 interaction and subsequently facilitated ubiquitin-dependent degradation of PARP1. This degradation led to increased NAD+ levels, which in turn activated the SIRT1-CPT1A pathway, thereby promoting FAO and alleviating hepatic steatosis.

CONCLUSION

Hepatic deficiency of GAL1 alleviates hepatic steatosis by enhancing FAO through promotion of ubiquitin-dependent PARP1 degradation, thereby restoring NAD+ levels and activating the SIRT1-CPT1A pathway.