SENP3 senses oxidative stress-induced deSUMOylation of PPARα which functions in zinc alleviating high-fat-induced hepatic lipotoxicity in zebrafish

Zinc (Zn) is reported to participate in the regulation of lipid metabolism, but its function against metabolic dysfunction-associated steatotic liver disease (MASLD) remains elusive. Here, using male zebrafish as a model, we evaluated the influence and mechanism of dietary Zn supplementation in alleviating high-fat diet (HFD)-induced MASLD. Dietary Zn supplementation significantly alleviated HFD-induced lipid deposition, mitochondrial damage, oxidative stress, and the decline of β-oxidation levels, and ameliorated HFD-induced decrease of peroxisome proliferator-activated receptor alpha (PPARα) and SUMO2/3 protein expression and the oxidative stress-associated increase of nuclear factor erythroid 2-related factor 2 (NRF2), deSUMOylation enzymes (SENP1, SENP2, and SENP3) protein expression. Mechanistically, Zn attenuated oxidative stress-induced activation of the NRF2/SENP3 pathway, promoted SUMO3-dependent PPARα SUMOylation at Lys180, and inhibited SENP3-mediated deSUMOylation. Moreover, PPARα SUMOylation enhanced its protein stability and nuclear localization and was associated with increased downstream target-gene expression, thereby contributing to fatty acid β-oxidation and the attenuation of HFD-induced MASLD. Overall, our findings support a mechanistic model involving the mtROS-NRF2-SENP3-PPARα axis in Zn-mediated alleviation of HFD-induced hepatic lipotoxicity, while not excluding contributions from additional Zn-responsive pathways. These findings provided a novel insight into the prevention and treatment of MASLD, and suggested that SENP3 may serve as a potential therapeutic target.