Renalase deficiency suppresses hepatic triglyceride accumulation in the progression to MASLD / MASH by GAN diet in male mice

Abstract Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a growing public health concern characterized by hepatic triglyceride (TG) accumulation, inflammation, and fibrosis. Renalase is known for its role in blood pressure regulation and catecholamine metabolism, but recent evidence suggests broader cytokine‐like functions. Moreover, its involvement in MASLD remains unclear. In this study, we examined the effects of renalase deficiency on hepatic lipid metabolism in a Gubra Amylin NASH (GAN) diet‐induced MASLD model using renalase knockout (KO) mice. Our results show that renalase KO mice exhibited reduced hepatic TG levels, accompanied by decreased gene and protein expression of Srebf1 involved in lipid synthesis, and lower gene expressions of antioxidant and fibrosis markers in KO‐GAN compared with wild type (WT)‐GAN. Additionally, in vitro experiments using AML12 cells with renalase knockdown confirmed reduced intracellular TG accumulation and lipid synthesis gene expression. Notably, the phosphorylation of Akt was significantly reduced in the liver of renalase‐KO mice, indicating that Akt signaling plays a critical role in the observed decrease in hepatic TG levels. These findings suggest that renalase regulates hepatic lipid metabolism through the Akt–Srebf1 pathway, and its deficiency attenuates TG accumulation, suggesting that renalase may modulate early hepatic lipid deposition that progresses toward MASLD.