Mup3 ameliorates the dysregulation of glucose and lipid metabolism in MAFLD.

Abstract

Major urinary protein 3 (Mup3), belonging to the Mup family, is involved in metabolic regulation, but the exact regulatory pathways remain to be elucidated. In this study we investigated the function of Mup3 in regulating hepatic glucose and lipid metabolism. We established four mouse models of metabolic disorders, i.e. db/db and ob/ob obese mice, high-fat diet (HFD)-induced obese (DIO) mice and mice with methionine-choline-deficient (MCD) diet-induced metabolic-associated steatohepatitis (MASH). We found that the expression levels of Mup3 were significantly reduced in the livers of all the four model mice. Moreover, upregulation of Mup3 levels in the liver of HFD-induced obese mice and db/db mice via adeno-associated virus notably decreased blood glucose levels and hepatic triglyceride (TG) content, and improved glucose tolerance and insulin sensitivity. Conversely, Mup3 gene knockout exacerbated HFD-induced hyperglycemia and hepatic lipid accumulation and worsened glucose intolerance and insulin resistance (IR). Restoring the expression of Mup3 reversed these effects in the livers of Mup3. By conducting RNA sequencing (RNA-seq) analysis we revealed that Mup3 primarily modulated gluconeogenesis and the PI3K/AKT signaling cascades. We demonstrated that Mup3 downregulated the genes associated with hepatic gluconeogenesis and lipid synthesis while attenuating hepatic inflammation. These results suggest that Mup3 plays a central role in regulating glucose and lipid balance, highlighting its significance as a prospective treatment target for metabolic disorders, including diabetes and metabolic dysfunction-associated fatty liver disease (MAFLD).