Hepatic UGT2B-Mediated Testosterone Clearance Promotes Lipid Accumulation in High-Fat-Diet-Induced MASLD

Area of Science:

• Hepatology
• Endocrinology
• Metabolic Disorders

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to low testosterone in men.
• Hepatic cholesterol metabolism is altered in MASLD, yet its connection to testosterone remains unclear.

Purpose of the Study:

• To investigate the interplay between hepatic cholesterol biosynthesis, testosterone metabolism, and MASLD pathogenesis.
• To elucidate the role of uridine diphosphate-glucuronosyltransferase family 2 member B (UGT2B) enzymes in MASLD-associated testosterone changes.

Main Methods:

• Established a high-fat diet (HFD)-induced MASLD mouse model.
• Utilized transcriptomics, metabolomics, ELISA, Western blotting, and qPCR for comprehensive analysis.
• Conducted in vitro experiments with hepatocytes, oleic acid, testosterone, and UGT2B inhibitors.

Main Results:

• HFD increased hepatic cholesterol and activated cholesterol synthesis and testosterone metabolism pathways.
• UGT2B enzymes and aryl hydrocarbon receptor (AHR) were upregulated; blood testosterone initially rose then fell.
• In vitro, UGT2B inhibition restored testosterone's protective effect against lipid accumulation.

Conclusions:

• HFD induces dynamic, UGT2B-mediated hepatic testosterone metabolism in MASLD.
• Early compensatory testosterone increase is negated by enhanced UGT2B clearance, leading to depletion.
• Targeting hepatic UGT2B enzymes presents a potential therapeutic strategy for MASLD.