Hepatic glycogenesis antagonizes lipogenesis by blocking S1P via UDPG

Area of Science:

• Hepatology
• Metabolic Disease Research
• Molecular Biology

Background:

• Nonalcoholic fatty liver disease (NAFLD) is a growing health concern linked to disordered fat metabolism in hepatocytes.
• Current strategies for NAFLD prevention and treatment require a deeper understanding of cellular glucose metabolism.
• Identifying mechanisms that favor glycogen synthesis over fat storage is crucial for metabolic health.

Purpose of the Study:

• To elucidate the molecular mechanisms by which hepatocytes preferentially store glucose as glycogen instead of fat.
• To investigate the role of uridine diphosphate glucose (UDPG) in regulating lipogenesis and glycogenesis.
• To assess the therapeutic potential of UDPG in ameliorating NAFLD.

Main Methods:

• Investigated the interaction between UDPG and key regulators of lipogenesis in mouse and human hepatocytes.
• Utilized cell culture models and a mouse model of NAFLD.
• Administered UDPG to assess its effects on liver fat accumulation and glycogen synthesis.
• Examined UDPG transport to the Golgi apparatus and its effect on sterol regulatory element-binding proteins (SREBPs).

Main Results:

• Demonstrated that glycogenesis intermediate uridine diphosphate glucose (UDPG) actively antagonizes lipogenesis.
• Showed that UDPG inhibits the cleavage of sterol regulatory element-binding proteins (SREBPs) by site-1 protease (S1P) in the Golgi apparatus.
• Confirmed that UDPG administration effectively reduces fat accumulation and treats NAFLD in a mouse model and human organoids.

Conclusions:

• UDPG plays a critical role in directing glucose metabolism towards glycogen storage by inhibiting lipogenesis.
• The mechanism involves UDPG's interaction with S1P in the Golgi apparatus, preventing SREBP activation.
• UDPG represents a promising therapeutic target for managing NAFLD and other metabolic disorders characterized by hepatic fat accumulation.