Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism

Area of Science:

• Biochemistry
• Molecular Biology
• Metabolic Diseases

Background:

• Excess nutrient accumulation impairs liver function and is linked to obesity-related nonalcoholic fatty liver disease (NAFLD).
• The molecular signals mediating hepatocyte adaptation to obesogenic diets are not fully understood.
• Post-translational modification by small ubiquitin-like modifier (SUMO) dynamically regulates cellular processes, including gene expression.

Purpose of the Study:

• To investigate the role of Prox1 SUMOylation in regulating hepatic fasting metabolism.
• To determine if nutrient-sensitive SUMOylation of Prox1 is altered in diet-induced obesity.
• To explore therapeutic potential of modulating Prox1 SUMOylation for metabolic health.

Main Methods:

• Analysis of Prox1 SUMOylation status in mice under different feeding conditions (ad libitum, refed, fasted).
• Generation and use of hepatocyte-selective SUMOylation-deficient Prox1 mutant mice.
• High-fat/high-fructose diet feeding to induce obesity.
• Measurement of systemic cholesterol levels and liver bile acid detoxifying pathways.

Main Results:

• Prox1 SUMOylation at lysine 556 is sensitive to fasting cues in normal mice but becomes less sensitive in diet-induced obesity.
• Hepatocyte-specific knock-in of a SUMOylation-deficient Prox1 mutant reduced systemic cholesterol.
• This genetic modification induced liver bile acid detoxifying pathways during fasting in obese mice.

Conclusions:

• Prox1 SUMOylation acts as a nutrient-sensitive regulator of hepatic fasting metabolism.
• Dysregulated Prox1 SUMOylation in obesity contributes to metabolic dysfunction.
• Targeting the Prox1 SUMOylation switch could be a novel therapeutic strategy for metabolic diseases.