Absence of the intracellular lipolytic inhibitor G0S2 enhances intravascular triglyceride clearance and abolishes diet-induced hypertriglyceridemia.

Summary

Genetic deletion of G0S2 abolishes diet-induced hypertriglyceridemia and attenuates atherogenesis by enhancing whole-body triglyceride clearance via increased LPL concentration/activity from white adipose tissue. WAT transplantation from G0S2-deficient mice normalizes plasma TG in hypertriglyceridemic mice, suggesting adipocyte G0S2 as a drug target to coordinate intracellular and intravascular lipolysis.

Key Findings

• G0S2 deletion in mice abolishes diet-induced hypertriglyceridemia and reduces atherogenesis by enhancing whole-body TG clearance.
• Increased circulating LPL concentration/activity originates predominantly from white adipose tissue; WAT transplantation from G0S2-deficient mice normalizes plasma TG.
• Absence of G0S2 improves insulin sensitivity, decreases ANGPTL4, and stabilizes adipocyte LPL protein; effects reversed by ATGL inhibition.

Clinical Implications

Pharmacologic inhibition of G0S2, or strategies that enhance adipose LPL stability/activity, could offer a novel approach to rapidly lower triglycerides and reduce atherosclerotic risk.

Limitations

• Preclinical murine data; human validation of efficacy/safety for targeting G0S2 is needed.
• Potential off-target metabolic effects and long-term consequences of modulating adipose lipolysis remain to be assessed.

Future Directions

Develop specific G0S2 inhibitors and assess triglyceride-lowering efficacy and vascular outcomes in relevant large-animal models; explore patient subsets with severe hypertriglyceridemia for early clinical translation.