VPS13C regulates triglyceride homeostasis and adipocyte differentiation

Background Hypertriglyceridemia is a major risk factor for cardiometabolic diseases. VPS13C is a genome-wide significant locus for triglyceride with an incomplete understanding of its functional role in triglyceride biology. In this study, we investigated the transcriptomic associations and functional roles of VPS13C in triglyceride metabolism. Methods We analyzed VPS13C expression in subcutaneous adipose tissue and assessed fasting serum lipid levels (including total cholesterol and triglycerides) in participants from the Africa America Diabetes Mellitus (AADM) study. In parallel, we conducted functional studies in 3T3-L1 mouse adipocytes, where Vps13c was knocked down using siRNA. We then evaluated markers of adipogenesis, lipogenesis, and triglyceride metabolism. Results In human subjects, VPS13C expression in subcutaneous adipose tissue was inversely associated with fasting triglyceride levels but showed non-significant correlation with total cholesterol. In 3T3-L1 cells, Vps13c knockdown impaired adipocyte differentiation, evidenced by reduced lipid droplet formation and lower intracellular levels of triglycerides, glycerol, and fatty acids. This knockdown also led to significant downregulation of Pparg expression and suppression of PPARγ-mediated pathways, as well as genes involved in adipogenesis and lipogenesis. Conclusion VPS13C is associated with circulating triglyceride levels and plays a critical role in adipocyte differentiation, adipogenesis and lipogenesis. These findings suggest that VPS13C may play an important role in triglyceride-related metabolic disorders.