Sleeve gastrectomy improves lipid dysmetabolism by downregulating the USP20-HSPA2 axis in diet-induced obese mice

INTRODUCTION: Obesity is a metabolic disease accompanied by abnormalities in lipid metabolism that can cause hyperlipidemia, non-alcoholic fatty liver disease, and artery atherosclerosis. Sleeve gastrectomy (SG) is a type of bariatric surgery that can effectively treat obesity and improve lipid metabolism. However, its specific underlying mechanism remains elusive. METHODS: We performed SG, and sham surgery on two groups of diet-induced obese mice. Histology and lipid analysis were used to evaluate operation effect. Immunohistochemistry, immunoblotting, real-time quantitative PCR, immunoprecipitation, immunofluorescence and mass spectrometry were used to reveal the potential mechanisms of SG. RESULTS: Compared to the sham group, the SG group displayed a downregulation of deubiquitinase ubiquitin-specific peptidase 20 (USP20). Moreover, USP20 could promote lipid accumulation in vitro. Co-immunoprecipitation and mass spectrometry analyses showed that heat-shock protein family A member 2 (HSPA2) potentially acts as a substrate of USP20. HSPA2 was also downregulated in the SG group and could promote lipid accumulation in vitro. Further research showed that USP20 targeted and stabilized HSPA2 via the ubiquitin-proteasome pathway. CONCLUSION: The downregulation of the USP20-HSPA2 axis in diet-induced obese mice following SG improved lipid dysmetabolism, indicating that USP20-HSPA2 axis was a noninvasive therapeutic target to be investigated in the future.