SIRT5 Facilitates Liver Steatosis Progression via Promoting SDH Desuccinylation During High‐Fat Diet Feeding

Background and Aims Obesity is one of the main factors that causes liver steatosis. While the mechanism remains to be elucidated. Methods SIRT5 was knocked down in male C57/BL6 mice via tail vein injection of adenovirus, which were then fed either normal chow or a high‐fat diet. Glucose and lipid content was detected in the serum, and the liver tissue was harvested for further analysis. We also used primary rat hepatocytes and a hepatocyte cell line L02 cells to explore the role of SIRT5 in regulating lipid overload‐induced hepatocyte injury. Finally, rAAV‐induced SDHC knockdown was applied to investigate the role of SDHC in HFD‐induced liver steatosis. Results High‐fat diet results in upregulation of SIRT5 and causes desuccinylation of mitochondrial proteins including SDH. Adenovirus‐driven SIRT5 knockdown of SIRT5 induces alleviated high‐fat diet‐induced hepatic injury and preserves mitochondrial function. We also show that SIRT5 knockdown reduces oxidative stress of hepatocytes both in vivo and in vitro. Mechanistically, SIRT5 in hepatocytes facilitates the desuccinylation of mitochondrial proteins including SDH, reducing SDH activity, which results in mitochondrial dysfunction. Furthermore, SIRT5 specifically inhibits the expression of SDHC at the post‐transcriptional level, and SDHC knockdown deteriorates lipid overload‐induced hepatic lipotoxicity. Conclusion and Implications Our findings underscore the critical role of SIRT5 in the progress of liver steatosis and provide novel insights into the regulation of SDH by SIRT5‐mediated desuccinylation that affects mitochondrial function. Moreover, our results suggest that targeting SIRT5 may offer a therapeutic strategy for liver steatosis.