Knockdown of Salusin‐β Downregulates FTO to Inhibit Lipid Synthesis and Promote Lipolysis to Attenuate NAFLD

ABSTRACT Background Non‐alcoholic fatty liver disease is now a significant public health issue globally. Salusin‐β, a vasoactive peptide, plays a role in lipid metabolism regulation, but its mechanism remains unreported. Methods We studied the effects of Salusin‐β on lipid metabolism and its mechanism by creating a NAFLD model in C57BL/6J mice and inducing steatosis in HepG2 cells. Then, shSalusin‐β lentivirus was applied to transfect into the animals and cells, and the degree of lipid accumulation was assessed by staining and various biochemical indexes. Subsequently, Semi‐Quantitative PCR, Western Blot, molecular docking, and Co‐Immunoprecipitation were utilised to probe the downstream target FTO and then to verify the protein and mRNA changes of liposynthesis and catabolism genes downstream of FTO. Overexpressed FTO lentivirus was further employed to confirm this mechanism. Results The results showed that knockdown of Salusin‐β significantly attenuated the degree of lipid accumulation in mice and cells. In addition, shSalusin‐β inhibited the expression of FTO, thereby inhibiting the expression of downstream sterol regulatory element binding protein‐1c, fatty acid synthase, and promoting the expression of peroxisome proliferators‐activated receptors α and carnitine palmitoyl transferase 1. Transfection of overexpressed FTO then eliminated the regulatory effect of shSalusin‐β on downstream molecules. Conclusions In conclusion, knockdown of Salusin‐β reduced FTO production, thereby alleviating lipid metabolism disorders. This provides a potential mechanism for elucidating the reduction of lipid metabolism by knockdown of Salusin‐β and a potential target for the treatment of NAFLD.