Faster lipid β‐oxidation rate by acetyl‐CoA carboxylase 2 inhibition alleviates high‐glucose‐induced insulin resistance via SIRT1/PGC‐1α in human podocytes

Abstract Diabetic nephropathy (DN) is becoming a research hotspot in recent years because the prevalence is high and the prognosis is poor. Lipid accumulation in podocytes induced by hyperglycemia has been shown to be a driving mechanism underlying the development of DN. However, the mechanism of lipotoxicity remains unclear. Increasing evidence shows that acetyl‐CoA carboxylase 2 (ACC2) plays a crucial role in the metabolism of fatty acid, but its effect in podocyte injury of DN is still unclear. In this study, we investigated whether ACC2 could be a therapeutic target of lipid deposition induced by hyperglycemia in the human podocytes. Our results showed that high glucose (HG) triggered significant lipid deposition with a reduced β‐oxidation rate. It also contributed to the downregulation of phosphorylated ACC2 (p‐ACC2), which is an inactive form of ACC2. Knockdown of ACC2 by sh‐RNA reduced lipid deposition induced by HG. Additionally, ACC2‐shRNA restored the expression of glucose transporter 4 (GLUT4) on the cell surface, which was downregulated in HG and normalized in the insulin signaling pathway. We verified that ACC2‐shRNA alleviated cell injury, apoptosis, and restored the cytoskeleton disturbed by HG. Mechanistically, SIRT1/PGC‐1α is close related to the insulin metabolism pathway. ACC2‐shRNA could restore the expression of SIRT1/PGC‐1α, which was downregulated in HG. Rescue experiment revealed that inhibition of SIRT1 by EX‐527 counteracted the effect of ACC2‐shRNA. Taken together, our data suggest that podocyte injury mediated by HG‐induced insulin resistance and lipotoxicity could be alleviated by ACC2 inhibition via SIRT1/PGC‐1α.