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.

• Authors: Qinglian Wang, Bing Zhao, Jie Zhang, Jingshu Sun, Simeng Wang, Xinyu Zhang, Ying Xu, Rong Wang
• Journal: Journal of biochemical and molecular toxicology (J Biochem Mol Toxicol) Vol. 35 Issue 7 Pg. e22797 (Jul 2021) ISSN: 1099-0461 [Electronic] United States
• PMID: 33957017 (Publication Type: Journal Article)
• Copyright: © 2021 Wiley Periodicals LLC.

Chemical References

• PPARGC1A protein, human
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• RNA, Small Interfering
• SIRT1 protein, human
• Sirtuin 1
• ACACB protein, human
• Acetyl-CoA Carboxylase
• Glucose

Topics

• Acetyl-CoA Carboxylase (antagonists & inhibitors, genetics, metabolism)
• Glucose (pharmacology)
• Humans
• Insulin Resistance
• Lipid Metabolism
• Oxidation-Reduction
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (genetics, metabolism)
• Podocytes (metabolism)
• RNA, Small Interfering (genetics, pharmacology)
• Sirtuin 1 (genetics, metabolism)