Faster lipid β‐oxidation rate by acetyl‐CoA carboxylase 2 inhibition alleviates high‐glucose‐induced insulin resistance via SIRT1/PGC‐1α in human podocytes
| Autor: | Bing Zhao, Jingshu Sun, Simeng Wang, Qinglian Wang, Rong Wang, Jie Zhang, Ying Xu, Xinyu Zhang |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Health Toxicology and Mutagenesis Toxicology Biochemistry Podocyte 03 medical and health sciences 0302 clinical medicine Insulin resistance Sirtuin 1 Downregulation and upregulation Internal medicine medicine Humans RNA Small Interfering Molecular Biology 030102 biochemistry & molecular biology biology Podocytes Chemistry Glucose transporter Acetyl-CoA carboxylase General Medicine Lipid Metabolism medicine.disease Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Pyruvate carboxylase Glucose medicine.anatomical_structure Endocrinology Lipotoxicity 030220 oncology & carcinogenesis biology.protein Molecular Medicine Insulin Resistance Oxidation-Reduction GLUT4 Acetyl-CoA Carboxylase |
| Zdroj: | Journal of Biochemical and Molecular Toxicology. 35 |
| ISSN: | 1099-0461 1095-6670 |
| DOI: | 10.1002/jbt.22797 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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