He Fang, Jin Jie-Qiong, Qin Qing-Qing, Zheng Yong-Qin, Li Ting-Ting, Zhang Yun, He Jun-Dong
Medical Faculty, Kunming University of Science and Technology, Kunming, China.
Institute of Basic and Clinical Medicine, Key Laboratory for Clinical Virology, Key Laboratory for Birth Defects and Genetic Diseases, the First People's Hospital of Yunnan Province, Kunming, China.
Cell Physiol Biochem. 2018;46(5):2165-2172. doi: 10.1159/000489546. Epub 2018 Apr 28.
BACKGROUND/AIMS: Abnormal fatty acid β oxidation has been associated with obesity and type 2 diabetes. Resistin is an adipokine that has been considered as a potential factor in obesity-mediated insulin resistance and type 2 diabetes. However, the effect of resistin on fatty acid β oxidation needs to be elucidated.
We detected the effects of resistin on the expression of fatty acid oxidation (FAO) transcriptional regulatory genes, the fatty acid transport gene, and mitochondrial β-oxidation genes using real-time PCR. The rate of FAO was measured using 14C-palmitate. Immunofluorescence assay and western blot analysis were used to explore the underlying molecular mechanisms.
Resistin leads to a reduction in expression of the FAO transcriptional regulatory genes ERRα and NOR1, the fatty acid transport gene CD36, and the mitochondrial β-oxidation genes CPT1, MCAD, and ACO. Importantly, treatment with resistin led to a reduction in the rate of cellular fatty acid oxidation. In addition, treatment with resistin reduced phosphorylation of acetyl CoA carboxylase (ACC) (inhibitory). Mechanistically, resistin inhibited the activation of CREB, resulting in suppression of PGC-1α. Importantly, overexpressing PGC-1α can rescue the inhibitory effects of resistin on fatty acid β oxidation.
Activating the transcriptional activity of CREB using small molecular chemicals is a potential pharmacological strategy for preventing the inhibitory effects of resistin on fatty acid β oxidation.
背景/目的：异常的脂肪酸β氧化与肥胖和2型糖尿病相关。抵抗素是一种脂肪因子，被认为是肥胖介导的胰岛素抵抗和2型糖尿病的潜在因素。然而，抵抗素对脂肪酸β氧化的影响尚待阐明。
我们使用实时PCR检测了抵抗素对脂肪酸氧化（FAO）转录调节基因、脂肪酸转运基因和线粒体β氧化基因表达的影响。使用14C-棕榈酸酯测量FAO速率。采用免疫荧光测定和蛋白质印迹分析来探究潜在的分子机制。
抵抗素导致FAO转录调节基因ERRα和NOR1、脂肪酸转运基因CD36以及线粒体β氧化基因CPT1、MCAD和ACO的表达降低。重要的是，用抵抗素处理导致细胞脂肪酸氧化速率降低。此外，用抵抗素处理降低了乙酰辅酶A羧化酶（ACC）（抑制性）的磷酸化。从机制上讲，抵抗素抑制CREB的激活，导致PGC-1α的抑制。重要的是，过表达PGC-1α可以挽救抵抗素对脂肪酸β氧化的抑制作用。
使用小分子化学物质激活CREB的转录活性是一种潜在的药理学策略，可防止抵抗素对脂肪酸β氧化的抑制作用。
