Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei 230032, China.
Life Sci. 2016 Jul 15;157:158-167. doi: 10.1016/j.lfs.2016.06.008. Epub 2016 Jun 11.
Fenofibrate (FF) is commonly used clinically as a lipid-lowering drug, but whether it participates in endoplasmic reticulum (ER) stress and decreases inflammation in skeletal muscle is still unknown. The aim of this study is to determine whether FF treatment reduces insulin resistance (IR) by alleviating ER stress and downstream inflammation in skeletal muscle tissues and cells.
Female SD rats were randomly divided into groups receiving the standard chow diet (SCD), a high-fat diet (HFD), or HFD plus FF (HFD+FF). The rats in the latter two groups were subjected to a standard HFD for 20weeks, then the HFD+FF rats were administered FF (30mg/kg once daily via gavage) for another 8weeks. Whole-body IR, expression of peroxisome proliferator-activated receptor α (PPARα), ER stress-related genes, and inflammatory genes in the soleus muscle were assessed. The differentiated C2C12 myotubes were treated with palmitic acid or pretreated with fenofibric acid or 4-phenylbutyric acid (4-PBA), etomoxir, and the expression of ER stress, beta-oxidation-related genes, inflammatory genes, Toll-like receptor 4 (TLR4), and insulin-signaling-related molecules were determined.
Eight weeks of FF treatment attenuated HFD-induced IR by decreased tribbles 3 (TRB3) expression, ER stress and inflammation in skeletal muscle. FA pretreatment markedly inverted the PA-induced expression of TLR4 and downstream inflammatory genes, activated ER stress, improved β-oxidation and insulin signaling in differentiated myotube cells.
FF treatment significantly improved HFD-induced IR in skeletal muscle and PA-induced IR in myotube cells, which may be related to reduced ER stress-induced inflammation.
非诺贝特（FF）临床上常被用作降脂药物，但它是否参与内质网（ER）应激并降低骨骼肌炎症尚不清楚。本研究旨在确定 FF 治疗是否通过减轻骨骼肌组织和细胞的 ER 应激和下游炎症来改善胰岛素抵抗（IR）。
雌性 SD 大鼠随机分为接受标准饲料（SCD）、高脂肪饮食（HFD）或 HFD 加 FF（HFD+FF）的组。后两组大鼠接受标准 HFD 喂养 20 周，然后 HFD+FF 大鼠再给予 FF（30mg/kg 每日一次灌胃）治疗 8 周。评估腓肠肌中全身 IR、过氧化物酶体增殖物激活受体α（PPARα）表达、ER 应激相关基因和炎症基因。用棕榈酸处理分化的 C2C12 肌管或用非诺贝特酸或 4-苯丁酸（4-PBA）、埃托莫西汀预处理，测定 ER 应激、β-氧化相关基因、炎症基因、Toll 样受体 4（TLR4）和胰岛素信号相关分子的表达。
8 周的 FF 治疗通过降低三肽重复蛋白 3（TRB3）表达、骨骼肌 ER 应激和炎症来减轻 HFD 诱导的 IR。FA 预处理显著逆转了 PA 诱导的 TLR4 及其下游炎症基因的表达，激活了分化肌管细胞的 ER 应激，改善了β-氧化和胰岛素信号。
FF 治疗可显著改善 HFD 诱导的骨骼肌 IR 和 PA 诱导的肌管细胞 IR，这可能与减轻 ER 应激诱导的炎症有关。
