游离脂肪酸受体1的激活通过一条p38依赖途径改善肝脂肪变性。 - Suppr | 超能文献

Abstract

Hepatic steatosis is highly correlated with insulin resistance and diabetes. Although, it has been demonstrated that activation of free fatty acid receptor 1 (FFAR1) by agonists showed benefits for the improvement of diabetes, the effects of FFAR1 agonists on hepatic steatosis were unknown. In this study, a high fat diet (HFD)-induced hepatic steatosis animal model was utilized to evaluate the effects of an FFAR1 agonist, GW9508, on hepatic lipid accumulation, and HepG2 hepatoma cells were also used to clarify the possible mechanisms. Administration of GW9508 significantly decreased the hepatic lipid accumulation with decreased expressions of lipogenesis-related proteins in HFD mice. Knockdown of hepatic Ffar1 by lentiviral vectors containing short hairpin RNA targeted to Ffar1 diminished the effect of GW9508 in HFD mice. In addition, GW9508 decreased oleic acid-induced lipid accumulation in HepG2 cells by decreases in the expression of lipogenesis-related proteins. Moreover, GW9508 downregulated the expression of sterol regulatory element-binding protein 1 (SREBP1) through a p38-dependent pathway, whereas knockdown of Ffar1 in HepG2 cells diminished the effect of GW9508 on the decrease in SREBP1. Considering all these results together, GW9508 exerts a therapeutic effect to improve hepatic steatosis through a p38-dependent pathway. Thus, investigation of chemicals that act on FFAR1 might be a new strategy for the treatment of hepatic steatosis.

摘要

肝脂肪变性与胰岛素抵抗和糖尿病高度相关。尽管已经证明激动剂激活游离脂肪酸受体1（FFAR1）对改善糖尿病有益，但FFAR1激动剂对肝脂肪变性的影响尚不清楚。在本研究中，利用高脂饮食（HFD）诱导的肝脂肪变性动物模型来评估FFAR1激动剂GW9508对肝脏脂质蓄积的影响，同时也使用HepG2肝癌细胞来阐明可能的机制。给予GW9508可显著降低HFD小鼠的肝脏脂质蓄积，并降低脂肪生成相关蛋白的表达。用靶向Ffar1的短发夹RNA慢病毒载体敲低肝脏Ffar1可减弱GW9508对HFD小鼠的作用。此外，GW9508通过降低脂肪生成相关蛋白的表达减少了油酸诱导的HepG2细胞脂质蓄积。而且，GW9508通过p38依赖途径下调固醇调节元件结合蛋白1（SREBP1）的表达，而在HepG2细胞中敲低Ffar1可减弱GW9508对SREBP1降低的作用。综合所有这些结果，GW9508通过p38依赖途径发挥治疗作用以改善肝脂肪变性。因此，研究作用于FFAR1的化学物质可能是治疗肝脂肪变性的一种新策略。