Hepatic mTOR-AKT2-Insig2 signaling pathway contributes to the improvement of hepatic steatosis after Roux-en-Y Gastric Bypass in mice
Hepatic mTOR-AKT2-Insig2 signaling pathway contributes to the improvement of hepatic steatosis after Roux-en-Y Gastric Bypass in mice
复制标题
肝脏 mTOR-AKT2-Insig2 信号通路有助于改善小鼠 Roux-en-Y 胃绕道术后肝脏脂肪变性
DOI：
10.1016/j.bbadis.2018.12.014
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发表时间：
2019-03-01
影响因子：
6.2
通讯作者：
Xu, Geyang
中科院分区：
文献类型：
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作者：
Pan, Qinling;Qin, Tingfeng;Xu, Geyang
Roux-en-Y胃旁路(RYGB)仍是治疗非酒精性脂肪性肝病(NAFLD)最有效的选择之一。然而，潜在的机制尚不清楚。在这里，我们评估了肥胖小鼠在接受或不接受RYGB手术后，肝脏机制靶雷帕霉素(MTOR)-AKT2-胰岛素诱导基因2(Insig2)信号、成脂转录因子和脂肪合成酶之间的关系。DMSO和雷帕霉素饮食诱导肥胖(DIO)小鼠肝脏mTOR活性和Insig2a活性均受到刺激，而AKT2、类固醇反应元件结合蛋白1c(SREBP1c)、过氧化物酶体增殖物激活受体γ(PPAR Gamma)、乙酰辅酶A羧基酶(ACC)和脂肪酸合成酶(Fas)等造脂基因表达均降低。RYGB能明显逆转雷帕霉素诱导的DIO小鼠肝脏脂肪生成增加和mTOR信号转导减弱。RYGB通过抑制新生脂肪生成显著改善高脂饮食和雷帕霉素诱导的肝脏脂肪变性。尾静脉注射腺病毒介导的p70核糖体蛋白亚基6激酶1(Ad-S6K1)可改善肝脏脂肪变性。在DIO小鼠中，注射Ad-S6K1抑制AKT2、SREBP1c、PPARγ和脂肪生成相关基因，同时刺激Insig2a。Ad-S6K1可减少油酸诱导的小鼠原代肝细胞脂质沉积。提示mTOR-AKT2-Insig2信号通路参与了RYGB对高脂饮食诱导的肝脏脂肪变性的改善作用。
Roux-en-Y Gastric Bypass (RYGB) remains one of the most effective options in treatment of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms are not clear yet. Here, we evaluated the relationship among hepatic mechanistic target of rapamycin (mTOR)-AKT2-insulin-induced gene 2 (Insig2) signaling, lipogenic transcription factors and lipid synthesis enzymes in obese mice with or without RYGB operation. Hepatic mTOR activity and Insig2a were stimulated, while AKT2, sterol response element-binding protein 1c (SREBP1c), peroxisome proliferator-activated receptor gamma (PPAR gamma), lipogenic genes such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) were decreased by Roux-en-Y Gastric Bypass in both DMSO and rapamycin treated diet-induced obese (DIO) mice. Increment of hepatic lipogenesis and decline of mTOR signaling induced by rapamycin were significantly reversed by RYGB in DIO mice. RYGB significantly improved high-fat diet- and rapamycin- induced hepatic steatosis by suppression of de novo lipogenesis. Administration of adenovirus-mediated p70 ribosomal protein subunit 6 kinase 1 (Ad-S6K1) from tail vein improved hepatic steatosis. Infusion of Ad-S6K1 suppressed AKT2, SREBP1c, PPAR gamma, and lipogenesis-related genes while stimulating Insig2a in DIO mice. Ad-S6K1 decreased oleic acid-induced lipid deposition in primary mouse hepatocytes. Our results suggest that mTOR-AKT2-Insig2 signaling pathway contributes to the improvement effect of RYGB on hepatic steatosis induced by high-fat diet.