GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway
GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway
复制标题
DOI：
10.1016/j.bbrc.2016.05.086
复制
发表时间：
2016-08-05
影响因子：
3.1
通讯作者：
Dong, Ming
中科院分区：
文献类型：
--
作者：
He, Qin;Sha, Sha;Dong, Ming
非酒精性脂肪性肝病（NAFLD）的发病率逐年上升，NAFLD正迅速成为全球最常见的肝病。临床研究发现，胰高血糖素样肽-1（GLP-1）类似物利拉鲁肽（LRG）不仅可以降低血糖水平，还可以改善肝脂肪酶，尤其是在2型糖尿病（T2 DM）患者中。此外，增强自噬减少肝细胞中的脂质积累。本研究的目的是探讨LRG对肝细胞脂肪变性的影响以及自噬的可能作用。我们用高脂饮食（HFD）建立肥胖小鼠模型，并在人L-O2细胞中用游离脂肪酸（FFA）诱导肝细胞脂肪变性。各组分别加入LRG和两种自噬抑制剂氯喹（CQ）和巴弗洛霉素A1（Baf）。检测各组的脂质谱和形态学改变。本研究采用免疫组织化学、免疫荧光染色和透射电子显微镜（TEM）检测自噬。Western blot检测SQSTM 1（P62）、LC 3B、沿着mTOR、磷酸化mTOR（p-mTOR）、AMPK、磷酸化AMPK（p-AMPK）和Beclin 1等信号通路蛋白的表达。我们的研究结果表明，LRG通过诱导自噬改善肝细胞脂肪变性，并参与AMPK/mTOR通路。这些发现提示了LRG对肝脏脂肪变性的积极作用的重要机制，并为LRG在NAFLD的临床应用提供了新的证据。(C)2016 Elsevier Inc. All rights reserved.
The incidence of nonalcoholic fatty liver disease (NAFLD) keeps rising year by year, and NAFLD is rapidly becoming the most common liver disease worldwide. Clinical studies have found that glucagon-like peptide-1 (GLP-1) analogue, liraglutide (LRG), cannot only reduce glucose levels, but also improve hepatic lipase, especially in patients also with type 2 diabetes mellitus (T2DM). In addition, enhancing autophagy decreases lipid accumulation in hepatocytes. The aim of the present study is to explore the effect of LRG on hepatocyte steatosis and the possible role of autophagy. We set up an obesity mouse model with a high-fat diet (HFD) and induced hepatocyte steatosis with free fatty acids (FFA) in human L-O2 cells. LRG and two inhibitors of autophagy, Chloroquine (CQ) and bafilomycin A1 (Baf), were added into each group, respectively. The lipid profiles and morphological modifications of each group were tested. Immunohistochemistry, immunofluorescence staining and transmission electron microscopy (TEM) were used to measure autophagy in this study. The autophagy protein expression of SQSTM1 (P62), and LC3B, along with the signaling pathway proteins of mTOR, phosphorylated mTOR (p-mTOR), AMPK, phosphorylated AMPK (p-AMPK) and Beclin1, were evaluated by western blot. Our results showed that LRG improved hepatocyte steatosis by inducing autophagy, and the AMPK/mTOR pathway is involved. These findings suggest an important mechanism for the positive effects of LRG on hepatic steatosis, and provide new evidence for clinical use of LRG in NAFLD. (C) 2016 Elsevier Inc. All rights reserved.