The GR-gp78 Pathway is involved in Hepatic Lipid Accumulation Induced by Overexpression of 11β-HSD1.
The GR-gp78 Pathway is involved in Hepatic Lipid Accumulation Induced by Overexpression of 11β-HSD1.
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GR-gp78通路参与了11β-HSD1过表达诱导的肝脏脂质积累。
DOI：
10.7150/ijbs.42376
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发表时间：
2022
影响因子：
9.2
通讯作者：
Li, Guoping
中科院分区：
文献类型：
--
作者：
Hu, Mengliang;Han, Tingting;Pan, Qiyu;Ni, Dongsheng;Gao, Fengyi;Wang, Liying;Ren, Hangjiang;Zhang, Xiaoyi;Jiao, Haoyun;Wang, Yuefeng;Dai, Dapeng;Man, Yong;Tang, Weiqing;Sun, Yue;Li, Wei;Li, Jian;Li, Guoping
糖皮质激素是调节脂质代谢的重要参与者。在组织特异性水平上，糖皮质激素信号由11β-羟基类固醇脱氢酶1（11β-HSD 1）控制。先前已显示在非酒精性脂肪性肝病（NAFLD）期间11β-HSD 1表达上调，而11β-HSD 1抑制已显示在NAFLD中降低肝脏脂质，但潜在机制仍不清楚。本研究通过体外细胞培养和体内肝细胞特异性转基因11β-HSD 1小鼠模型，探讨11β-HSD 1在脂代谢紊乱中的调控机制。我们发现11β-HSD 1过表达激活糖皮质激素受体并促进其核转位，然后刺激gp 78。gp 78的诱导显著降低Insig 2的表达，但不降低Insig 1的表达，这导致脂肪生成调节蛋白包括SREBP 1、FAS、SCD 1和ACC 1的上调。我们的研究结果表明，11β-HSD 1过表达诱导脂质积聚，至少部分通过GR/gp 78/Insig 2/SREBP 1途径，这可能是一个潜在的诊断和治疗NAFLD的治疗靶点。
Glucocorticoids are essential participants in the regulation of lipid metabolism. On a tissue-specific level, glucocorticoid signal is controlled by 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1). Up-regulation of 11β-HSD1 expression during non-alcoholic fatty liver disease (NAFLD) has been previously shown, while 11β-HSD1 inhibition has been shown to reduce hepatic lipids in NAFLD, but the underlying mechanisms remain unclear. Here, in this study, we created in vitro cell culture and in vivo transgenic hepatocyte-specific 11β-HSD1 mouse models of NAFLD to determine the regulatory mechanisms of 11β-HSD1 during lipid metabolism dysfunction. We found that 11β-HSD1 overexpression activated glucocorticoid receptors and promoted their nuclear translocation, and then stimulating gp78. The induction of gp78 sharply reduced expression of Insig2, but not Insig1, which led to up-regulation of lipogenesis regulatory proteins including SREBP1, FAS, SCD1, and ACC1. Our results suggested that overexpression of 11β-HSD1 induced lipid accumulation, at least partially through the GR/gp78/Insig2/SREBP1 pathway, which may serve as a potential diagnostic and therapeutic target for treatment of NAFLD.
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影响因子：
9.8
作者：
Li, Guoping;Hernandez-Ono, Antonio;Crooke, Rosanne M.;Graham, Mark J.;Ginsberg, Henry N.
通讯作者：
Ginsberg, Henry N.
非酒精性脂肪肝疾病（NAFLD） - 对药物代谢酶和转运蛋白的发病机理，分类和影响。
影响因子：
5.9
作者：
Cobbina E;Akhlaghi F
通讯作者：
Akhlaghi F
Insig1/SREBP1/SCD1 设定点的适应性变化有助于脂肪组织应对因肥胖而增加的储存需求。
影响因子：
7.7
作者：
Carobbio S;Hagen RM;Lelliott CJ;Slawik M;Medina-Gomez G;Tan CY;Sicard A;Atherton HJ;Barbarroja N;Bjursell M;Bohlooly-Y M;Virtue S;Tuthill A;Lefai E;Laville M;Wu T;Considine RV;Vidal H;Langin D;Oresic M;Tinahones FJ;Fernandez-Real JM;Griffin JL;Sethi JK;López M;Vidal-Puig A
通讯作者：
Vidal-Puig A
影响因子：
8.8
作者：
Liu, Ying;Conlon, Donna M.;Morrisey, Edward E.
通讯作者：
Morrisey, Edward E.
影响因子：
4.5
作者：
Paglialunga S;Dehn CA
通讯作者：
Dehn CA