Liver X receptor negatively regulates fibroblast growth factor 21 in the fatty liver induced by cholesterol-enriched diet
Liver X receptor negatively regulates fibroblast growth factor 21 in the fatty liver induced by cholesterol-enriched diet
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DOI：
10.1016/j.jnutbio.2011.03.023
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发表时间：
2012-07-01
影响因子：
5.6
通讯作者：
Takeda, Eiji
中科院分区：
文献类型：
--
作者：
Uebanso, Takashi;Taketani, Yutaka;Takeda, Eiji
胆固醇稳态在转录水平上受肝脏X受体（liver X receptor， LXR）调控，但LXR是否能影响肝内脂解相关基因的表达水平尚不清楚。最近的证据表明，成纤维细胞生长因子21 （FGF21）调节肝脏脂肪分解和脂肪酸利用。在本研究中，我们研究了LXR在FGF21基因表达中的作用，FGF21基因表达与肝脏中胆固醇和甘油三酯代谢之间的串音信号的调节有关。一项体内胆固醇饲养试验表明，摄入过量的胆固醇增加了胆固醇分解代谢相关基因的表达以及脂肪酸生物合成相关基因的表达。此外，积累的胆固醇抑制FGF21和激素敏感脂肪酶（HSL）基因的表达。饲喂胆固醇15天后，肝脏甘油三酯浓度与肝脏中FGF21和HSL基因的表达水平呈负相关。LXR激动剂TO-901317可抑制小鼠原代肝细胞和HepG2细胞中FGF21基因的表达。启动子缺失研究和电泳迁移率转移实验显示，人类FGF21启动子至少有一个LXR响应元件位于-37至-22 bp之间。综上所述，LXR在转录水平上抑制FGF21基因的表达，并可能抑制脂肪分解和脂质利用，从而保护肝脏免受有毒胆固醇的过度积累。(C) 2012爱思唯尔公司版权所有。
Cholesterol homeostasis is regulated by the liver X receptor (LXR) at the transcriptional level, but it remains unknown whether LXR can affect expression levels of intrahepatic lipolysis related gene. Recent evidence has demonstrated that fibroblast growth factor 21 (FGF21) regulates hepatic lipolysis and fatty acid utilization. In the present study, we examined the role of LXR in FGF21 gene expression associated with regulation of cross-talk signals between cholesterol and triglyceride metabolism in the liver. An in vivo cholesterol feeding test revealed that intake of excess cholesterol increased cholesterol catabolism related gene expression as well as fatty-acid biosynthesis related gene expression. Moreover, the accumulated cholesterol suppressed FGF21 and hormone-sensitive lipase (HSL) gene expression. After 15-day cholesterol feeding, hepatic triglyceride concentrations were negatively correlated with expression levels of the FGF21 and HSL genes in the liver. An LXR agonist (TO-901317) repressed the FGF21 gene expression in mouse primary hepatocytes and HepG2 cells. A promoter deletion study and electrophoretic mobility shift assay revealed that the human FGF21 promoter has at least one LXR response element located from -37 to -22 bp. In summary, LXR represses FGF21 gene expression at the transcription level and might suppress lipolysis and lipid utilization to protect the liver from excess accumulation of toxic cholesterol. (C) 2012 Elsevier Inc. All rights reserved.