Crosstalk of hepatocyte nuclear factor 4a and glucocorticoid receptor in the regulation of lipid metabolism in mice fed a high-fat-high-sugar diet.
Crosstalk of hepatocyte nuclear factor 4a and glucocorticoid receptor in the regulation of lipid metabolism in mice fed a high-fat-high-sugar diet.
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在高脂高糖饮食喂养的小鼠中，肝细胞核因子4α和糖皮质激素受体在脂质代谢调节中的相互作用。
DOI：
10.1186/s12944-022-01654-6
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发表时间：
2022-05-25
影响因子：
4.5
通讯作者：
Alnouti, Yazen
中科院分区：
文献类型：
--
作者：
Lu, Hong;Lei, Xiaohong;Winkler, Rebecca;John, Savio;Kumar, Devendra;Li, Wenkuan;Alnouti, Yazen
肝细胞核因子4α（HNF4α）和糖皮质激素受体（GR）是肝脏代谢的主要调节因子，在脂肪性肝病中表达下调。本研究旨在阐明HNF4α和GR下调在脂肪肝和高脂血症中的作用。
对肝脏特异性HNF4α或GR杂合子（HET）和敲除（KO）的成年小鼠喂食高脂肪高糖饮食（HFHS）15天。用分析试剂盒测定肝脏和循环脂质的变化，通过实时定量PCR和蛋白质印迹法对这些小鼠肝脏mRNA和蛋白质表达的变化进行定量。通过液相色谱 - 质谱/质谱法对血清和肝脏胆汁酸水平进行定量。利用荧光素酶报告基因检测确定HNF4α和GR在调节肝脏基因表达中的作用。
与喂食HFHS的野生型小鼠相比，HNF4α HET小鼠脂质分解代谢基因下调，脂肪生成基因诱导，肝脏和血液脂质水平升高，而HNF4α KO小鼠出现脂肪肝但有轻度低脂血症，脂质流出基因下调，脂质摄取、合成和储存基因诱导。鹅去氧胆酸和脱氧胆酸的血清水平在HNF4α HET小鼠中趋于降低，但在HNF4α KO小鼠中显著升高，这与胆汁酸合成的限速酶细胞色素P450 7a1显著下调有关。在喂食HFHS的HNF4α HET小鼠中，主要的脂肪生成调节因子固醇调节元件结合蛋白 - 1（SREBP - 1）的肝脏mRNA和蛋白质表达被诱导。在报告基因检测中，HNF4α与辅阻遏物小异二聚体伴侣协同强烈抑制肝脏X受体对小鼠和人SREBP - 1C启动子的反式激活。在HNF4α KO小鼠中，肝细胞核GR蛋白趋于减少。肝脏特异性GR敲除的喂食HFHS的小鼠肝脏脂质增加，SREBP - 1C和过氧化物酶体增殖物激活受体γ（PPARγ）被诱导，这与这些小鼠肝脏中HNF4α蛋白水平显著降低有关。在报告基因检测中，GR和HNF4α协同/累加诱导脂质分解代谢基因。
HNF4α和GR对脂质分解代谢基因的诱导以及对脂肪生成基因的抑制可能介导了对HFHS诱导的脂肪肝和高脂血症的早期抵抗。
在线版本包含补充材料，可在10.1186/s12944 - 022 - 01654 - 6获取。
Hepatocyte nuclear factor 4α (HNF4α) and glucocorticoid receptor (GR), master regulators of liver metabolism, are down-regulated in fatty liver diseases. The present study aimed to elucidate the role of down-regulation of HNF4α and GR in fatty liver and hyperlipidemia. Adult mice with liver-specific heterozygote (HET) and knockout (KO) of HNF4α or GR were fed a high-fat-high-sugar diet (HFHS) for 15 days. Alterations in hepatic and circulating lipids were determined with analytical kits, and changes in hepatic mRNA and protein expression in these mice were quantified by real-time PCR and Western blotting. Serum and hepatic levels of bile acids were quantified by LC-MS/MS. The roles of HNF4α and GR in regulating hepatic gene expression were determined using luciferase reporter assays. Compared to HFHS-fed wildtype mice, HNF4α HET mice had down-regulation of lipid catabolic genes, induction of lipogenic genes, and increased hepatic and blood levels of lipids, whereas HNF4α KO mice had fatty liver but mild hypolipidemia, down-regulation of lipid-efflux genes, and induction of genes for uptake, synthesis, and storage of lipids. Serum levels of chenodeoxycholic acid and deoxycholic acid tended to be decreased in the HNF4α HET mice but dramatically increased in the HNF4α KO mice, which was associated with marked down-regulation of cytochrome P450 7a1, the rate-limiting enzyme for bile acid synthesis. Hepatic mRNA and protein expression of sterol-regulatory-element-binding protein-1 (SREBP-1), a master lipogenic regulator, was induced in HFHS-fed HNF4α HET mice. In reporter assays, HNF4α cooperated with the corepressor small heterodimer partner to potently inhibit the transactivation of mouse and human SREBP-1C promoter by liver X receptor. Hepatic nuclear GR proteins tended to be decreased in the HNF4α KO mice. HFHS-fed mice with liver-specific KO of GR had increased hepatic lipids and induction of SREBP-1C and PPARγ, which was associated with a marked decrease in hepatic levels of HNF4α proteins in these mice. In reporter assays, GR and HNF4α synergistically/additively induced lipid catabolic genes. induction of lipid catabolic genes and suppression of lipogenic genes by HNF4α and GR may mediate the early resistance to HFHS-induced fatty liver and hyperlipidemia. The online version contains supplementary material available at 10.1186/s12944-022-01654-6.
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影响因子：
4.8
作者：
Blanquart, C;Barbier, O;Glineur, C
通讯作者：
Glineur, C
DOI：
10.1073/pnas.96.20.11041
发表时间：
1999-09-28
影响因子：
11.1
作者：
Brown, MS;Goldstein, JL
通讯作者：
Goldstein, JL
影响因子：
5.1
作者：
Bhushan, Bharat;Michalopoulos, George K.
通讯作者：
Michalopoulos, George K.
影响因子：
2.3
作者：
Bellentani, Stefano;Scaglioni, Federica;Bedogni, Giorgio
通讯作者：
Bedogni, Giorgio
DOI：
10.1258/ebm.2011.011255
发表时间：
2012-01
期刊：
Experimental biology and medicine (Maywood, N.J.)
影响因子：
--
作者：
Beier JI;Arteel GE
通讯作者：
Arteel GE