• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

肝细胞核因子4α对胆汁酸生物合成的调控

Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4alpha.

作者信息

Inoue Yusuke, Yu Ai-Ming, Yim Sun Hee, Ma Xiaochao, Krausz Kristopher W, Inoue Junko, Xiang Charlie C, Brownstein Michael J, Eggertsen Gösta, Björkhem Ingemar, Gonzalez Frank J

机构信息

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

出版信息

J Lipid Res. 2006 Jan;47(1):215-27. doi: 10.1194/jlr.M500430-JLR200. Epub 2005 Nov 1.

DOI:10.1194/jlr.M500430-JLR200
PMID:16264197
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1413576/
Abstract

Hepatocyte nuclear factor 4alpha (HNF4alpha) regulates many genes that are preferentially expressed in liver. Mice lacking hepatic expression of HNF4alpha (HNF4alphaDeltaL) exhibited markedly increased levels of serum bile acids (BAs) compared with HNF4alpha-floxed (HNF4alphaF/F) mice. The expression of genes involved in the hydroxylation and side chain beta-oxidation of cholesterol, including oxysterol 7alpha-hydroxylase, sterol 12alpha-hydroxylase (CYP8B1), and sterol carrier protein x, was markedly decreased in HNF4alphaDeltaL mice. Cholesterol 7alpha-hydroxylase mRNA and protein were diminished only during the dark cycle in HNF4alphaDeltaL mice, whereas expression in the light cycle was not different between HNF4alphaDeltaL and HNF4alphaF/F mice. Because CYP8B1 expression was reduced in HNF4alphaDeltaL mice, it was studied in more detail. In agreement with the mRNA levels, CYP8B1 enzyme activity was absent in HNF4alphaDeltaL mice. An HNF4alpha binding site was found in the mouse Cyp8b1 promoter that was able to direct HNF4alpha-dependent transcription. Surprisingly, cholic acid-derived BAs, produced as a result of CYP8B1 activity, were still observed in the serum and gallbladder of these mice. These studies reveal that HNF4alpha plays a central role in BA homeostasis by regulation of genes involved in BA biosynthesis, including hydroxylation and side chain beta-oxidation of cholesterol in vivo.

摘要

肝细胞核因子4α（HNF4α）调控许多在肝脏中优先表达的基因。与HNF4α基因敲除（HNF4αF/F）小鼠相比，缺乏肝脏HNF4α表达（HNF4αDeltaL）的小鼠血清胆汁酸（BAs）水平显著升高。参与胆固醇羟基化和侧链β-氧化的基因表达，包括氧化固醇7α-羟化酶、固醇12α-羟化酶（CYP8B1）和固醇载体蛋白x，在HNF4αDeltaL小鼠中显著降低。胆固醇7α-羟化酶的mRNA和蛋白仅在HNF4αDeltaL小鼠的黑暗周期中减少，而在光照周期中，HNF4αDeltaL和HNF4αF/F小鼠之间的表达没有差异。由于HNF4αDeltaL小鼠中CYP8B1表达降低，因此对其进行了更详细的研究。与mRNA水平一致，HNF4αDeltaL小鼠中不存在CYP8B1酶活性。在小鼠Cyp8b1启动子中发现了一个HNF4α结合位点，该位点能够指导HNF4α依赖的转录。令人惊讶的是，在这些小鼠的血清和胆囊中仍观察到由CYP8B1活性产生的胆酸衍生的胆汁酸。这些研究表明，HNF4α通过调控参与胆汁酸生物合成的基因，包括体内胆固醇的羟基化和侧链β-氧化，在胆汁酸稳态中发挥核心作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e52/1413576/132bfd139eeb/nihms-5999-0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e52/1413576/3506a2d7f326/nihms-5999-0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e52/1413576/ddd3aed03191/nihms-5999-0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e52/1413576/ecbd4436e286/nihms-5999-0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e52/1413576/fc972714ed41/nihms-5999-0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e52/1413576/6a236624291c/nihms-5999-0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e52/1413576/49fa1bc19f10/nihms-5999-0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e52/1413576/323e48cd2fbc/nihms-5999-0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e52/1413576/132bfd139eeb/nihms-5999-0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e52/1413576/3506a2d7f326/nihms-5999-0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e52/1413576/ddd3aed03191/nihms-5999-0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e52/1413576/ecbd4436e286/nihms-5999-0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e52/1413576/fc972714ed41/nihms-5999-0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e52/1413576/6a236624291c/nihms-5999-0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e52/1413576/49fa1bc19f10/nihms-5999-0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e52/1413576/323e48cd2fbc/nihms-5999-0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e52/1413576/132bfd139eeb/nihms-5999-0009.jpg

相似文献

1
Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4alpha.肝细胞核因子4α对胆汁酸生物合成的调控
J Lipid Res. 2006 Jan;47(1):215-27. doi: 10.1194/jlr.M500430-JLR200. Epub 2005 Nov 1.
2
Transcriptional regulation of the human sterol 12alpha-hydroxylase gene (CYP8B1): roles of heaptocyte nuclear factor 4alpha in mediating bile acid repression.人类固醇12α-羟化酶基因（CYP8B1）的转录调控：肝细胞核因子4α在介导胆汁酸抑制中的作用。
J Biol Chem. 2001 Nov 9;276(45):41690-9. doi: 10.1074/jbc.M105117200. Epub 2001 Sep 4.
3
On the mechanism of bile acid inhibition of rat sterol 12alpha-hydroxylase gene (CYP8B1) transcription: roles of alpha-fetoprotein transcription factor and hepatocyte nuclear factor 4alpha.胆汁酸抑制大鼠固醇12α-羟化酶基因（CYP8B1）转录的机制：甲胎蛋白转录因子和肝细胞核因子4α的作用
Biochim Biophys Acta. 2002 Jun 13;1583(1):63-73. doi: 10.1016/s1388-1981(02)00186-5.
4
Cytokine regulation of human sterol 12alpha-hydroxylase (CYP8B1) gene.细胞因子对人固醇12α-羟化酶（CYP8B1）基因的调控
Am J Physiol Gastrointest Liver Physiol. 2005 Apr;288(4):G685-95. doi: 10.1152/ajpgi.00207.2004. Epub 2004 Nov 18.
5
Multiple mechanisms regulate circadian expression of the gene for cholesterol 7alpha-hydroxylase (Cyp7a), a key enzyme in hepatic bile acid biosynthesis.多种机制调节胆固醇7α-羟化酶（Cyp7a）基因的昼夜节律表达，Cyp7a是肝脏胆汁酸生物合成中的关键酶。
J Biol Rhythms. 2007 Aug;22(4):299-311. doi: 10.1177/0748730407302461.
6
Hepatocyte Nuclear Factor 4α Prevents the Steatosis-to-NASH Progression by Regulating p53 and Bile Acid Signaling (in mice).肝细胞核因子 4α 通过调节 p53 和胆汁酸信号转导预防脂肪变性向 NASH 进展（在小鼠中）。
Hepatology. 2021 Jun;73(6):2251-2265. doi: 10.1002/hep.31604. Epub 2021 May 14.
7
Suppression of cholesterol 7alpha-hydroxylase transcription and bile acid synthesis by an alpha1-antitrypsin peptide via interaction with alpha1-fetoprotein transcription factor.α1-抗胰蛋白酶肽通过与甲胎蛋白转录因子相互作用抑制胆固醇7α-羟化酶转录及胆汁酸合成
J Biol Chem. 2002 Nov 8;277(45):42973-80. doi: 10.1074/jbc.M205089200. Epub 2002 Sep 9.
8
Comparative regulation of major enzymes in the bile acid biosynthesis pathway by cholesterol, cholate and taurine in mice and rats.胆固醇、胆酸盐和牛磺酸对小鼠和大鼠胆汁酸生物合成途径中主要酶的比较调节作用
Life Sci. 2005 Jul 1;77(7):746-57. doi: 10.1016/j.lfs.2004.11.036. Epub 2005 Mar 19.
9
Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis.共抑制复合物亚基GPS2参与调控人类胆汁酸生物合成的转录途径。
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15665-70. doi: 10.1073/pnas.0706736104. Epub 2007 Sep 25.
10
The role of alpha1-fetoprotein transcription factor/LRH-1 in bile acid biosynthesis: a known nuclear receptor activator that can act as a suppressor of bile acid biosynthesis.甲胎蛋白转录因子/LRH-1在胆汁酸生物合成中的作用：一种已知的核受体激活剂，可作为胆汁酸生物合成的抑制剂。
J Biol Chem. 2004 Apr 16;279(16):16813-21. doi: 10.1074/jbc.M400646200. Epub 2004 Feb 6.

引用本文的文献

1
Comprehensive molecular analysis of early‑onset gastric cancer identifies novel genes implicated in disease characterization and progression (Review).早发性胃癌的综合分子分析确定了与疾病特征和进展相关的新基因（综述）。
Oncol Rep. 2025 Aug;54(2). doi: 10.3892/or.2025.8931. Epub 2025 Jun 20.
2
Upregulation of Taurine Biosynthesis and Bile Acid Conjugation with Taurine through FXR in a Mouse Model with Human-like Bile Acid Composition.在具有类人胆汁酸组成的小鼠模型中，通过法尼醇X受体（FXR）上调牛磺酸生物合成及牛磺酸与胆汁酸的结合。
Metabolites. 2023 Jul 5;13(7):824. doi: 10.3390/metabo13070824.
3
Mitochondrial Cholesterol Metabolites in a Bile Acid Synthetic Pathway Drive Nonalcoholic Fatty Liver Disease: A Revised "Two-Hit" Hypothesis.

本文引用的文献

1
Feedback regulation of bile acid synthesis in human liver: importance of HNF-4alpha for regulation of CYP7A1.人肝脏中胆汁酸合成的反馈调节：肝细胞核因子4α对细胞色素P450 7A1调节的重要性。
Biochem Biophys Res Commun. 2005 May 6;330(2):395-9. doi: 10.1016/j.bbrc.2005.02.170.
2
Regulation of bile acid synthesis: pathways, nuclear receptors, and mechanisms.胆汁酸合成的调控：途径、核受体及机制
J Hepatol. 2004 Mar;40(3):539-51. doi: 10.1016/j.jhep.2003.11.006.
3
Hepatocyte nuclear factor 4alpha is a central regulator of bile acid conjugation.
胆汁酸合成途径中的线粒体胆固醇代谢物驱动非酒精性脂肪性肝病：修正的“双重打击”假说。
Cells. 2023 May 20;12(10):1434. doi: 10.3390/cells12101434.
4
HNF4α in Hepatocyte Health and Disease.HNF4α 在肝细胞健康和疾病中的作用。
Semin Liver Dis. 2023 May;43(2):234-244. doi: 10.1055/a-2097-0660. Epub 2023 May 22.
5
Caloric restriction remodels the hepatic chromatin landscape and bile acid metabolism by modulating the gut microbiota.热量限制通过调节肠道微生物群重塑肝脏染色质景观和胆汁酸代谢。
Genome Biol. 2023 Apr 30;24(1):98. doi: 10.1186/s13059-023-02938-5.
6
Liver's influence on the brain through the action of bile acids.肝脏通过胆汁酸的作用对大脑产生影响。
Front Neurosci. 2023 Feb 2;17:1123967. doi: 10.3389/fnins.2023.1123967. eCollection 2023.
7
PPARα activation partially drives NAFLD development in liver-specific Hnf4a-null mice.过氧化物酶体增殖物激活受体α 的激活部分驱动肝特异性 Hnf4a 敲除小鼠的非酒精性脂肪性肝病的发生。
J Biochem. 2023 Apr 26;173(5):393-411. doi: 10.1093/jb/mvad005.
8
A High Hepatic Uptake of Conjugated Bile Acids Promotes Colorectal Cancer-Associated Liver Metastasis.结合胆汁酸的高肝脏摄取促进结直肠癌相关肝转移。
Cells. 2022 Nov 28;11(23):3810. doi: 10.3390/cells11233810.
9
Coffee modulates insulin-hepatocyte nuclear factor-4α-Cyp7b1 pathway and reduces oxysterol-driven liver toxicity in a nonalcoholic fatty liver disease mouse model.咖啡调节胰岛素-肝细胞核因子-4α-Cyp7b1 通路，降低非酒精性脂肪肝病小鼠模型中氧化固醇驱动的肝毒性。
Am J Physiol Gastrointest Liver Physiol. 2022 Nov 1;323(5):G488-G500. doi: 10.1152/ajpgi.00179.2022. Epub 2022 Oct 4.
10
Fibroblast growth factor 15/19 expression, regulation, and function: An overview.成纤维细胞生长因子 15/19 的表达、调控与功能：概述。
Mol Cell Endocrinol. 2022 May 15;548:111617. doi: 10.1016/j.mce.2022.111617. Epub 2022 Mar 15.
肝细胞核因子4α是胆汁酸结合的核心调节因子。
J Biol Chem. 2004 Jan 23;279(4):2480-9. doi: 10.1074/jbc.M311015200. Epub 2003 Oct 28.
4
Regulation of human sterol 27-hydroxylase gene (CYP27A1) by bile acids and hepatocyte nuclear factor 4alpha (HNF4alpha).胆汁酸和肝细胞核因子4α（HNF4α）对人类胆固醇27-羟化酶基因（CYP27A1）的调控
Gene. 2003 Aug 14;313:71-82. doi: 10.1016/s0378-1119(03)00631-0.
5
Microarray analysis using amplified mRNA from laser capture microdissection of microscopic hepatocellular precancerous lesions and frozen hepatocellular carcinomas reveals unique and consistent gene expression profiles.使用从显微肝细胞癌前病变和冷冻肝细胞癌的激光捕获显微切割获得的扩增mRNA进行微阵列分析，揭示了独特且一致的基因表达谱。
Toxicol Pathol. 2003 May-Jun;31(3):295-303. doi: 10.1080/01926230390204333.
6
Cholic acid mediates negative feedback regulation of bile acid synthesis in mice.胆酸介导小鼠胆汁酸合成的负反馈调节。
J Clin Invest. 2002 Oct;110(8):1191-200. doi: 10.1172/JCI16309.
7
On the mechanism of bile acid inhibition of rat sterol 12alpha-hydroxylase gene (CYP8B1) transcription: roles of alpha-fetoprotein transcription factor and hepatocyte nuclear factor 4alpha.胆汁酸抑制大鼠固醇12α-羟化酶基因（CYP8B1）转录的机制：甲胎蛋白转录因子和肝细胞核因子4α的作用
Biochim Biophys Acta. 2002 Jun 13;1583(1):63-73. doi: 10.1016/s1388-1981(02)00186-5.
8
Redundant pathways for negative feedback regulation of bile acid production.胆汁酸生成负反馈调节的冗余途径。
Dev Cell. 2002 Jun;2(6):721-31. doi: 10.1016/s1534-5807(02)00187-9.
9
Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis.核受体SHP的缺失会损害但不会消除胆汁酸合成的负反馈调节。
Dev Cell. 2002 Jun;2(6):713-20. doi: 10.1016/s1534-5807(02)00154-5.
10
Defective ureagenesis in mice carrying a liver-specific disruption of hepatocyte nuclear factor 4alpha (HNF4alpha ). HNF4alpha regulates ornithine transcarbamylase in vivo.携带肝特异性肝细胞转录因子4α（HNF4α）缺失的小鼠尿素生成缺陷。HNF4α在体内调节鸟氨酸转氨甲酰酶。
J Biol Chem. 2002 Jul 12;277(28):25257-65. doi: 10.1074/jbc.M203126200. Epub 2002 May 6.