Suppr超能文献

胆汁酸在胆汁淤积、炎症和癌症中的代谢与信号传导

Bile Acid Metabolism and Signaling in Cholestasis, Inflammation, and Cancer.

作者信息

Li Tiangang, Apte Udayan

机构信息

Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, USA.

Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, USA.

出版信息

Adv Pharmacol. 2015;74:263-302. doi: 10.1016/bs.apha.2015.04.003. Epub 2015 May 27.

Abstract

Bile acids are synthesized from cholesterol in the liver. Some cytochrome P450 (CYP) enzymes play key roles in bile acid synthesis. Bile acids are physiological detergent molecules, so are highly cytotoxic. They undergo enterohepatic circulation and play important roles in generating bile flow and facilitating biliary secretion of endogenous metabolites and xenobiotics and intestinal absorption of dietary fats and lipid-soluble vitamins. Bile acid synthesis, transport, and pool size are therefore tightly regulated under physiological conditions. In cholestasis, impaired bile flow leads to accumulation of bile acids in the liver, causing hepatocyte and biliary injury and inflammation. Chronic cholestasis is associated with fibrosis, cirrhosis, and eventually liver failure. Chronic cholestasis also increases the risk of developing hepatocellular or cholangiocellular carcinomas. Extensive research in the last two decades has shown that bile acids act as signaling molecules that regulate various cellular processes. The bile acid-activated nuclear receptors are ligand-activated transcriptional factors that play critical roles in the regulation of bile acid, drug, and xenobiotic metabolism. In cholestasis, these bile acid-activated receptors regulate a network of genes involved in bile acid synthesis, conjugation, transport, and metabolism to alleviate bile acid-induced inflammation and injury. Additionally, bile acids are known to regulate cell growth and proliferation, and altered bile acid levels in diseased conditions have been implicated in liver injury/regeneration and tumorigenesis. We will cover the mechanisms that regulate bile acid homeostasis and detoxification during cholestasis, and the roles of bile acids in the initiation and regulation of hepatic inflammation, regeneration, and carcinogenesis.

摘要

胆汁酸在肝脏中由胆固醇合成。一些细胞色素P450(CYP)酶在胆汁酸合成中起关键作用。胆汁酸是生理性去污剂分子,因此具有高度细胞毒性。它们进行肠肝循环,在产生胆汁流动以及促进内源性代谢物和外源性物质的胆汁分泌以及膳食脂肪和脂溶性维生素的肠道吸收方面发挥重要作用。因此,在生理条件下,胆汁酸的合成、运输和池大小受到严格调控。在胆汁淤积时,胆汁流动受损导致胆汁酸在肝脏中蓄积,引起肝细胞和胆管损伤及炎症。慢性胆汁淤积与纤维化、肝硬化以及最终的肝衰竭相关。慢性胆汁淤积还会增加发生肝细胞癌或胆管细胞癌的风险。过去二十年的广泛研究表明,胆汁酸作为信号分子调节各种细胞过程。胆汁酸激活的核受体是配体激活的转录因子,在胆汁酸、药物和外源性物质代谢的调节中起关键作用。在胆汁淤积时,这些胆汁酸激活的受体调节参与胆汁酸合成、结合、运输和代谢的基因网络,以减轻胆汁酸诱导的炎症和损伤。此外,已知胆汁酸调节细胞生长和增殖,疾病状态下胆汁酸水平的改变与肝损伤/再生和肿瘤发生有关。我们将阐述胆汁淤积期间调节胆汁酸稳态和解毒的机制,以及胆汁酸在肝脏炎症、再生和致癌作用的起始和调节中的作用。

相似文献

1
Bile Acid Metabolism and Signaling in Cholestasis, Inflammation, and Cancer.
Adv Pharmacol. 2015;74:263-302. doi: 10.1016/bs.apha.2015.04.003. Epub 2015 May 27.
2
Bile salts and cholestasis.
Dig Liver Dis. 2010 Jun;42(6):409-18. doi: 10.1016/j.dld.2010.03.015.
3
Bile acid metabolism and signaling.
Compr Physiol. 2013 Jul;3(3):1191-212. doi: 10.1002/cphy.c120023.
4
Role of farnesoid X receptor in cholestasis.
J Dig Dis. 2016 Aug;17(8):501-509. doi: 10.1111/1751-2980.12378.
5
Bile Acids in Cholestasis and its Treatment.
Ann Hepatol. 2017 Nov;16(Suppl. 1: s3-105.):s53-s57. doi: 10.5604/01.3001.0010.5497.
6
Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury.
Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2063-8. doi: 10.1073/pnas.0409794102. Epub 2005 Jan 31.
7
Nuclear receptors as therapeutic targets in cholestatic liver diseases.
Br J Pharmacol. 2009 Jan;156(1):7-27. doi: 10.1111/j.1476-5381.2008.00030.x.
9
Bile acid signaling in metabolic disease and drug therapy.
Pharmacol Rev. 2014 Oct;66(4):948-83. doi: 10.1124/pr.113.008201.
10

引用本文的文献

2
HNF4α contributes to hepatic CAR dysfunction in polymicrobial sepsis.
Front Immunol. 2025 Aug 19;16:1625104. doi: 10.3389/fimmu.2025.1625104. eCollection 2025.
4
Cholic acid as a treatment for cerebrotendinous xanthomatosis: a comprehensive review of safety and efficacy.
Orphanet J Rare Dis. 2025 Jul 29;20(1):387. doi: 10.1186/s13023-025-03889-9.
5
Unraveling the Regulatory Impact of LncRNA Hnf1aos1 on Hepatic Homeostasis in Mice.
Noncoding RNA. 2025 Jul 4;11(4):52. doi: 10.3390/ncrna11040052.
6
Differential Protective Roles of c-Jun N-terminal Kinase-2 in Nonparenchymal Liver Cells and Hepatocytes During Cholestasis.
Cell Mol Gastroenterol Hepatol. 2025 Jul 16;19(11):101588. doi: 10.1016/j.jcmgh.2025.101588.
8
The gut microbiota-bile acid axis: a crucial regulator of immune function and metabolic health.
World J Microbiol Biotechnol. 2025 Jun 25;41(7):215. doi: 10.1007/s11274-025-04395-7.
10
Bile acid regulation of xenobiotic nuclear receptors on the expressions of orosomucoids in the liver.
Am J Physiol Endocrinol Metab. 2025 Jun 1;328(6):E940-E951. doi: 10.1152/ajpendo.00417.2024. Epub 2025 May 6.

本文引用的文献

1
Progressive familial intrahepatic cholestasis.
J Clin Exp Hepatol. 2014 Mar;4(1):25-36. doi: 10.1016/j.jceh.2013.10.005. Epub 2013 Nov 23.
2
Recent advances in the development of farnesoid X receptor agonists.
Ann Transl Med. 2015 Jan;3(1):5. doi: 10.3978/j.issn.2305-5839.2014.12.06.
3
Novel therapeutic targets in primary biliary cirrhosis.
Nat Rev Gastroenterol Hepatol. 2015 Mar;12(3):147-58. doi: 10.1038/nrgastro.2015.12. Epub 2015 Feb 3.
5
Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid.
Gastroenterology. 2015 Apr;148(4):751-61.e8. doi: 10.1053/j.gastro.2014.12.005. Epub 2014 Dec 11.
7
The role of CYP3A4 in the biotransformation of bile acids and therapeutic implication for cholestasis.
Ann Transl Med. 2014 Jan;2(1):7. doi: 10.3978/j.issn.2305-5839.2013.03.02.
8
Bile acid signaling in metabolic disease and drug therapy.
Pharmacol Rev. 2014 Oct;66(4):948-83. doi: 10.1124/pr.113.008201.

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验