Li Tiangang, Apte Udayan
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.
Adv Pharmacol. 2015;74:263-302. doi: 10.1016/bs.apha.2015.04.003. Epub 2015 May 27.
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.
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。