胆汁酸代谢调控网络在肝脏疾病中的靶向治疗策略与分子机制

摘要/Abstract

摘要： 胆汁酸(BAs)作为多功能信号分子,不仅调控自身在肠肝循环中的代谢与转运,还在脂质和葡萄糖稳态的调节中发挥关键作用。BAs不仅能够塑造菌群结构,同时也被菌群代谢。BAs转运、代谢及信号传导功能的紊乱可影响肠道功能,导致肠道屏障破坏,并且与多种肝脏疾病的发生密切相关,包括胆汁淤积性疾病、代谢功能障碍相关脂肪性肝病(MASLD)、肝纤维化、肝细胞癌及胆管细胞癌等。本文将总结BAs信号传导、代谢及转运机制的最新研究进展,重点关注胆汁淤积和代谢性肝病的转录调控机制及以BAs为靶点的新型治疗策略。

关键词: 胆汁酸代谢, 胆汁淤积, 代谢性疾病, 分子机制, 靶向治疗

杨雨霏, 蔡晓波, 陆伦根. 胆汁酸代谢调控网络在肝脏疾病中的靶向治疗策略与分子机制[J]. 肝脏, 2025, 30(3): 295-298.

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参考文献

[1] Fuchs C D, Trauner M. Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology[J]. Nat Rev Gastroenterol Hepatol, 2022, 19(7): 432-450.
[2] Lin S, Wang S, Wang P, et al. Bile acids and their receptors in regulation of gut health and diseases[J]. Prog Lipid Res, 2023, 89: 101210.
[3] Cai J, Rimal B, Jiang C, et al. Bile acid metabolism and signaling, the microbiota, and metabolic disease[J]. Pharmacol Ther, 2022, 237: 108238.
[4] Inagaki T, Moschetta A, Lee Y K, et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor[J]. Proc Natl Acad Sci U S A, 2006, 103(10): 3920-3925.
[5] Schneider K M, Albers S, Trautwein C. Role of bile acids in the gut-liver axis[J]. J Hepatol, 2018, 68(5): 1083-1085.
[6] Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis[J]. N Engl J Med, 2016, 375(7): 631-643.
[7] Trauner M, Fuchs C D, Halilbasic E, et al. New therapeutic concepts in bile acid transport and signaling for management of cholestasis[J]. Hepatology, 2017, 65(4): 1393-1404.
[8] Mueller M, Thorell A, Claudel T, et al. Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity[J]. J Hepatol, 2015, 62(6): 1398-1404.
[9] Kowdley K V, Vuppalanchi R, Levy C, et al. A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis[J]. J Hepatol, 2020, 73(1): 94-101.
[10] Bowlus C L, Pockros P J, Kremer A E, et al. Long-term obeticholic acid therapy improves histological endpoints in patients with primary biliary cholangitis[J]. Clin Gastroenterol Hepatol, 2020, 18(5): 1170-1178.e1176.
[11] Trauner M, Chung C, Sterling K, et al. PRIMIS: design of a pivotal, randomized, phase 3 study evaluating the safety and efficacy of the nonsteroidal farnesoid X receptor agonist cilofexor in noncirrhotic patients with primary sclerosing cholangitis[J]. BMC Gastroenterol, 2023, 23(1): 75.
[12] Schramm C, Wedemeyer H, Mason A, et al. Farnesoid X receptor agonist tropifexor attenuates cholestasis in a randomised trial in patients with primary biliary cholangitis[J]. JHEP Rep, 2022, 4(11): 100544.
[13] Baghdasaryan A, Claudel T, Gumhold J, et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2^-/- (Abcb4^-/-) mouse cholangiopathy model by promoting biliary HCO₃^- output[J]. Hepatology, 2011, 54(4): 1303-1312.
[14] Hirschfield G M, Chazouillères O, Drenth J P, et al. Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A multicenter, randomized, double-blind, placebo-controlled phase II trial[J]. J Hepatol, 2019, 70(3): 483-493.
[15] Marzioni M, Alpini G, Saccomanno S, et al. Glucagon-like peptide-1 and its receptor agonist exendin-4 modulate cholangiocyte adaptive response to cholestasis[J]. Gastroenterology, 2007, 133(1): 244-255.
[16] Marzioni M, Alpini G, Saccomanno S, et al. Exendin-4, a glucagon-like peptide 1 receptor agonist, protects cholangiocytes from apoptosis[J]. Gut, 2009, 58(7): 990-997.
[17] Miethke A G, Zhang W, Simmons J, et al. Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice[J]. Hepatology, 2016, 63(2): 512-523.
[18] Bowlus C L, Eksteen B, Cheung A C, et al. Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: Open-label pilot study[J]. Hepatol Commun, 2023, 7(6).
[19] Caballero-Camino F J, Rodrigues P M, Wångsell F, et al. A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans[J]. Hepatology, 2023, 78(3): 709-726.
[20] Arab J P, Karpen S J, Dawson P A, et al. Bile acids and nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives[J]. Hepatology, 2017, 65(1): 350-362.
[21] Jahn D, Sutor D, Dorbath D, et al. Farnesoid X receptor-dependent and -independent pathways mediate the transcriptional control of human fibroblast growth factor 19 by vitamin A[J]. Biochim Biophys Acta, 2016, 1859(2): 381-392.
[22] Sanyal A J, Ratziu V, Loomba R, et al. Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis[J]. J Hepatol, 2023, 79(5): 1110-1120.
[23] Traussnigg S, Schattenberg J M, Demir M, et al. Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial[J]. Lancet Gastroenterol Hepatol, 2019, 4(10): 781-793.
[24] Liu X J, Liu C, Zhu L Y, et al. Hepalatide ameliorated progression of nonalcoholic steatohepatitis in mice[J]. Biomed Pharmacother, 2020, 126: 110053.
[25] Slijepcevic D, Roscam Abbing R L P, Fuchs C D, et al. Na(+) -taurocholate cotransporting polypeptide inhibition has hepatoprotective effects in cholestasis in mice[J]. Hepatology, 2018, 68(3): 1057-1069.
[26] Cariello M, Peres C, Zerlotin R, et al. Long-term administration of nuclear bile acid receptor FXR agonist prevents spontaneous hepatocarcinogenesis in abcb4(-/-) mice[J]. Sci Rep, 2017, 7(1): 11203.
[27] Wang Y D, Chen W D, Wang M, et al. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response[J]. Hepatology, 2008, 48(5): 1632-1643.
[28] Erice O, Labiano I, Arbelaiz A, et al. Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression[J]. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(4 Pt B): 1335-1344.