Hepatic bile acid accretion correlates with cholestatic liver injury and therapeutic response in Cyp2c70 knockout mice with a humanized bile acid composition.

IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2024-12-01 Epub Date: 2024-10-01 DOI:10.1152/ajpgi.00129.2024
Caroline Klindt, Jennifer K Truong, Ashley L Bennett, Kimberly J Pachura, Diran Herebian, Ertan Mayatepek, Tom Luedde, Matthias Ebert, Saul J Karpen, Paul A Dawson
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Abstract

Cyp2c70 knockout (KO) mice lack the liver enzyme responsible for synthesis of 6-hydroxylated muricholate bile acid species and possess a more hydrophobic human-like bile acid composition. Cyp2c70 KO mice develop cholestatic liver injury that can be prevented by the administration of an ileal bile acid transporter (IBAT) inhibitor. In this study, we investigated the potential of an ileal bile acid transporter (IBAT) inhibitor (SC-435) and steroidal farnesoid X receptor (FXR) agonist (cilofexor) to modulate established hepatobiliary injury and the consequent relationship of intrahepatic bile acid content and hydrophobicity to the cholestatic liver injury phenotype. Oral administration of SC-435, cilofexor, or combined treatment for 2 wk markedly reduced serum markers of liver injury and improved histological and gene expression markers of fibrosis, liver inflammation, and ductular reaction in male and female Cyp2c70 KO mice, with the greatest benefit in the combination treatment group. The IBAT inhibitor and FXR agonist significantly reduced intrahepatic bile acid content but not hepatic bile acid pool hydrophobicity, and markers of liver injury were strongly correlated with intrahepatic total bile acid and taurochenodeoxycholic acid accretion. Biomarkers of liver injury increased linearly with similar hepatic thresholds for pathological accretion of hydrophobic bile acids in male and female Cyp2c70 KO mice. These findings further support targeting intrahepatic bile acid retention as a component of treatments for cholestatic liver disease.NEW & NOTEWORTHY Bile acids are implicated as a common contributor to the pathogenesis and progression of cholestatic liver disease. Using a mouse model with a humanized bile acid composition, we demonstrated that mono and combination therapy using an IBAT inhibitor and FXR nonsteroidal agonist were effective at reducing hepatic bile acid accretion and reversing liver injury, without reducing hepatic bile acid hydrophobicity. The findings support the concept of a therapeutically tractable threshold for bile acid-induced liver injury.

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使用人源化胆汁酸成分的 Cyp2c70 基因敲除小鼠的肝脏胆汁酸蓄积与胆汁淤积性肝损伤和治疗反应相关。
Cyp2c70 基因剔除(KO)小鼠缺乏负责合成 6- 羟基化的杂胆酸胆汁酸种类的肝酶,并具有更疏水的类人胆汁酸成分。Cyp2c70 KO 小鼠会出现胆汁淤积性肝脏损伤,而服用回肠胆汁酸转运体(IBAT)抑制剂可以预防这种损伤。在这项研究中,我们研究了回肠胆汁酸转运体(IBAT)抑制剂(SC-435)和类固醇 FXR 激动剂(cilofexor)调节已建立的肝胆损伤的潜力,以及肝内胆汁酸含量和疏水性与胆汁淤积性肝损伤表型之间的关系。在雌雄 Cyp2c70 KO 小鼠中,口服 SC-435、cilofexor 或联合治疗 2 周可明显降低肝损伤的血清标志物,改善纤维化、肝脏炎症和导管反应的组织学和基因表达标志物,其中联合治疗组获益最大。IBAT 抑制剂和 FXR 激动剂能显著降低肝内胆汁酸含量,但不能降低肝内胆汁酸池疏水度,肝损伤标志物与肝内总胆汁酸和牛磺鹅去氧胆酸增量密切相关。在雌雄 Cyp2c70 KO 小鼠中,肝损伤的生物标志物与疏水胆汁酸病理性增生的肝阈值相似,呈线性增加。这些发现进一步支持将肝内胆汁酸潴留作为治疗胆汁淤积性肝病的目标。
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来源期刊
CiteScore
9.40
自引率
2.20%
发文量
104
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Gastrointestinal and Liver Physiology publishes original articles pertaining to all aspects of research involving normal or abnormal function of the gastrointestinal tract, hepatobiliary system, and pancreas. Authors are encouraged to submit manuscripts dealing with growth and development, digestion, secretion, absorption, metabolism, and motility relative to these organs, as well as research reports dealing with immune and inflammatory processes and with neural, endocrine, and circulatory control mechanisms that affect these organs.
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Simultaneous optical imaging of gastric slow waves and contractions in the in vivo porcine stomach. Parenteral nutrition results in peripheral ileal to hepatic circadian discordance in mice. AHCC inhibited hepatic stellate cells activation by regulation of cytoglobin induction via TLR2-SAPK/JNK pathway and collagen production via TLR4-NF-κβ pathway. Formal degree programs in physiology promote careers of clinical scientists and benefit basic science departments. Hepatic bile acid accretion correlates with cholestatic liver injury and therapeutic response in Cyp2c70 knockout mice with a humanized bile acid composition.
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