Ileal bile acid transporter inhibition in Cyp2c70 KO mice ameliorates cholestatic liver injury.
Ileal bile acid transporter inhibition in Cyp2c70 KO mice ameliorates cholestatic liver injury.
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DOI：
10.1016/j.jlr.2022.100261
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发表时间：
2022-09
影响因子：
6.5
通讯作者：
Karpen, Saul J.
中科院分区：
文献类型：
--
作者：
Truong, Jennifer K.;Bennett, Ashley L.;Klindt, Caroline;Donepudi, Ajay C.;Malla, Sudarshan R.;Pachura, Kimberly J.;Zaufel, Alex;Moustafa, Tarek;Dawson, Paul A.;Karpen, Saul J.
关键词：
Cyp2c70是啮齿动物体内的一种肝酶，负责合成初级的6-羟基鼠胆酸(BA)。Cyp2c70 KO小鼠缺乏保护性的亲水性小鼠酸，导致更像人类的BA成分，并随后导致胆汁淤积性肝损伤。药物抑制回肠BA转运体(IBAT)已被证明对胆汁淤积模型有治疗作用。在这里，我们的目标是确定SC-435抑制IBAT对Cyp2c70KO小鼠是否具有保护作用。与WT小鼠相比，我们发现雄性和雌性Cyp2c70KO小鼠血清肝损伤标志物水平增加，我们的肝脏组织学评估显示肝脏炎症增加，巨噬细胞浸润和胆管细胞增殖。我们证明，SC-435治疗后，血清和肝损伤的组织学标志物显著减少。此外，我们发现与免疫细胞激活和炎症相关的途径中的肝脏基因表达在Cyp2c70KO小鼠中显著上调，并降低到与IBAT抑制的WT无法区分的水平。Cyp2c70KO小鼠肝脏BA含量显著增加，富含鹅去氧胆酸，疏水性增强，表现出与人肝脏BA相似的疏水性指数值和红细胞溶解特性。此外，我们发现IBAT抑制降低了总的肝脏BA水平，但不影响肝脏BA的整体疏水性。这些结果表明，肝脏中可能存在疏水性BA的病理性积聚的阈值，减少肝脏BA的积聚足以减轻肝脏损伤，而不依赖于BA池的疏水性。
Cyp2c70 is the liver enzyme in rodents responsible for synthesis of the primary 6-hydroxylated muricholate bile acid (BA) species. Cyp2c70 KO mice are devoid of protective, hydrophilic muricholic acids, leading to a more human-like BA composition and subsequent cholestatic liver injury. Pharmacological inhibition of the ileal BA transporter (IBAT) has been shown to be therapeutic in cholestatic models. Here, we aimed to determine if IBAT inhibition with SC-435 is protective in Cyp2c70 KO mice. As compared to WT mice, we found male and female Cyp2c70 KO mice exhibited increased levels of serum liver injury markers, and our evaluation of liver histology revealed increased hepatic inflammation, macrophage infiltration, and biliary cell proliferation. We demonstrate serum and histologic markers of liver damage were markedly reduced with SC-435 treatment. Additionally, we show hepatic gene expression in pathways related to immune cell activation and inflammation were significantly upregulated in Cyp2c70 KO mice and reduced to levels indistinguishable from WT with IBAT inhibition. In Cyp2c70 KO mice, the liver BA content was significantly increased, enriched in chenodeoxycholic acid, and more hydrophobic, exhibiting a hydrophobicity index value and red blood cell lysis properties similar to human liver BAs. Furthermore, we determined IBAT inhibition reduced the total hepatic BA levels but did not affect overall hydrophobicity of the liver BAs. These findings suggest that there may be a threshold in the liver for pathological accretion of hydrophobic BAs and reducing hepatic BA accumulation can be sufficient to alleviate liver injury, independent of BA pool hydrophobicity.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
25.7
作者：
Arrese, M;Pizarro, M;Accatino, L
通讯作者：
Accatino, L
DOI：
10.1016/0005-2736(86)90081-7
发表时间：
1986-03-13
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
CHILD, P;RAFTER, J
通讯作者：
RAFTER, J
影响因子：
4.8
作者：
Dawson, PA;Haywood, J;Parks, JS
通讯作者：
Parks, JS
影响因子：
168.9
作者：
Gonzales, Emmanuel;Hardikar, Winita;Jacquemin, Emmanuel
通讯作者：
Jacquemin, Emmanuel