Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
J Lipid Res. 2022 Sep;63(9):100261. doi: 10.1016/j.jlr.2022.100261. Epub 2022 Aug 5.
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.
Cyp2c70 是啮齿动物中负责合成主要 6-羟基化 muricholate 胆汁酸 (BA) 种类的肝脏酶。Cyp2c70 KO 小鼠缺乏保护性、亲水性的 muricholic 酸，导致更类似于人类的 BA 组成和随后的胆汁淤积性肝损伤。已经证明，抑制回肠 BA 转运蛋白 (IBAT) 的药理学抑制在胆汁淤积模型中具有治疗作用。在这里，我们旨在确定用 SC-435 抑制 IBAT 是否对 Cyp2c70 KO 小鼠具有保护作用。与 WT 小鼠相比，我们发现雄性和雌性 Cyp2c70 KO 小鼠的血清肝损伤标志物水平升高，我们对肝组织学的评估显示肝炎症、巨噬细胞浸润和胆管细胞增殖增加。我们证明 SC-435 治疗显著降低了血清和组织学的肝损伤标志物。此外，我们表明 Cyp2c70 KO 小鼠中与免疫细胞激活和炎症相关的肝基因表达显著上调，并通过 IBAT 抑制降低至与 WT 小鼠无区别的水平。在 Cyp2c70 KO 小鼠中，肝 BA 含量显著增加，富含鹅脱氧胆酸，且更疏水，表现出与人类肝 BA 相似的疏水性指数值和红细胞溶血特性。此外，我们确定 IBAT 抑制降低了总肝 BA 水平，但不影响肝 BA 总体疏水性。这些发现表明，在肝脏中可能存在一个疏水 BA 病理性积累的阈值，并且减少肝 BA 积累足以缓解肝损伤，而不依赖于 BA 池的疏水性。
