Yntema Tess, Eijgenraam Tim R, Kloosterhuis Niels J, Havinga Rick, Koster Mirjam H, Hovingh Milaine V, de Boer Jan Freark, Koonen Debby P Y, Kuipers Folkert
Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Sci Rep. 2025 Jan 15;15(1):2100. doi: 10.1038/s41598-025-86183-9.
Bile acids (BAs) play important roles in the context of lipid homeostasis and inflammation. Based on extensive preclinical mouse studies, BA signaling pathways have been implicated as therapeutic targets for cardiovascular diseases. However, differences in BA metabolism between mice and humans hamper translation of preclinical outcomes. Recently, we generated Cyp2c70 mice with a human-like BA composition lacking mouse/rat specific muricholic acids. We employed this model to assess the consequences of a human-like BA pool on atherosclerosis and heart function in hypercholesterolaemic mice. We overexpressed a PCSK9 gain-of-function (GOF) mutation in the liver of male Cyp2c70 and Cyp2c70 control mice, and fed these mice a Western-type diet (WD) for 12 weeks. Cyp2c70 mice displayed a hydrophobic BA pool rich in chenodeoxycholic acid. Cyp2c70 mice showed reduced hepatic total cholesterol and triglycerides (p < 0.05) combined with lower plasma total cholesterol (p < 0.05) and triglycerides (p = 0.05) due to lower VLDL levels. Circulating white blood cells remained largely unaffected in Cyp2c70 mice. Interestingly, we found a trend (p = 0.08) towards smaller atherosclerotic lesions in the aortic root of Cyp2c70 mice, but no effect on cardiac morphology or function was observed. To conclude, a human-like BA composition ameliorated PCSK9-GOF-induced hypercholesterolaemia in WD-fed mice which translated into a tendency towards smaller atherosclerotic lesions.
胆汁酸（BAs）在脂质稳态和炎症方面发挥着重要作用。基于广泛的临床前小鼠研究，BA信号通路已被认为是心血管疾病的治疗靶点。然而，小鼠和人类之间BA代谢的差异阻碍了临床前研究结果的转化。最近，我们培育出了具有类似人类BA组成的Cyp2c70小鼠，其缺乏小鼠/大鼠特有的鼠胆酸。我们利用这个模型评估了类似人类的BA池对高胆固醇血症小鼠动脉粥样硬化和心脏功能的影响。我们在雄性Cyp2c70和Cyp2c70对照小鼠的肝脏中过表达了PCSK9功能获得性（GOF）突变，并给这些小鼠喂食西式饮食（WD）12周。Cyp2c70小鼠表现出富含鹅去氧胆酸的疏水性BA池。由于极低密度脂蛋白（VLDL）水平较低，Cyp2c70小鼠的肝脏总胆固醇和甘油三酯降低（p<0.05），同时血浆总胆固醇（p<0.05）和甘油三酯（p=0.05）也较低。Cyp2c70小鼠的循环白细胞在很大程度上未受影响。有趣的是，我们发现Cyp2c70小鼠主动脉根部的动脉粥样硬化病变有变小的趋势（p=0.08），但未观察到对心脏形态或功能的影响。总之，类似人类的BA组成改善了WD喂养小鼠中PCSK9-GOF诱导的高胆固醇血症，这转化为动脉粥样硬化病变有变小的趋势。
