胆固醇水平和胆汁酸代谢是代谢功能障碍相关脂肪性肝炎 (MASH) 进展的重要驱动因素。使用小鼠模型，我们研究了胆固醇加剧 MASH 的机制，以及同时服用考来烯胺（一种胆汁酸吸附树脂）和埃洛昔巴特（一种顶端钠依赖性胆汁酸转运蛋白抑制剂）对胆汁酸吸附和 MASH 状态的影响。喂食含有不同浓度胆固醇的高脂高果糖饮食，根据肝脏状况、饮水量、排便状况、胰岛素抵抗、胆汁酸水平、肠道通透性、动脉粥样硬化来确定脂肪肝的变化（在载脂蛋白 E 敲除小鼠中）和致癌作用（在二乙基亚硝胺小鼠中）。使用小干扰核糖核酸 (siRNA)，我们评估了在给予埃罗比昔巴特（E 组）、考来烯胺（C 组）或两者后，甾醇调节元件结合蛋白 1c (SREBP1c) 敲低对甘油三酯合成和脂肪肝状态的影响。 EC组）。我们发现EC组的血清丙氨酸氨基转移酶水平、血清脂质参数、血清初级胆汁酸浓度、肝脂质水平和纤维化面积比单一治疗组有更大的降低。 EC 组中由 eobixibat 引起的肠道通透性增加和水样腹泻得到完全改善。 EC组显示动脉粥样硬化模型的整个主动脉和主动脉瓣膜的斑块形成率降低，癌变模型的肿瘤计数和肿瘤负荷减少。肝脏中过多的游离胆固醇可促进脂肪肝疾病。在此，EC 联合治疗有效降低了 MASH 模型小鼠的游离胆固醇水平。我们的研究为联合疗法作为 MASH 的有效治疗方法提供了强有力的证据。版权所有 © 2023 作者。由 Wolters Kluwer Health, Inc. 代表美国肝病研究协会出版。

Cholesterol levels and bile acid metabolism are important drivers of metabolic dysfunction-associated steatohepatitis (MASH) progression. Using a mouse model, we investigated the mechanism by which cholesterol exacerbates MASH and the effect of colestyramine (a bile acid adsorption resin) and elobixibat (an apical sodium-dependent bile acid transporter inhibitor) concomitant administration on bile acid adsorption and MASH status.Mice were fed a high-fat high-fructose diet with varying concentrations of cholesterol to determine changes in fatty liver according to liver status, water intake, defecation status, insulin resistance, bile acid levels, intestinal permeability, atherosclerosis (in apolipoprotein E knockout mice), and carcinogenesis (in diethylnitrosamine mice). Using small interfering ribonucleic acid (siRNA), we evaluated the effect of sterol regulatory element binding protein 1c (SREBP1c) knockdown on triglyceride synthesis and fatty liver status following the administration of elobixibat (group E), colestyramine (group C), or both (group EC).We found greater reductions in serum alanine aminotransferase levels, serum lipid parameters, serum primary bile acid concentrations, hepatic lipid levels, and fibrosis area in EC group than in the monotherapy groups. Increased intestinal permeability and watery diarrhea caused by elobixibat were completely ameliorated in group EC. Group EC showed reduced plaque formation rates in the entire aorta and aortic valve of the atherosclerosis model, and reduced tumor counts and tumor burden in the carcinogenesis model.Excessive free cholesterol in the liver can promote fatty liver disease. Herein, combination therapy with EC effectively reduced free cholesterol levels in MASH model mice. Our study provides strong evidence for combination therapy as an effective treatment for MASH.Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.