Microsomal triglyceride transfer protein inhibitor lomitapide-induced liver toxicity is ameliorated by Triiodothyronine treatment following improved bile homeostasis and β-oxidation
Microsomal triglyceride transfer protein inhibitor lomitapide-induced liver toxicity is ameliorated by Triiodothyronine treatment following improved bile homeostasis and β-oxidation
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DOI：
10.1016/j.taap.2021.115825
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发表时间：
2022-01-01
影响因子：
3.8
通讯作者：
Jain, Mukul
中科院分区：
文献类型：
--
作者：
Patel, Vishal;Joharapurkar, Amit;Jain, Mukul
血脂异常或其严重版本，如家族性高胆固醇血症，导致心血管疾病的高风险。洛美他派是一种微粒体甘油三酯转移蛋白抑制剂，被批准用于治疗与肝脏脂肪蓄积相关的家族性高胆固醇血症。在这项工作中，我们研究了洛美他派和三碘甲状腺原氨酸（T-3）的组合在Zucker脂肪大鼠中的作用。每天一次给予这些大鼠洛美他派（1 mg/kg，PO）或T-3（13 μ g/kg，PO）或其组合，持续14天。给药期间每天记录一次体重和摄食量。在治疗结束时评估血清和肝脏脂质、葡萄糖耐量、血清转氨酶、胆汁、肝脏基因表达和肝脏组织学。洛美他派治疗降低了体重、摄食量、葡萄糖耐受不良和血脂，并升高了血清转氨酶和肝脏脂质。当与T3组合时，洛美他派显示出增强的体重、食物摄入、血清胆固醇、血清LDL和葡萄糖耐受不良的降低。联合治疗增加胆汁流速和胆汁胆固醇排泄率。联合T3与洛美他派减弱血清转氨酶和肝脏脂质的升高。联合给药后，肝脏ABCB 11、ABCG 5、ABCG 8、CYP 7A 1、CPT 1和ACOX 1表达增加。组织学分析表明，T3减弱了洛美他派引起的肝脏脂肪蓄积。这些数据表明，洛美他派与T3联合使用可降低洛美他派诱导的肝毒性，并为肥胖和葡萄糖耐受不良提供额外的益处。
Dyslipidemia or its severe version like familial hypercholesterolemia causes a high risk for cardiovascular diseases. Lomitapide, a microsomal triglyceride transfer protein inhibitor, is approved to treat familial hypercholesterolemia, associated with liver fat accumulation. In this work, we investigated the effect of the combination of lomitapide and triiodothyronine (T-3) in Zucker fatty rats. Lomitapide (1 mg/kg, PO), or T-3 (13 mu g/kg, PO), or their combination, were given to these rats once daily for fourteen days. Body weight and food intake were recorded once daily during the treatment period. Serum and hepatic lipids, glucose tolerance, serum aminotransferases, bile fluids, hepatic gene expression, and liver histology were assessed at the end of the treatment. Lomitapide treatment reduced body weight, food intake, glucose intolerance, and serum lipids, and elevated serum aminotransferases and liver lipids. When combined with T3, lomitapide showed an enhanced reduction in body weight, food intake, serum cholesterol, serum LDL, and glucose intolerance. The combination treatment increased bile flow rate and biliary cholesterol excretion rate. Combining T3 with lomitapide attenuated the elevation of serum aminotransferases and liver lipids. Hepatic ABCB11, ABCG5, ABCG8, CYP7A1, CPT1, and ACOX1 expressions were increased with combination treatment. Histological analysis indicated that T3 attenuated hepatic fat accumulation caused by lomitapide. These data suggests that combining lomitapide with T3 may reduce lomitapide-induced hepatic toxicity and provide additional benefits in obesity and glucose intolerance.