Ezetimibe Markedly Reduces Hepatic Triglycerides and Cholesterol in Rats Fed on Fish Oil by Increasing the Expression of Cholesterol Efflux Transporters
Ezetimibe Markedly Reduces Hepatic Triglycerides and Cholesterol in Rats Fed on Fish Oil by Increasing the Expression of Cholesterol Efflux Transporters
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DOI：
10.1124/jpet.120.265660
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发表时间：
2020-05
期刊：
影响因子：
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通讯作者：
Yuji Tanaka;T. Ikeda;H. Ogawa;T. Kamisako
中科院分区：
文献类型：
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作者：
Yuji Tanaka;T. Ikeda;H. Ogawa;T. Kamisako
除饮食治疗外，降血脂药物治疗可能是非酒精性脂肪性肝病（NAFLD）治疗的重要组成部分。依折替米贝可能是治疗NAFLD的一种很有前途的药物。鱼油中富含的N-3多不饱和脂肪酸可以降低啮齿类动物的血清和肝脏胆固醇和甘油三酯。本研究的目的是研究鱼油和依折替米对大鼠脂质代谢的联合影响。选取7周龄雄性sd - dawley大鼠，分别饲喂1)10%大豆油（C)、2)10%鱼油(F)、3）10%大豆油+ 0.005%依泽替米贝和4)10%鱼油+ 0.005%依泽替米贝（F+E） 4种不同的饲粮，采集肝脏、空肠、血液和粪便样品，持续4周。与C组相比，F+E组肝脏甘油三酯和胆固醇分别降低84%和86%，但粪便胆固醇未升高。在肝脏中，F+E饮食降低了脂肪生成酶的表达，而β-氧化相关基因没有增加。在F日粮中添加依折麦比，Abcg5/g8 mRNA的表达量增加了1380%/442%。这些基因表达变化与肝脏脂质降低有关。空肠Abcg5/g8 mRNA在F饲粮中添加依折麦布后分别提高了244%/841%。当在F日粮中添加依折麦比时，肝诱导Abcg5/8而非肠诱导与肝脏胆固醇的显著降低相关。这些数据表明，鱼油饮食和依折替米贝联合使用可能通过增加肝脏Abcg5/ 8和降低脂肪生成基因而对NAFLD有益。目前没有单一的治疗NAFLD的方法。因此，改变生活方式，包括饮食调节和体育锻炼也是重要的选择。在这项研究中，以依折替贝，一种胆固醇吸收抑制剂，被评估为治疗肝脂肪变性大鼠喂养不同的饮食。我们发现依折麦比和鱼油联合使用通过增加胆固醇外排转运体显著改善脂肪肝。鱼油制剂与依折麦布联合治疗NAFLD可能有效。
Besides diet therapy, hypolipidemic pharmacological therapy may be a crucial component of nonalcoholic fatty liver disease (NAFLD) treatment. Ezetimibe may be a promising drug for treatment of NAFLD. n-3 polyunsaturated fatty acids, which are abundant in fish oil, reduce serum and hepatic cholesterol and triglycerides in rodents. The aim of this study was to examine the combined effects of dietary fish oil and ezetimibe on lipid metabolism in rats. Seven-week-old male Sprague-Dawley rats were allocated to four different diets containing 1) 10% soybean oil (C), 2) 10% fish oil (F), 3) 10% soybean oil + 0.005% ezetimibe, and 4) 10% fish oil + 0.005% ezetimibe (F+E) for 4 weeks, when the liver, jejunum, blood, and fecal samples were collected. Compared with the C group, the F+E diet decreased hepatic triglycerides and cholesterol 84% and 86%, but it did not increase fecal cholesterol. In liver, the expression of lipogenic enzymes was decreased in the F+E diet, whereas β-oxidation–related genes were not increased. Abcg5/g8 mRNA expression was increased 1380%/442% when ezetimibe was added to the F diet. These gene expression changes are related to the decrease in hepatic lipids. In jejunum, Abcg5/g8 mRNA was increased 244%/841% when ezetimibe was added to the F diet. Hepatic induction of Abcg5/8 rather than intestinal induction correlates with the marked decrease in liver cholesterol when ezetimibe was added to the F diet. These data suggest that fish oil diet and ezetimibe in combination may be a beneficial therapy for NAFLD by increasing hepatic Abcg5/g8 and decreasing lipogenic genes. SIGNIFICANCE STATEMENT There is currently no single treatment for NAFLD. Thus, lifestyle modifications including dietary regulation and physical activity are also important options. In this study, ezetimibe, a cholesterol absorption inhibitor, was evaluated for the treatment of liver steatosis in rats fed on the different diets. We found that ezetimibe and fish oil in combination markedly improved fatty liver by increasing cholesterol efflux transporters. The combination therapy of fish oil agents and ezetimibe may be effective for NAFLD.