BACKGROUND The LDL-C lowering effect of ezetimibe has been attributed primarily to increased catabolism of LDL-C via up-regulation of LDL receptor (LDLR) and decreased cholesterol absorption. Recently, ezetimibe has been demonstrated to have reverse cholesterol transport (RCT) promoting effects in mice, hamsters and humans. However, the underlying mechanisms are still not clear. The aim of this study is to investigate whether ezetimibe improves RCT-related protein expression in LDLR-/- hamsters. METHODS A high-fat diet was used to induce a human-like hyperlipidemia in LDLR-/- hamsters. Lipid profiles were assayed by commercially available kits, and the effects of ezetimibe on lipid metabolism-related protein expression were carried out via western blot. RESULTS Our data demonstrated that ezetimibe administration significantly reduced plasma total cholesterol (~ 51.6% reduction, P < 0.01) and triglyceride (from ~ 884.1 mg/dL to ~ 277.3 mg/dL) levels in LDLR-/- hamsters fed a high-fat diet. Ezetimibe administration (25 mg/kg/d) significantly promoted the protein expression of cholesterol 7 alpha-hydroxylase A1 (CYP7A1), LXRβ and peroxisome proliferator-activated receptor (PPAR) γ; and down-regulated the protein expression of PPARα and PPARβ. However, it showed no significant effect on sterol regulatory element-binding protein (SREBP)-1c, SREBP-2, proprotein convertase subtilisin/kexin type 9 (PCSK9), Niemann-Pick C1-like 1 (NPC1L1), and ATP-biding cassette (ABC) G5/G8. CONCLUSION Ezetimibe may accelerate the transformation from cholesterol to bile acid via promoting CYP7A1 and thereby enhance RCT. As a compensatory mechanism of TG lowering, ezetimibe promoted the protein expression of PPARγ and decreased PPARα and β. These results are helpful in explaining the lipid-lowering effects of ezetimibe and the potential compensatory mechanisms.

中文翻译：

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Ezetimibe促进CYP7A1并调节PPARs，作为LDL受体缺失仓鼠的一种补偿机制。

背景技术依泽替米贝的LDL-C降低作用主要归因于通过上调LDL受体（LDLR）和降低胆固醇吸收而增加了LDL-C的分解代谢。最近，已证明依泽替米贝在小鼠，仓鼠和人类中具有促进胆固醇逆向转运（RCT）的作用。但是，其潜在机制仍不清楚。这项研究的目的是调查依折麦布是否可以改善LDLR-/-仓鼠中RCT相关的蛋白表达。方法采用高脂饮食在LDLR-/-仓鼠中诱发人样高脂血症。用可商购的试剂盒测定脂质谱，通过蛋白质印迹法测定依泽替米贝对脂质代谢相关蛋白表达的影响。结果我们的数据表明，以高脂喂养的LDLR-/-仓鼠，服用依泽替米贝可显着降低血浆总胆固醇（降低约51.6％，P <0.01）和甘油三酸酯（从〜884.1 mg / dL至〜277.3 mg / dL）水平。饮食。给予依泽替米贝（25 mg / kg / d）可显着促进胆固醇7α-羟化酶A1（CYP7A1），LXRβ和过氧化物酶体增殖物激活受体（PPAR）γ的蛋白表达。下调PPARα和PPARβ的蛋白表达。但是，它对固醇调节元件结合蛋白（SREBP）-1c，SREBP-2，前蛋白转化酶枯草杆菌蛋白酶/ kexin 9型（PCSK9），Niemann-Pick C1样1（NPC1L1）和ATP竞标没有显着影响卡匣（ABC）G5 / G8。结论依泽替米贝可能通过促进CYP7A1促进胆固醇从胆汁酸向胆汁酸的转化，从而增强RCT。依泽替米贝作为降低TG的补偿​​机制，促进了PPARγ的蛋白表达，并降低了PPARα和β。这些结果有助于解释依折麦布的降脂作用和潜在的补偿机制。