Data_Sheet_1_Expressing the Human Cholesteryl Ester Transfer Protein Minigene Improves Diet-Induced Fatty Liver and Insulin Resistance in Female Mice.PDF

Mounting evidence has shown that CETP has important physiological roles in adapting to chronic nutrient excess, specifically, to protect against diet-induced insulin resistance. However, the underlying mechanisms for the protective roles of CETP in metabolism are not yet clear. Mice naturally lack CETP expression. We used transgenic mice with a human CETP minigene (huCETP) controlled by its natural flanking region to further understand CETP-related physiology in response to obesity. Female huCETP mice and their wild-type littermates were fed a high-fat diet for 6 months. Blood lipid profile and liver lipid metabolism were studied. Insulin sensitivity was analyzed with euglycemic-hyperinsulinemic clamp studies combined with 3H-glucose tracer techniques. While high-fat diet feeding induced obesity for huCETP mice and their wild-type littermates lacking CETP expression, insulin sensitivity was higher for female huCETP mice than for their wild-type littermates. There was no difference in insulin sensitivity for male huCETP mice vs. littermates. The increased insulin sensitivity in females was largely caused by the better insulin-mediated suppression of hepatic glucose production. In huCETP females, CETP in the circulation decreased HDL-cholesterol content and increased liver cholesterol uptake and liver cholesterol and oxysterol contents, which was associated with the upregulation of LXR target genes in long-chain polyunsaturated fatty acid biosynthesis and PPARα target genes in fatty acid β-oxidation in the liver. The upregulated fatty acid β-oxidation may account for the improved fatty liver and liver insulin action in female huCETP mice. This study provides further evidence that CETP has beneficial physiological roles in the metabolic adaptation to nutrient excess by promoting liver fatty acid oxidation and hepatic insulin sensitivity, particularly for females.

越来越多的证据表明，胆固醇酯转运蛋白（cholesteryl ester transfer protein，CETP）在应对慢性营养过剩的生理过程中发挥关键作用，具体可抵御饮食诱导的胰岛素抵抗。然而，CETP在代谢中发挥保护作用的潜在分子机制尚未明确。小鼠天然不表达CETP。本研究使用携带受其天然侧翼序列调控的人源CETP小基因（human CETP minigene，huCETP）的转基因小鼠，以进一步探究肥胖状态下与CETP相关的生理机制。将雌性huCETP小鼠与其野生型同窝仔鼠饲喂高脂饲料6个月，随后检测其血脂谱与肝脏脂质代谢情况，并采用正常血糖-高胰岛素钳夹技术结合氚标记葡萄糖示踪技术分析小鼠的胰岛素敏感性。尽管高脂饲料饲喂使huCETP小鼠与天然缺乏CETP表达的野生型同窝仔鼠均出现肥胖，但雌性huCETP小鼠的胰岛素敏感性显著高于其野生型同窝仔鼠；而雄性huCETP小鼠与同窝野生型小鼠的胰岛素敏感性无显著差异。雌性小鼠胰岛素敏感性的提升，主要源于胰岛素介导的肝脏葡萄糖生成抑制作用增强。在雌性huCETP小鼠体内，循环中的CETP可降低高密度脂蛋白胆固醇（HDL-cholesterol）含量，同时提升肝脏胆固醇摄取量以及肝脏胆固醇与氧固醇的含量，该变化与肝脏内长链多不饱和脂肪酸生物合成相关的肝X受体（LXR）靶基因，以及脂肪酸β氧化相关的过氧化物酶体增殖物激活受体α（PPARα）靶基因的上调表达密切相关。上调的脂肪酸β氧化作用可改善雌性huCETP小鼠的脂肪肝与肝脏胰岛素敏感性。本研究进一步证实，CETP可通过促进肝脏脂肪酸氧化与肝脏胰岛素敏感性，在营养过剩的代谢适应过程中发挥有益生理功能，该效应在雌性个体中尤为显著。