Dataset for: Male apoE*3-Leiden.CETP – mice on high-fat high-cholesterol diet exhibit a biphasic dyslipidemic response, mimicking the changes in plasma lipids observed through life in men.

The physiological adaptations resulting in the development of the metabolic syndrome in man occur over a time span of several decades. This combined with the prohibitive financial cost and ethical concerns to measure key metabolic parameters repeatedly in subjects for the major part of their life span, makes that comprehensive longitudinal human data sets are virtually non-existent. While experimental mice are often used, little is known whether this species is in fact an adequate model to better understand the mechanisms that drive the metabolic syndrome in man.
We took up the challenge to study the response of male apoE*3-Leiden.CETP mice (with a humanized lipid profile) to a high-fat high-cholesterol diet for six months. Study parameters include body weight, food intake, plasma and liver lipids, hepatic transcriptome, VLDL – triglyceride production and importantly the use of stable isotopes to measure hepatic de novo lipogenesis, gluconeogenesis, and biliary/fecal sterol secretion to assess metabolic fluxes.
The key observations include 1) high inter-individual variation, 2) a largely unaffected hepatic transcriptome at 2, 3 and 6 months, 3) a biphasic response curve of the main metabolic features over time, and 4) maximum insulin resistance preceding dyslipidemia. The biphasic response in plasma triglyceride and total cholesterol appears to mimic that of men in cross-sectional studies. Combined, these observations suggest that studies such as these can help to delineate the causes of metabolic derangements in patients suffering from metabolic syndrome.

人类代谢综合征的发展过程中，其生理适应机制的形成跨越了几十年。加之在个体生命周期的大部分时间里，反复测量关键代谢参数所面临的巨大经济成本和伦理考量，使得全面的纵向人体数据集几乎不存在。尽管实验鼠常被用作研究对象，但对于该物种是否能够充分模拟人类代谢综合征的驱动机制，了解甚微。我们接受挑战，研究具有人源化脂质谱的雄性apoE*3-Leiden.CETP小鼠（经高脂肪高胆固醇饮食喂养六个月）的反应。研究参数包括体重、食物摄入、血浆和肝脏脂质、肝脏转录组、VLDL-甘油三酯生成以及稳定同位素在测量肝脏从头合成脂质、糖异生以及胆汁/粪便固醇分泌中的应用，以评估代谢通量。关键观察结果包括：1）个体间差异显著；2）在2、3和6个月时，肝脏转录组基本未受影响；3）主要代谢特征随时间呈现的双相反应曲线；4）在血脂异常出现之前，最大程度的胰岛素抵抗。血浆甘油三酯和总胆固醇的双相反应曲线似乎与横断面研究中男性的表现相似。综合这些观察结果，表明此类研究有助于阐明患有代谢综合征的患者的代谢紊乱原因。