Lede Vera, Franke Christin, Meusel Andrej, Teupser Daniel, Ricken Albert, Thiery Joachim, Schiller Jürgen, Huster Daniel, Schöneberg Torsten, Schulz Angela
Molecular Biochemistry, Rudolf-Schönheimer-Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany.
Institute of Medical Physics and Biophysics, Medical Faculty, University of Leipzig, Leipzig, Germany.
PLoS One. 2016 Dec 28;11(12):e0167888. doi: 10.1371/journal.pone.0167888. eCollection 2016.
Dysfunction of the melanocortin system can result in severe obesity accompanied with dyslipidemia and symptoms of the metabolic syndrome but the effect on vascular atherogenesis is not known. To study the impact of obesity and dyslipidemia on the cardiovascular system, we generated mice double-deficient for the melanocortin type 4 receptor (Mc4rmut mice) and the LDL receptor (Ldlr-/- mice). Mc4rmut mice develop obesity due to hyperphagia. Double-mutant mice (Mc4rmut;Ldlr-/-) exhibited massive increases in body weight, plasma cholesterol and triacylglycerol levels and developed atherosclerosis. Atherosclerotic lesion size was affected throughout the aortic root and brachiocephalic artery not only under semisynthetic, cholesterol-containing diet but also under cholesterol-free standard chow. The Mc4rmut mice developed a hepatic steatosis which contributes to increased plasma cholesterol levels even under cholesterol-free standard chow. Transcripts of cholesterol biosynthesis components and liver cholesterol levels did not significantly differ between wild-type and all mutant mouse strains but RNA sequencing data and biochemical measurements point to an altered bile acid elimination in Mc4rmut;Ldlr-/-. Therefore, the unchanged endogenous cholesterol biosynthesis together with a reduced hepatic VLDL and LDL-cholesterol clearance most likely led to increased plasma lipid levels and consequently to atherosclerosis in this animal model. Our data indicate that dysfunction of the melanocortin-regulated food intake and the resulting obesity significantly add to the proatherogenic lipoprotein profile caused by LDL receptor deficiency and, therefore, can be regarded as relevant risk factor for atherosclerosis.
黑皮质素系统功能障碍可导致严重肥胖，并伴有血脂异常和代谢综合征症状，但对血管动脉粥样硬化的影响尚不清楚。为了研究肥胖和血脂异常对心血管系统的影响，我们培育了黑素皮质素4型受体双缺陷小鼠（Mc4rmut小鼠）和低密度脂蛋白受体缺陷小鼠（Ldlr-/-小鼠）。Mc4rmut小鼠因摄食过多而肥胖。双突变小鼠（Mc4rmut;Ldlr-/-）体重、血浆胆固醇和甘油三酯水平大幅升高，并发展为动脉粥样硬化。不仅在含胆固醇的半合成饮食条件下，而且在无胆固醇的标准饲料喂养下，整个主动脉根部和头臂动脉的动脉粥样硬化病变大小均受到影响。Mc4rmut小鼠出现肝脂肪变性，即使在无胆固醇的标准饲料喂养下，也会导致血浆胆固醇水平升高。野生型和所有突变小鼠品系之间胆固醇生物合成成分的转录本和肝脏胆固醇水平没有显著差异，但RNA测序数据和生化测量结果表明，Mc4rmut;Ldlr-/-小鼠的胆汁酸清除发生了改变。因此，在该动物模型中，内源性胆固醇生物合成不变，同时肝脏极低密度脂蛋白和低密度脂蛋白胆固醇清除率降低，很可能导致血浆脂质水平升高，进而导致动脉粥样硬化。我们的数据表明，黑皮质素调节的食物摄入功能障碍以及由此导致的肥胖显著增加了由低密度脂蛋白受体缺陷引起的促动脉粥样硬化脂蛋白谱，因此可被视为动脉粥样硬化的相关危险因素。
