Dataset Information

Severe Atherosclerosis and Hypercholesterolemia in Mice Lacking Both the Melanocortin Type 4 Receptor and Low Density Lipoprotein Receptor.

ABSTRACT: 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.

SUBMITTER: Lede V

PROVIDER: S-EPMC5193345 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Severe Atherosclerosis and Hypercholesterolemia in Mice Lacking Both the Melanocortin Type 4 Receptor and Low Density Lipoprotein Receptor.

Lede Vera V Franke Christin C Meusel Andrej A Teupser Daniel D Ricken Albert A Thiery Joachim J Schiller Jürgen J Huster Daniel D Schöneberg Torsten T Schulz Angela A

PloS one 20161228 12

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 in ...[more]

PMID: 28030540

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Project description:Rabbits (Oryctolagus cuniculus) have been the very frequently used as animal models in the study of human lipid metabolism and atherosclerosis, because they have similar lipoprotein metabolism to humans. Most of hyperlipidemia and atherosclerosis rabbit models are produced by feeding rabbits a high-cholesterol diet. Gene editing or knockout (KO) offered another means of producing rabbit models for study of the metabolism of lipids and lipoproteins. Even so, apolipoprotein (Apo)E KO rabbits must be fed a high-cholesterol diet to induce hyperlipidemia. In this study, we used the CRISPR/Cas9 system anchored exon 7 of low-density lipoprotein receptor (LDLR) in an attempt to generate KO rabbits. We designed two sgRNA sequences located in E7:g.7055-7074 and E7:g.7102-7124 of rabbit LDLR gene, respectively. Seven LDLR-KO founder rabbits were generated, and all of them contained biallelic modifications. Various mutational LDLR amino acid sequences of the 7 founder rabbits were subjected to tertiary structure modeling with SWISS-MODEL, and results showed that the structure of EGF-A domain of each protein differs from the wild-type. All the founder rabbits spontaneously developed hypercholesterolemia and atherosclerosis on a normal chow (NC) diet. Analysis of their plasma lipids and lipoproteins at the age of 12 weeks revealed that all these KO rabbits exhibited markedly increased levels of plasma TC (the highest of which was 1013.15 mg/dl, 20-fold higher than wild-type rabbits), LDL-C (the highest of which was 730.00 mg/dl, 35-fold higher than wild-type rabbits) and TG accompanied by reduced HDL-C levels. Pathological examinations of a founder rabbit showed prominent aortic atherosclerosis lesions and coronary artery atherosclerosis.In conclusion, we have reported the generation LDLR-KO rabbit model for the study of spontaneous hypercholesterolemia and atherosclerosis on a NC diet. The LDLR-KO rabbits should be a useful rabbit model of human familial hypercholesterolemia (FH) for the simulations of human primary hypercholesterolemia and such models would allow more exact research into cardio-cerebrovascular disease.

Dataset Information

Severe Atherosclerosis and Hypercholesterolemia in Mice Lacking Both the Melanocortin Type 4 Receptor and Low Density Lipoprotein Receptor.

Publications

Severe Atherosclerosis and Hypercholesterolemia in Mice Lacking Both the Melanocortin Type 4 Receptor and Low Density Lipoprotein Receptor.

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