title: 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.
authors.affiliation: Molecular Biochemistry, Rudolf-Schönheimer-Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Lede
authors.affiliation: Molecular Biochemistry, Rudolf-Schönheimer-Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Franke
authors.affiliation: 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.
authors.forename: Andrej
authors.initials: A
authors.lastname: Meusel
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Medical Faculty, University of Leipzig, Leipzig, Germany.|Institute of Laboratory Medicine, Ludwig Maximilians University Munich, Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Teupser
authors.affiliation: Institute of Anatomy, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Ricken
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Thiery
authors.affiliation: Institute of Medical Physics and Biophysics, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schiller
authors.affiliation: Institute of Medical Physics and Biophysics, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Huster
authors.affiliation: Molecular Biochemistry, Rudolf-Schönheimer-Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Schöneberg
authors.affiliation: Molecular Biochemistry, Rudolf-Schönheimer-Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Angela
authors.identifier: http://orcid.org/0000-0003-2336-1573
authors.initials: A
authors.lastname: Schulz
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D001647:Bile Acids and Salts / Q000096:biosynthesis; D049628:Body Size / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis / Q000494:pharmacology; D004032:Diet; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000172:deficiency* / Q000235:genetics*; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics*
chemical_list: D001647:Bile Acids and Salts; D012333:RNA, Messenger; D044105:Receptor, Melanocortin, Type 4; D011973:Receptors, LDL; D002784:Cholesterol