title: Altered hepatic lipid metabolism in mice lacking both the melanocortin type 4 receptor and low density lipoprotein receptor.
abstract: Obesity is often associated with dyslipidemia and hepatosteatosis. A number of animal models of non-alcoholic fatty liver disease (NAFLD) are established but they significantly differ in the molecular and biochemical changes depending on the genetic modification and diet used. Mice deficient for melanocortin type 4 receptor (Mc4rmut) develop hyperphagia, obesity, and subsequently NAFLD already under regular chow and resemble more closely the energy supply-driven obesity found in humans. This animal model was used to assess the molecular and biochemical consequences of hyperphagia-induced obesity on hepatic lipid metabolism. We analyzed transcriptome changes in Mc4rmut mice by RNA sequencing and used high resolution 1H magic angle spinning NMR spectroscopy and MALDI-TOF mass spectrometry to assess changes in the lipid composition. On the transcriptomic level we found significant changes in components of the triacylglycerol metabolism, unsaturated fatty acids biosynthesis, peroxisome proliferator-activated receptor signaling pathways, and lipid transport and storage compared to the wild-type. These findings were supported by increases in triacylglycerol, monounsaturated fatty acid, and arachidonic acid levels. The transcriptome signatures significantly differ from those of other NAFLD mouse models supporting the concept of hepatic subphenotypes depending on the genetic background and diet. Comparative analyses of our data with previous studies allowed for the identification of common changes and genotype-specific components and pathways involved in obesity-associated NAFLD.
authors.affiliation: Molecular Biochemistry, Rudolf-Schönheimer-Institute of Biochemistry, University of Leipzig, Leipzig, Germany.
authors.forename: Vera
authors.identifier: http://orcid.org/0000-0001-6045-2605
authors.initials: V
authors.lastname: Lede
authors.affiliation: Institute of Medical Physics and Biophysics, University of Leipzig, Leipzig, Germany.
authors.forename: Andrej
authors.initials: A
authors.lastname: Meusel
authors.affiliation: Hospital for Children & Adolescents, Department of Women and Child Health, Center for Pediatric Research Leipzig, University of Leipzig, Leipzig, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Garten
authors.affiliation: Institute of Medical Physics and Biophysics, University of Leipzig, Leipzig, Germany.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Popkova
authors.affiliation: Hospital for Children & Adolescents, Department of Women and Child Health, Center for Pediatric Research Leipzig, University of Leipzig, Leipzig, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Penke
authors.affiliation: Heart and Vascular Center, Bad Bevensen, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Franke
authors.affiliation: Institute of Anatomy, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Ricken
authors.affiliation: Molecular Biochemistry, Rudolf-Schönheimer-Institute of Biochemistry, University of Leipzig, Leipzig, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Schulz
authors.affiliation: Hospital for Children & Adolescents, Department of Women and Child Health, Center for Pediatric Research Leipzig, University of Leipzig, Leipzig, Germany.
authors.forename: Wieland
authors.initials: W
authors.lastname: Kiess
authors.affiliation: Institute of Medical Physics and Biophysics, University of Leipzig, Leipzig, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Huster
authors.affiliation: Molecular Biochemistry, Rudolf-Schönheimer-Institute of Biochemistry, University of Leipzig, Leipzig, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Schöneberg
authors.affiliation: Institute of Medical Physics and Biophysics, University of Leipzig, Leipzig, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schiller
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006937:Hypercholesterolemia / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D050356:Lipid Metabolism; D050155:Lipogenesis / Q000235:genetics*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D009765:Obesity / Q000150:complications; D044105:Receptor, Melanocortin, Type 4 / Q000172:deficiency* / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics
chemical_list: C574273:MC4R protein, mouse; D044105:Receptor, Melanocortin, Type 4; D011973:Receptors, LDL