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IDOL regulates systemic energy balance through control of neuronal VLDLR expression.
Lee, Stephen D; Priest, Christina; Bjursell, Mikael; Gao, Jie; Arneson, Douglas V; Ahn, In Sook; Diamante, Graciel; van Veen, J Edward; Massa, Megan G; Calkin, Anna C; Kim, Jason; Andersén, Harriet; Rajbhandari, Prashant; Porritt, Michelle; Carreras, Alba; Ahnmark, Andrea; Seeliger, Frank; Maxvall, Ingela; Eliasson, Pernilla; Althage, Magnus; Åkerblad, Peter; Lindén, Daniel; Cole, Tracy A; Lee, Richard; Boyd, Helen; Bohlooly-Y, Mohammad; Correa, Stephanie M; Yang, Xia; Tontonoz, Peter; Hong, Cynthia.
Afiliação
  • Lee SD; Department of Pathology and Laboratory Medicine, Department of Biological Chemistry, and Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Priest C; Department of Pathology and Laboratory Medicine, Department of Biological Chemistry, and Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Bjursell M; Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Gao J; Department of Pathology and Laboratory Medicine, Department of Biological Chemistry, and Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Arneson DV; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Ahn IS; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Diamante G; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
  • van Veen JE; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Massa MG; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Calkin AC; Department of Pathology and Laboratory Medicine, Department of Biological Chemistry, and Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Kim J; Department of Pathology and Laboratory Medicine, Department of Biological Chemistry, and Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Andersén H; Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Rajbhandari P; Department of Pathology and Laboratory Medicine, Department of Biological Chemistry, and Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Porritt M; Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Carreras A; Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Ahnmark A; Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Seeliger F; Pathology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
  • Maxvall I; Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Eliasson P; Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Althage M; Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Åkerblad P; Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Lindén D; Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Cole TA; Division of Endocrinology, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  • Lee R; Central Nervous System Group, Antisense Drug Discovery, Ionis Pharmaceuticals, Inc, Carlsbad, CA, USA.
  • Boyd H; Central Nervous System Group, Antisense Drug Discovery, Ionis Pharmaceuticals, Inc, Carlsbad, CA, USA.
  • Bohlooly-Y M; Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca; Cambridge Science Park, Cambridge, UK.
  • Correa SM; Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Yang X; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Tontonoz P; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Hong C; Department of Pathology and Laboratory Medicine, Department of Biological Chemistry, and Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. PTontonoz@mednet.ucla.edu.
Nat Metab ; 1(11): 1089-1100, 2019 11.
Article em En | MEDLINE | ID: mdl-32072135
ABSTRACT
Liver X receptors limit cellular lipid uptake by stimulating the transcription of Inducible Degrader of the LDL Receptor (IDOL), an E3 ubiquitin ligase that targets lipoprotein receptors for degradation. The function of IDOL in systemic metabolism is incompletely understood. Here we show that loss of IDOL in mice protects against the development of diet-induced obesity and metabolic dysfunction by altering food intake and thermogenesis. Unexpectedly, analysis of tissue-specific knockout mice revealed that IDOL affects energy balance, not through its actions in peripheral metabolic tissues (liver, adipose, endothelium, intestine, skeletal muscle), but by controlling lipoprotein receptor abundance in neurons. Single-cell RNA sequencing of the hypothalamus demonstrated that IDOL deletion altered gene expression linked to control of metabolism. Finally, we identify VLDLR rather than LDLR as the primary mediator of IDOL effects on energy balance. These studies identify a role for the neuronal IDOL-VLDLR pathway in metabolic homeostasis and diet-induced obesity.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores de LDL / Ubiquitina-Proteína Ligases / Metabolismo Energético / Neurônios Limite: Animals Idioma: En Ano de publicação: 2019 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores de LDL / Ubiquitina-Proteína Ligases / Metabolismo Energético / Neurônios Limite: Animals Idioma: En Ano de publicação: 2019 Tipo de documento: Article