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NBEAL1 controls SREBP2 processing and cholesterol metabolism and is a susceptibility locus for coronary artery disease.
Bindesbøll, Christian; Aas, Aleksander; Ogmundsdottir, Margret Helga; Pankiv, Serhiy; Reine, Trine; Zoncu, Roberto; Simonsen, Anne.
Afiliação
  • Bindesbøll C; Department of Molecular Medicine, Institute of Basic Medical Sciences and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 1112 Blindern, 0317, Oslo, Norway. christian.bindesboll@gmail.com.
  • Aas A; Department of Molecular Medicine, Institute of Basic Medical Sciences and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 1112 Blindern, 0317, Oslo, Norway.
  • Ogmundsdottir MH; Department of Biochemistry and Molecular Biology, Biomedical Center, Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101, Reykjavik, Iceland.
  • Pankiv S; Department of Molecular Medicine, Institute of Basic Medical Sciences and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 1112 Blindern, 0317, Oslo, Norway.
  • Reine T; Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, 1112 Blindern, 0317, Oslo, Norway.
  • Zoncu R; Section for Interphase genetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, 0424, Oslo, Norway.
  • Simonsen A; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 94720, USA.
Sci Rep ; 10(1): 4528, 2020 03 11.
Article em En | MEDLINE | ID: mdl-32161285
Dysregulated cholesterol homeostasis promotes the pathology of atherosclerosis, myocardial infarction and strokes. Cellular cholesterol is mainly regulated at the transcriptional level by SREBP2, but also through uptake of extracellular cholesterol from low density lipoproteins (LDL) via expression of LDL receptors (LDLR) at the cell surface. Identification of the mechanisms involved in regulation of these processes are thus key to understand the pathology of coronary artery disease. Here, we identify the large and poorly characterized BEACH domain protein Neurobeachin-like (NBEAL) 1 as a Golgi- associated protein required for regulation of cholesterol metabolism. NBEAL1 is most abundantly expressed in arteries. Genetic variants in NBEAL1 are associated with decreased expression of NBEAL1 in arteries and increased risk of coronary artery disease in humans. We show that NBEAL1 regulates cholesterol metabolism by modulating LDLR expression in a mechanism involving interaction with SCAP and PAQR3 and subsequent SREBP2-processing. Thus, low expression of NBEAL1 may lead to increased risk of coronary artery disease by downregulation of LDLR levels.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença da Artéria Coronariana / Proteínas Sanguíneas / Colesterol / Locos de Características Quantitativas / Suscetibilidade a Doenças / Proteína de Ligação a Elemento Regulador de Esterol 2 Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença da Artéria Coronariana / Proteínas Sanguíneas / Colesterol / Locos de Características Quantitativas / Suscetibilidade a Doenças / Proteína de Ligação a Elemento Regulador de Esterol 2 Idioma: En Ano de publicação: 2020 Tipo de documento: Article