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Damaging mutations in liver X receptor-α are hepatotoxic and implicate cholesterol sensing in liver health.
Lockhart, Sam M; Muso, Milan; Zvetkova, Ilona; Lam, Brian Y H; Ferrari, Alessandra; Schoenmakers, Erik; Duckett, Katie; Leslie, Jack; Collins, Amy; Romartínez-Alonso, Beatriz; Tadross, John A; Jia, Raina; Gardner, Eugene J; Kentistou, Katherine; Zhao, Yajie; Day, Felix; Mörseburg, Alexander; Rainbow, Kara; Rimmington, Debra; Mastantuoni, Matteo; Harrison, James; Nus, Meritxell; Guma'a, Khalid; Sherratt-Mayhew, Sam; Jiang, Xiao; Smith, Katherine R; Paul, Dirk S; Jenkins, Benjamin; Koulman, Albert; Pietzner, Maik; Langenberg, Claudia; Wareham, Nicholas; Yeo, Giles S; Chatterjee, Krishna; Schwabe, John; Oakley, Fiona; Mann, Derek A; Tontonoz, Peter; Coll, Anthony P; Ong, Ken; Perry, John R B; O'Rahilly, Stephen.
Afiliação
  • Lockhart SM; Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK. sl908@cam.ac.uk.
  • Muso M; Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK. mm2445@cam.ac.uk.
  • Zvetkova I; Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Lam BYH; Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Ferrari A; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA.
  • Schoenmakers E; Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Duckett K; Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Leslie J; Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • Collins A; Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • Romartínez-Alonso B; Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, UK.
  • Tadross JA; Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Jia R; Department of Histopathology and Cambridge Genomics Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • Gardner EJ; Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Kentistou K; Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Zhao Y; Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Day F; Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Mörseburg A; Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Rainbow K; Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Rimmington D; Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Mastantuoni M; Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Harrison J; Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Nus M; Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Guma'a K; VPD Heart and Lung Research Institute, Dept. Medicine, University of Cambridge, Cambridge, UK.
  • Sherratt-Mayhew S; VPD Heart and Lung Research Institute, Dept. Medicine, University of Cambridge, Cambridge, UK.
  • Jiang X; Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Smith KR; Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Paul DS; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
  • Jenkins B; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
  • Koulman A; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
  • Pietzner M; Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Langenberg C; NIHR BRC Core Metabolomics and Lipidomics Laboratory, Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Wareham N; Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Yeo GS; NIHR BRC Core Metabolomics and Lipidomics Laboratory, Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Chatterjee K; Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Schwabe J; Computational Medicine, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Oakley F; Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
  • Mann DA; Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Tontonoz P; Computational Medicine, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Coll AP; Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
  • Ong K; Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Perry JRB; Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • O'Rahilly S; Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Nat Metab ; 6(10): 1922-1938, 2024 Oct.
Article em En | MEDLINE | ID: mdl-39322746
ABSTRACT
Liver X receptor-α (LXRα) regulates cellular cholesterol abundance and potently activates hepatic lipogenesis. Here we show that at least 1 in 450 people in the UK Biobank carry functionally impaired mutations in LXRα, which is associated with biochemical evidence of hepatic dysfunction. On a western diet, male and female mice homozygous for a dominant negative mutation in LXRα have elevated liver cholesterol, diffuse cholesterol crystal accumulation and develop severe hepatitis and fibrosis, despite reduced liver triglyceride and no steatosis. This phenotype does not occur on low-cholesterol diets and can be prevented by hepatocyte-specific overexpression of LXRα. LXRα knockout mice exhibit a milder phenotype with regional variation in cholesterol crystal deposition and inflammation inversely correlating with steatosis. In summary, LXRα is necessary for the maintenance of hepatocyte health, likely due to regulation of cellular cholesterol content. The inverse association between steatosis and both inflammation and cholesterol crystallization may represent a protective action of hepatic lipogenesis in the context of excess hepatic cholesterol.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Colesterol / Receptores X do Fígado / Fígado / Mutação Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Colesterol / Receptores X do Fígado / Fígado / Mutação Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article