ArticleNature metabolism2024
Damaging mutations in liver X receptor-α are hepatotoxic and implicate cholesterol sensing in liver health.
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Article in Nature metabolism, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14citing papers in PubMed
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Who cites it
14 citing papers in PubMed.
- An oral, liver-restricted LXR inverse agonist for dyslipidemia: preclinical development and phase 1 trial.Nature medicine · 2026Trial
- CIDEB and CGI-58 differentially regulate liver lipid-droplet cholesterol to modulate metabolic dysfunction-associated steatohepatitis severity.Cell reports · 2026Article
- Article
- Oxysterol undersulfation promotes osteoarthritis by fueling chondrocyte lipid accumulation.Nature communications · 2026Article
- Balancing cholesterol metabolism in the liver and gut: perspectives in health and disease.Nature reviews. Gastroenterology & hepatology · 2026Review
- Liver Stiffness Directs Intrahepatic Cholesterol Accumulation Through YAP/TAZ in Metabolic Dysfunction-Associated Steatotic Liver Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Role of liver X receptors in the pathogenesis and treatment of chronic liver disease (Review).Molecular medicine reports · 2026Review
- Global and regional burden of liver cancer attributable to drug use in elderly patients: a 1990-2021 analysis from the GBD study.Frontiers in oncology · 2026Article
- Synergistic Effect of Liraglutide and Strength-Endurance Exercise Training on Hepatic Oxidative Stress and Lipid Metabolism in Middle-Aged Male Rats.Antioxidants (Basel, Switzerland) · 2025Article
- Genomic Crosstalk Between Nuclear Receptors in Hormone-dependent Cancers.Endocrinology · 2025Review
- The pathogenesis of hepatic steatosis in MASLD: a lipid droplet perspective.The Journal of clinical investigation · 2025Article
- Liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction-associated steatohepatitis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Exploring the Roles of Liver X Receptors in Lipid Metabolism and Immunity in Atherosclerosis.Biomolecules · 2025Review
- A mutation in LXRα uncovers a role for cholesterol sensing in limiting metabolic dysfunction-associated steatohepatitis.Nature communications · 2025Article
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Authors and funding
42 authors.
Sam M Lockhart *Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK. sl908@cam.ac.uk.ORCID http://orcid.org/0000-0003-2092-4350
Milan Muso *Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK. mm2445@cam.ac.uk.ORCID http://orcid.org/0009-0004-4268-1817
Ilona ZvetkovaMedical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Brian Y H LamMedical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0002-3638-9025
Alessandra FerrariDepartment of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA.
Erik SchoenmakersMedical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0003-0674-8282
Katie DuckettMedical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Jack LeslieNewcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.ORCID http://orcid.org/0000-0001-6443-2396
Amy CollinsNewcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.ORCID http://orcid.org/0000-0003-3619-2588
Beatriz Romartínez-AlonsoInstitute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, UK.ORCID http://orcid.org/0000-0002-3061-6696
John A TadrossMedical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0002-8424-1252
Raina JiaMedical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Eugene J GardnerMedical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0001-9671-1533
Katherine KentistouMedical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0002-5816-664X
Yajie ZhaoMedical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0002-2747-0219
Felix DayMedical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0003-3789-7651
Alexander MörseburgMedical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Kara RainbowMedical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Debra RimmingtonMedical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Matteo MastantuoniMedical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
James HarrisonVPD Heart and Lung Research Institute, Dept. Medicine, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0003-4960-5062
Meritxell NusVPD Heart and Lung Research Institute, Dept. Medicine, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0002-6378-8910
Khalid Guma'aMedical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0009-0000-3835-6115
Sam Sherratt-MayhewMedical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0009-0001-6197-3645
Xiao JiangCentre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Katherine R SmithCentre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Dirk S PaulCentre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.ORCID http://orcid.org/0000-0002-8230-0116
Benjamin JenkinsMedical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0003-0038-9709
Albert KoulmanMedical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0001-9998-051X
Maik PietznerMedical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0003-3437-9963
Claudia LangenbergMedical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0002-5017-7344
Nicholas WarehamMedical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0003-1422-2993
Giles S YeoMedical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0001-8823-3615
Krishna ChatterjeeMedical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
John SchwabeDepartment of Histopathology and Cambridge Genomics Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.ORCID http://orcid.org/0000-0003-2865-4383
Fiona OakleyNewcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.ORCID http://orcid.org/0000-0001-8692-1836
Derek A MannNewcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.ORCID http://orcid.org/0000-0003-0950-243X
Peter TontonozDepartment of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA.ORCID http://orcid.org/0000-0003-1259-0477
Anthony P CollMedical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Ken OngMedical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
John R B PerryMedical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0001-6483-3771
Stephen O'RahillyMedical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK. so104@cam.ac.uk.ORCID http://orcid.org/0000-0003-2199-4449
Funding
Women's CancersP30CA016042 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Samuel Wheeler French · 1985 to 2026
$134.5MTransgenic & Knock-out MouseP30DK063491 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Andrea L Hevener · 2003 to 2026
$40.4MThe Nuclear Receptor-Aster Pathway in Enterohepatic MetabolismR01DK126779 · NIDDK · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI TONTONOZ, PETER J · 2020 to 2024
$2.4MMedical Research Council MR/K001949/1NCI NIH HHS P30 CA016042NIDDK NIH HHS P30 DK063491NIDDK NIH HHS R01 DK126779Wellcome TrustWellcome Trust (Wellcome) WT 095515/Z/11/ZWellcome Trust (Wellcome) WT 225479/Z/22
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.
Indexed as
CholesterolLiverLiver X ReceptorsMutationAnimalsFatty LiverFemaleHepatocytesHumansLipogenesisMaleMiceMice, KnockoutCholesterolLiver X Receptors
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