Damaging mutations in liver X receptor-α are hepatotoxic and implicate cholesterol sensing in liver health PMID: 39322746

ADC Targets in Oncology

2026-04-10

Damaging mutations in liver X receptor-α are hepatotoxic and implicate cholesterol sensing in liver health

Nat Metab. 2024 Oct;6(10):1922-1938. doi: 10.1038/s42255-024-01126-4.

Sam M Lockhart ^# ¹ , Milan Muso ^# ² , Ilona Zvetkova ³ , Brian Y H Lam ³ , Alessandra Ferrari ⁴ , Erik Schoenmakers ³ , Katie Duckett ³ , Jack Leslie ⁵ , Amy Collins ⁵ , Beatriz Romartínez-Alonso ⁶ , John A Tadross ³ ⁷ , Raina Jia ⁸ , Eugene J Gardner ⁸ , Katherine Kentistou ⁸ , Yajie Zhao ⁸ , Felix Day ⁸ , Alexander Mörseburg ³ ⁸ , Kara Rainbow ³ , Debra Rimmington ³ , Matteo Mastantuoni ³ , James Harrison ⁹ , Meritxell Nus ⁹ , Khalid Guma'a ³ , Sam Sherratt-Mayhew ³ , Xiao Jiang ¹⁰ , Katherine R Smith ¹⁰ , Dirk S Paul ¹⁰ , Benjamin Jenkins ³ ¹¹ , Albert Koulman ³ ¹¹ , Maik Pietzner ⁸ ¹² ¹³ , Claudia Langenberg ⁸ ¹² ¹³ , Nicholas Wareham ⁸ , Giles S Yeo ³ , Krishna Chatterjee ³ , John Schwabe ⁷ , Fiona Oakley ⁵ , Derek A Mann ⁵ , Peter Tontonoz ⁴ , Anthony P Coll ³ , Ken Ong ⁸ , John R B Perry ⁸ , Stephen O'Rahilly ¹⁴ ¹⁵

Affiliations

1. Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK. [email protected].
2. Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK. [email protected].
3. Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
4. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA.
5. Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
6. Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, UK.
7. Department of Histopathology and Cambridge Genomics Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
8. Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
9. VPD Heart and Lung Research Institute, Dept. Medicine, University of Cambridge, Cambridge, UK.
10. Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
11. NIHR BRC Core Metabolomics and Lipidomics Laboratory, Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
12. Computational Medicine, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
13. Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
14. Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK. [email protected].
15. NIHR Cambridge Biomedical Research Centre, Cambridge, UK. [email protected].
# Contributed equally.

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.