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Lookup NU author(s): Amy Collins, Professor Fiona OakleyORCiD, Professor Derek Mann
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024.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.
Author(s): Lockhart SM, Muso M, Zvetkova I, Lam BYH, Ferrari A, Schoenmakers E, Duckett K, Leslie J, Collins A, Romartinez-Alonso B, Tadross JA, Jia R, Gardner EJ, Kentistou K, Zhao Y, Day F, Morseburg A, Rainbow K, Rimmington D, Mastantuoni M, Harrison J, Nus M, Guma'a K, Sherratt-Mayhew S, Jiang X, Smith KR, Paul DS, Jenkins B, Koulman A, Pietzner M, Langenberg C, Wareham N, Yeo GS, Chatterjee K, Schwabe J, Oakley F, Mann DA, Tontonoz P, Coll AP, Ong K, Perry JRB, O'Rahilly S
Publication type: Article
Publication status: Published
Journal: Nature Metabolism
Year: 2024
Pages: epub ahead of print
Online publication date: 25/09/2024
Acceptance date: 05/08/2024
Date deposited: 08/10/2024
ISSN (electronic): 2522-5812
Publisher: Nature Research
URL: https://doi.org/10.1038/s42255-024-01126-4
DOI: 10.1038/s42255-024-01126-4
Data Access Statement: The UKBB phenotype and whole-exome sequencing data described here are publicly available to registered researchers through the UKBB data access protocol. Information about registration for access to the data is available at https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access. Data for this study were obtained under Resource Application no. 9905. Data from the Fenland cohort can be requested by bona fide researchers for specified scientific purposes via the study website (https://www.mrc-epid.cam.ac.uk/research/studies/fenland/information-for-researchers/). Data will either be shared through an institutional data-sharing agreement or arrangements will be made for analyses to be conducted remotely without the necessity for data transfer. More at https://www.nature.com/articles/s42255-024-01126-4#data-availability and Code availability at https://www.nature.com/articles/s42255-024-01126-4#code-availability
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