| Title: |
Damaging mutations in liver X receptor-α are hepatotoxic and implicate cholesterol sensing in liver health. |
| Authors: |
Lockhart, SM; Muso, M; Zvetkova, I; Lam, BYH; Ferrari, A; Schoenmakers, E; Duckett, K; Leslie, J; Collins, A; Romartínez-Alonso, B; Tadross, JA; Jia, R; Gardner, EJ; Kentistou, K; Zhao, Y; Day, F; Mörseburg, 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 |
| Publisher Information: |
Springer Nature |
| Publication Year: |
2024 |
| Collection: |
Queen Mary University of London: Queen Mary Research Online (QMRO) |
| Subject Terms: |
Animals; Liver X Receptors; Cholesterol; Humans; Mice; Liver; Male; Female; Mutation; Knockout; Fatty Liver; Lipogenesis; Hepatocytes |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
1922 - 1938 |
| Language: |
English |
| Relation: |
Nat Metab; https://qmro.qmul.ac.uk/xmlui/handle/123456789/103524 |
| DOI: |
10.1038/s42255-024-01126-4 |
| Availability: |
https://qmro.qmul.ac.uk/xmlui/handle/123456789/103524; https://doi.org/10.1038/s42255-024-01126-4 |
| Rights: |
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. ; © The Author(s) 2024 |
| Accession Number: |
edsbas.587EA2EA |
| Database: |
BASE |