| Title: | Damaging mutations in liver X receptor-α are hepatotoxic and implicate cholesterol sensing in liver health |
| Journal: | Nature Metabolism |
| Published: | 25 Sep 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39322746/ |
| DOI: | https://doi.org/10.1038/s42255-024-01126-4 |
Publication 13442
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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.</p>
13 Keywords
- Animals
- Cholesterol
- Fatty Liver
- Female
- Hepatocytes
- Humans
- Lipogenesis
- Liver
- Liver X Receptors
- Male
- Mice
- Mice, Knockout
- Mutation
42 Authors
- Sam M. Lockhart
- Milan Muso
- Ilona Zvetkova
- Brian Y. H. Lam
- Alessandra Ferrari
- Erik Schoenmakers
- Katie Duckett
- Jack Leslie
- Amy Collins
- Beatriz Romartínez-Alonso
- John A. Tadross
- Raina Jia
- Eugene J. Gardner
- Katherine Kentistou
- Yajie Zhao
- Felix Day
- Alexander Mörseburg
- Kara Rainbow
- Debra Rimmington
- Matteo Mastantuoni
- James Harrison
- Meritxell Nus
- Khalid Guma'a
- Sam Sherratt-Mayhew
- Xiao Jiang
- Katherine R. Smith
- Dirk S. Paul
- Benjamin Jenkins
- Albert Koulman
- Maik Pietzner
- Claudia Langenberg
- Nicholas Wareham
- Giles S. Yeo
- Krishna Chatterjee
- John Schwabe
- Fiona Oakley
- Derek A. Mann
- Peter Tontonoz
- Anthony P. Coll
- Ken Ong
- John R. B. Perry
- Stephen O'Rahilly
1 Application
| Application ID | Title |
|---|---|
| 9905 | Using genetics to elucidate the relationship between socioeconomic/behavioural traits and disease |
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