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

Journal

Nature metabolism

ISSN: 2522-5812

Titre abrégé: Nat Metab

Pays: Germany

ID NLM: 101736592

Informations de publication

Date de publication:
25 Sep 2024

Historique:

received: 17 05 2024

accepted: 05 08 2024

medline: 26 9 2024

pubmed: 26 9 2024

entrez: 25 9 2024

Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1038/s42255-024-01126-4 PMID: 39322746

pubmed: 39322746

doi: 10.1038/s42255-024-01126-4

pii: 10.1038/s42255-024-01126-4

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Subventions

Organisme : Wellcome Trust (Wellcome)

ID : WT 095515/Z/11/Z

Organisme : Wellcome Trust (Wellcome)

ID : WT 225479/Z/22

Informations de copyright

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