Mechanistic basis for protection against fatty liver disease byCIDEBloss-of-function mutations
Abstract
Background & Aims
Somatic and germlineCIDEBmutations are associated with protection from chronic liver diseases. The mechanistic basis and whetherCIDEBsuppression would be an effective therapy against fatty liver disease remain unclear.
Methods
21CIDEBsomatic mutations were introduced into cells to assess functionality. In vivo screening was used to traceCidebmutant clones in mice fed normal chow, western (WD), and choline-deficient, L-amino acid-defined, high-fat (CDA-HFD) diets. Constitutive and conditionalCidebknockout mice were generated to studyCidebin liver disease. Isotope tracing was used to evaluate fatty acid oxidation and de novo lipogenesis. Transcriptomics, lipidomics, and metabolic analyses were utilized to explore molecular mechanisms. Double knockout models (Cideb/AtglandCideb/Ppara) tested mechanisms underlyingCidebloss.
Results
MostCIDEBmutations showed that they impair function, and lineage-tracing showed that loss-of-function clones were positively selected with some, but not all fatty liver inducing diets.CidebKO mice were protected from WD, CDA-HFD, and alcohol diets, but had the greatest impact on CDA-HFD induced liver disease. Hepatocyte-specificCidebdeletion could ameliorate disease after MASLD establishment, modeling the impact of therapeutic siRNAs.Cidebloss protected livers via increased β-oxidation, specifically through ATGL and PPARa activation.
Conclusions
Cidebdeletion is more protective in some types of fatty liver disease. β-oxidation is an important component of theCidebprotective mechanism.CIDEBinhibition represents a promising approach, and somatic mutations inCIDEBmight predict the patient populations that might benefit the most.
Related articles
Related articles are currently not available for this article.