Somatic loss-of-function mutations in CIDEB reduce hepatic steatosis by increasing lipolysis and fatty acid oxidation

Background & Aims

Somatic and germline CIDEB mutations are associated with protection from chronic liver diseases. The mechanistic basis and whether CIDEB suppression would be an effective therapy against fatty liver disease remain unclear.

Methods

21 CIDEB somatic mutations were introduced into cells to assess functionality. In vivo screening was used to trace Cideb mutant clones in mice fed normal chow, western (WD), and choline-deficient, L-amino acid-defined, high-fat (CDA-HFD) diets. Constitutive and conditional Cideb knockout mice were generated to study Cideb in 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/Atgl and Cideb/Pparα) tested mechanisms underlying Cideb loss.

Results

Most CIDEB mutations showed that they impair function, and lineage-tracing showed that loss-of-function clones were positively selected with CDA-HFD, but not all fatty liver inducing diets. Cideb KO mice were protected from WD, CDA-HFD, and alcohol diets, but had the greatest impact on CDA-HFD induced liver disease. Hepatocyte-specific Cideb deletion could ameliorate disease after metabolic dysfunction-associated steatotic liver disease (MASLD) establishment, modeling the impact of therapeutic siRNAs. Cideb loss protected livers via increased β-oxidation, specifically through ATGL and PPARα activation.

Conclusions

Cideb deletion is more protective in some types of fatty liver disease. β-oxidation is an important component of the Cideb protective mechanism. CIDEB inhibition represents a promising approach, and somatic mutations in CIDEB might predict the patient populations that might benefit the most.

Impact and Implications

It is not clear why somatic and germline CIDEB mutations are protective in MASLD. Cideb mutations are predominantly loss of function, and Cideb-deficient clones selectively expand in specific dietary contexts such as CDA-HFD-induced MASLD. Consistently, liver-wide deletion of Cideb ameliorates MASLD most profoundly after CDA-HFD feeding. Mechanistically, Cideb deficiency enhances hepatic fatty acid β-oxidation via ATGL and PPARα activation. These findings suggest that CIDEB inhibition might be most effective in patients with the subtypes of MASLD that promote the expansion of CIDEB mutant clones.