Sex-specific KDM6A-HNF4A-CREBH network controls lipoprotein cholesterol metabolism and atherosclerosis via epigenetic reprograming of hepatocytes.
Summary
This mechanistic study identifies KDM6A as a female-biased epigenetic regulator that partners with HNF4A to activate CREBH-driven lipid metabolic programs, maintaining cardioprotective lipoprotein profiles. Hepatocyte-specific Kdm6a loss in female mice induces pro-atherogenic lipoproteins and atherosclerosis under stress, while males are largely spared.
Key Findings
- KDM6A downregulation in female human hepatocytes disrupts lipoprotein regulatory gene programs.
- Female hepatocyte-specific Kdm6a deficiency causes pro-atherogenic lipoprotein profiles and increased atherosclerosis under stress.
- KDM6A cooperates with HNF4A to enable CREBH-dependent transcription of lipid metabolic genes.
Clinical Implications
While preclinical, these findings suggest sex-informed strategies for dyslipidemia and atherosclerosis, potentially leveraging KDM6A/CREBH pathway modulation in females.
Why It Matters
Revealing a sex-linked epigenetic mechanism for hepatic cholesterol control advances understanding of cardiometabolic sex differences and nominates KDM6A-HNF4A-CREBH as a therapeutic axis.
Limitations
- Preclinical findings without interventional human data.
- Limited exploration of male biology and translational therapeutic feasibility.
Future Directions
Test pharmacologic modulation of the KDM6A-HNF4A-CREBH axis in sex-stratified preclinical models and assess biomarkers of pathway activity in human dyslipidemia.
Study Information
- Study Type
- Basic/Mechanistic Research
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic evidence from human cells and mouse models
- Study Design
- OTHER