Heart failure & cardiomyopathies
XBP1s-EDEM2 Prevents the Onset and Development of Heart Failure with Preserved Ejection Fraction (HFpEF) by Ameliorating Cardiac Lipotoxicity
Authors' conclusion
We demonstrate a cardioprotective mechanism regulating myocardial lipid homeostasis.
Study context
- Population
- C57BL/6 male mice under metabolic stress (high-fat diet and L-NAME); rat cardiomyocytes and human iPSC-derived cardiomyocytes; human hearts
Main finding
As reported in the abstract
- Lipid overload with reduced XBP1 in human heart under metabolic stress
- EDEM2 decreased in human and mouse HFpEF hearts
- EDEM2 identified as new target of XBP1s in cardiomyocytes
- EDEM2 knockdown: lipid droplet accumulation, higher myocardial TG and diglycerides, aggravated oxidative stress, hypertrophy, and onset and progression of HFpEF under metabolic stress
- XBP1s ablation: similar lipid disturbance and cardiac phenotypes, reversed by EDEM2 overexpression
- With EDEM2, SEC23A mediated intracellular translocation of ATGL under fatty acid stimulation, inhibiting ATGL degradation and excess lipid droplets
- EDEM2 prevention of lipid overload was ATGL-dependent
- Cardiac XBP1s or EDEM2 restoration mitigated lipid deposition, preserved myocardial lipid profiles and prevented HFpEF development
Original publication
XBP1s-EDEM2 Prevents the Onset and Development of HFpEF by Ameliorating Cardiac Lipotoxicity. Circulation. Published 25 March 2025. doi:10.
Summarised from the published abstract; every number is checked against it