Introduction: The liver X-receptor (LXR) is a nuclear hormone receptor and a crucial regulator of lipid homeostasis in mammals. It has been shown that LXR activation endogenously reprograms cellular lipid profiles towards elevated PUFA levels. Here, we investigated whether LXR lipid reprogramming takes place in cardiac tissue and exerts cardio-protective effects.

Methods: HL-1 cells were treated with 1nM of the LXR agonist (AZ876) and 500µM of oleic acid over 24h to evaluate lipid formation within the cardiomyocytes. Following this, male 129SV mice were treated with the LXR Agonist (AZ876, 20 µmol/kg/day) for 11 days. Starting from day 6 mice were injected with the nonselective β-agonist isoproterenol (ISO) for four consecutive days to induce subendocardial fibrosis in the presence of preserved systolic function. One Day after the last ISO injection the mice were echocardiographically characterized

Results: HL-1 cells treated with the LXR agonist and oleic acid show an increased formation of lipid droplets within the cardiomyocyte. ISO treatment in the animals led to a marked impairment of global longitudinal strain (GLS) (VEH vs. ISO, -19,07±1,27 vs. -15,43±1,76, **p≤0,01) which could be significantly improved by the LXR-Agonist (ISO vs. ISO/LXR-Ago., -15,43±1,76 vs. -19,05±3,66, **p≤0,01). Other strain parameters (radial, circumferential) were not influenced. Systolic function was not affected neither by ISO nor by the LXR-Agonist. Histological examination also revealed a significant reduction of ISO-induced subendocardial fibrosis in the LXR-Agonist treated group. MS-based lipid profile analysis of cardiac tissue revealed an increase in PUFA levels, notably increases in DHA. This was accompanied by a overall reduction in SFA concentration.

Conclusion: These findings indicate that pharmacological LXR activation alters cardiomyocyte lipid content associated with the prevention of subendocardial damage and an improvement of GLS parameters in a model of cardiac fibrosis. Cardiac lipidome analyses revealed a detailed LXR-induced cardiac lipid alteration. Pharmacological LXR activation may provide a promising approach for the prevention and therapy of cardiac fibrosis potentially involving cardiac lipid modulation.