Aims: 

Liver X receptors (LXRs) are ligand activated nuclear transcription factors functioning as regulators of fatty acid, cholesterol and glucose metabolism. Cardiac LXR expression is so far not characterized, although the heart utilizes both fatty acids and glucose as energy substrate. We aimed to investigate a potential role of LXRs in the heart.

Methods: 

Hearts were isolated and subjected to global ischemia, and reperfusion using langendoff apparatus in extra vivo. In vivo myocardial infarction was induced by ligation of the left anterior descending coronary artery for 24 hours, the hearts were analyzed for infarct size lipid accumulation and triglycerides constitution.

Results: 

LXRa and b mRNA were expressed in the mouse heart. Cardiomyocyte HL-1 cells and freshly isolated adult CMs had lower gene expression of LXRs than cardiac fibroblast. In both tissue and cells, LXRb expression was higher than LXRa. Transcriptional activity of LXR was modulated in vivo by the LXR agonist GW3965, which increased expression of the target genes Stearoyl-CoA desaturase 1 (SCD-1), Sterol regulatory element-binding protein 1c (SREBP-1c) and ATP binding cassette transporter A 1 (ABCA 1) in the ventricle. In parallel, intracellular lipid droplets accumulated in cardiomyocytes. Triglyceride analysis of the left ventricle revealed an increased palmitoleic acid / palmitic acid ratio, further suggesting increased SCD-1 activity. A similar response to GW3965 was seen in HL-1 cells. Gene expression of LXRb was increased post MI as well as target genes, whereas LXRa was unchanged. In isolated ischemia-reperfused hearts, GW3965 stimulation decrease the myocardial infracted size about 50%.

Conclusion: 

These results indicate that LXRs activation by the agonist GW3965 lead to increased target gene expression and accumulation of lipid droplets in the heart. LXRs play a role in cardiac lipid metabolism, potentially also in the post-ischemic heart.