Liver-X-receptors (LXRs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. The two popular homologous receptor subtypes, LXR alpha and LXR beta, exhibit differential expression patterns, thereby probably playing different roles in different contexts. This study aimed to evaluate the different roles of the two LXR subtypes and the mechanisms underlying their protection of cardiomyocytes against high-glucose stress. Silencing of LXR alpha, but not LXR beta impaired normal LXR-mediated cardioprotective effects against high glucose-induced oxidative stress, apoptosis, and inflammation. Mechanistically, silencing of small ubiquitin-like modifier (SUMO)] or SUM02/3 did not affect LXR-mediated cardioprotective effects; however, these were impaired in response to nuclear receptor core pressor (NCoR) silencing. Together, these findings indicate that LXR alpha, but not LXR beta, protects against high glucose-induced cardiomyocyte injury, probably via the NCoR-dependent transrepression of down-stream target genes. 2018 Elsevier Inc. All rights reserved.