Published online Aug 26, 2013. doi: 10.4330/wjc.v5.i8.305
Revised: June 3, 2013
Accepted: July 18, 2013
Published online: August 26, 2013
Processing time: 182 Days and 17.3 Hours
AIM: To investigate the role of [breast and ovarian cancer susceptibility 1 (BRCA1)-associated RING domain 1 (BARD1)]/BRCA1 E3-ubiquitin ligase complex in governing the stability of mutant liver X receptor-α (LXR-α) protein in coronary heart disease (CHD) subjects.
METHODS: The expression analysis of various genes was carried out by quantitative real time polymerase chain reaction and western blotting within blood mononuclear cells of human CHD subjects at various stages of coronary occlusion and their corresponding normal healthy counterparts. Immunoprecipitation experiments were performed to establish protein interactions between LXR-α and BARD1. Peripheral blood mononuclear cells were cultured and exposed to Vitamin D3 and Cisplatin to validate the degradation of mutant LXR-α protein in CHD subjects by BARD1/BRCA1 complex.
RESULTS: The expression of mutant LXR-α protein in CHD subjects was found to decrease gradually with the severity of coronary occlusion exhibiting a strong negative correlation, r = -0.975 at P < 0.001. Further, the expression of BARD1 and BRCA1 also increased with the disease severity, r = 0.895 and 0.873 respectively (P < 0.001). Immunoprecipitation studies established that BARD1/BRCA1 complex degrades mutant LXR-αvia ubiquitination. The absence of functional LXR-α protein resulted in increased expression of inflammatory cytokines such as interleukin (IL)-6, IL-8 and interferon-γ and decreased expression of ABCA1 (ATP-binding cassette A1) (r = 0.932, 0.949, 0.918 and -0.902 with respect to Gensini score; P < 0.001). Additionally, cell culture experiments proved that Vitamin D3 could prevent the degradation of mutant LXR-α and restore its functional activity to some extent.
CONCLUSION: Mutant LXR-α protein in CHD subjects is degraded by BARD1/BRCA1 complex and Vitamin D3 can rescue and restore its function.
Core tip: The present study proposes that the stability of mutant liver X receptor-α (LXR-α) protein in blood mononuclear cells of human coronary heart disease (CHD) subjects is governed by its ubiquitination dependent degradation by [breast and ovarian cancer susceptibility 1 (BRCA1)-associated RING domain1 (BARD1)]/BRCA1 E3 ubiquitin ligase complex. Additionally, BARD1/BRCA1 expression shows an increasing trend with respect to severity of coronary occlusion. This degradation is rescued to some extent by the ability of Vitamin D3 to bind mutant LXR-α protein thus providing warranted evidence that dietary supplementation of Vitamin D3 in such subjects may be exploited therapeutically.