Functional genomics of blood cellular LXR-α gene in human coronary heart disease

Dave, Vivek Priy; Kaul, Deepak; Sharma, Yash Pal; Bhattacharya, Rajasri

doi:10.1016/j.yjmcc.2008.12.020

Cited by 21 publications

(25 citation statements)

References 30 publications

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“…As reported earlier [17] , we observed similar pattern of 3 critical mutations in the ligand binding domain and increased transcriptional expression of LXR-α with respect to increasing coronary occlusion (data not shown) in all subjects employed in this study. In contrast, LXR-α protein expression was found to decrease with increasing severity of coronary occlusion and exhibited a strong negative correlation with gensini score ( Figure 1A and B).…”

Section: Resultssupporting

confidence: 90%

“…This degradation of LXR-α protein also explains the increasing expression of inflammatory cytokines IFN-γ, IL-6 and IL-8 and decreasing expression of ABCA1 (responsible for cholesterol efflux particularly from macrophages) with increasing coronary occlusion ( Figures 1D and 3C-F), which would ultimately result in increased vascular inflammation and foam cell formation. Thus, though the expression of LXR-α increases with the severity of the disease at the transcriptional level [17] (data not shown for subjects employed in present study), there is absence of functional LXR-α protein in CHD subjects ( Figure 1A and B). To confirm the interaction between the two proteins, immunoprecipitation studies were performed which showed a strong association between mutant LXR-α and BARD1 in CHD subjects as compared to the normal healthy counterparts.…”

Section: Discussionmentioning

confidence: 52%

“…However, synthetic agonists for the LXR-α activation designed as therapeutic agents for the regression of coronary atherosclerosis did not meet the expected success. This anomaly got further compounded by the observation in CHD patients who exhibited increasing transcriptional expression of LXR-α, within their PBMCs, with corresponding increase in severity of coronary occlusion [17] . This paradox was partly resolved by our earlier studies which showed that ligand binding domain of LXR-α protein in CHD subjects harbors a unique genetic aberration (involving Asp324, Pro327 and Arg328) which prevents its physiological ligands from binding and activating the LXR-α protein, thus rendering it non-functional [17] .…”

Section: Discussionmentioning

confidence: 99%

“…This anomaly got further compounded by the observation in CHD patients who exhibited increasing transcriptional expression of LXR-α, within their PBMCs, with corresponding increase in severity of coronary occlusion [17] . This paradox was partly resolved by our earlier studies which showed that ligand binding domain of LXR-α protein in CHD subjects harbors a unique genetic aberration (involving Asp324, Pro327 and Arg328) which prevents its physiological ligands from binding and activating the LXR-α protein, thus rendering it non-functional [17] . Further, this mutant LXR-α gene product was shown to acquire by default affinity for Vitamin D3 which can restore the function of mutated LXR-α protein to some extent [23] .…”

Section: Discussionmentioning

confidence: 99%

“…Paradoxically there is an increased expression of LXR-α with the corresponding increase in severity of coronary occlusion [17] . Further work has partly resolved this paradox by revealing three critical mutations in its ligand binding domain involving Asp324, Pro327 and Arg328 which compromises its ability to interact and get activated by its natural ligands [17] . But to fully understand this apparent paradox it is imperative to explore the stability and expression of this mutant LXR-α protein.…”

Section: Introductionmentioning

confidence: 99%

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Blood cellular mutant LXR-α protein stability governs initiation of coronary heart disease

Arora

Kaul²,

Sharma³

2013

WJC

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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 nega- culture experiments proved that Vitamin D3 could prevent the degradation of mutant LXR-α and restore its functional activity to some extent. BRIEF ARTICLE World Journal of CONCLUSION:Mutant LXR-α protein in CHD subjects is degraded by BARD1/BRCA1 complex and Vitamin D3 can rescue and restore its function.

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Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Blood cellular mutant LXR-α protein stability governs initiation of coronary heart disease

Arora

Kaul²,

Sharma³

2013

WJC

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Emerging role of liver X receptors in cardiac pathophysiology and heart failure

2015

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Liver X receptors (LXRs) are master regulators of metabolism and have been studied for their pharmacological potential in vascular and metabolic disease. Besides their established role in metabolic homeostasis and disease, there is mounting evidence to suggest that LXRs may exert direct beneficial effects in the heart. Here, we aim to provide a conceptual framework to explain the broad mode of action of LXRs and how LXR signaling may be an important local and systemic target for the treatment of heart failure. We discuss the potential role of LXRs in systemic conditions associated with heart failure, such as hypertension, diabetes, and renal and vascular disease. Further, we expound on recent data that implicate a direct role for LXR activation in the heart, for its impact on cardiomyocyte damage and loss due to ischemia, and effects on cardiac hypertrophy, fibrosis, and myocardial metabolism. Taken together, the accumulating evidence supports the notion that LXRs may represent a novel therapeutic target for the treatment of heart failure.

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LXR-α genomics programmes neuronal death observed in Alzheimer’s disease

Raina

Kaul

2010

Apoptosis

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Keeping in view the fact that the most pathognomonic feature of Alzheimer's disease is the abnormal processing of neuronal cell membrane amyloid precursor protein accompanied by significantly elevated human serum and CSF levels of 24-hydroxycholesterol recognised widely as the specific endogenous ligand of Liver X receptor (LXR-α), the present study was addressed to explore the epigenomic-pathway (if any) that connects LXR-α activation with the genes recognised to be involved in the regulation of aberrant Abeta production leading to the generation of toxic and inflammatory mediators responsible for neuronal death. The results of such a study revealed that LXR-α activation by its specific endogenous or exogenous ligands within neuroblastoma cells resulted in the over-expression of PAR-4 gene accompanied by suppression of AATF gene through its inherent capacity to regulate genes coding for SREBP and NF-κB. Over-expression of PAR-4 gene was accompanied by aberrant Abeta production followed by ROS generation and subsequent death of neuroblastoma cells used in the present study as a cellular model for neurons. Further based upon these results, it was proposed that Abeta-induced heme oxygenase-1 can ensure cholesterol-oxidation to provide endogenous ligands for the sustained activation of neuronal LXR-α dependent epigenomic-pathway leading to neuronal death observed in Alzheimer's disease.

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Functional genomics of blood cellular LXR-α gene in human coronary heart disease

Cited by 21 publications

References 30 publications

Blood cellular mutant LXR-α protein stability governs initiation of coronary heart disease

Blood cellular mutant LXR-α protein stability governs initiation of coronary heart disease

Emerging role of liver X receptors in cardiac pathophysiology and heart failure

LXR-α genomics programmes neuronal death observed in Alzheimer’s disease

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