scholarly journals Cholesterol-induced mammary tumorigenesis is enhanced by adiponectin deficiency: role of LDL receptor upregulation

Oncotarget ◽  
2013 ◽  
Vol 4 (10) ◽  
pp. 1804-1818 ◽  
Author(s):  
Jing Liu ◽  
Aimin Xu ◽  
Karen Siu-Ling Lam ◽  
Nai-Sum Wong ◽  
Jie Chen ◽  
...  
Keyword(s):  
Ldl Receptor ◽  
Mammary Tumorigenesis ◽  
Receptor Upregulation

Abstract 43: The Hypofunctional GPER P16L Variant is Associated With a Gene Dosage-Related Increase in Plasma LDL Cholesterol

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Yasin Hussain ◽  
Ross D Feldman ◽  
Qingming Ding ◽  
Jozef Chorazyczewski ◽  
Matthew R Ban ◽  
...  
Keyword(s):  
Genetic Variant ◽  
Ldl Cholesterol ◽  
Validation Cohort ◽  
Gene Dosage ◽  
Ldl Receptor ◽  
Receptor Expression ◽  
Significant Gene ◽  
Receptor Upregulation ◽  
Related Increase

Introduction: Estrogen deficiency is linked with dyslipidemia, especially in postmenopausal women, through a poorly understood mechanism. GPER is a recently recognized GPCR which is activated by estrogens. However, the role of GPER in mediating estrogen’s effects on lipid metabolism is unknown. We recently identified a common hypofunctional missense variant of GPER, namely P16L (allele frequency ~ 20%). We studied association of this with plasma LDL cholesterol levels. Further, we studied the role of GPER in regulating expression of the LDL receptor. Methods: Our discovery cohort was a genetically isolated population of Northern European descent (n=415), and our validation cohort consisted of 505 normal, healthy subjects 18-56 years of age from London, Ontario. Genomic DNA was extracted from whole blood and genotyped for GPER using a dedicated TaqMan assay. Additionally we examined the role of GPER on the regulation of LDL receptor expression by treatment with the GPER agonist, G1. Results: In the discovery cohort, the GPER P16L genetic variant was associated with a significant gene-dosage related increase in LDL cholesterol (CC [homozygous wild type] =3.18±0.84 (mean+SD); CT [heterozygote] =3.25±0.80; and TT [homozygous variant] =4.25±0.87 mmol/L, p<0.05). Total cholesterol concentrations followed a similar gradient across genotypes. In the validation cohort, the GPER P16L genetic variant was associated with a similar significant gene-dosage related increase in LDL cholesterol (CC =2.16±0.67; CT [heterozygote] =2.29±0.67; TT =2.40±0.84 mmol/L, p<0.05). In HepG2 cells expressing GPER, G1 mediated a concentration-dependent increase in LDL receptor expression. Pre-treating the cells with the GPER antagonist G15 attenuated the effect of G1 on LDL receptor upregulation. Further, downregulation of GPER expression via infection with a shGPER construct also attenuated G1's effect on LDL receptor upregulation. Conclusion: GPER activation upregulates LDL receptor expression. Further, carrying the hypofunctional P16L genetic variant of GPER, increases plasma LDL cholesterol in humans. In aggregate these data suggest an important role of GPER in regulation of LDL receptor expression and consequently LDL metabolism.

scholarly journals The role of cyclooxygenase-2 on endurance exercise training in female LDL-receptor knockout ovariectomized mice

2013 ◽  
Vol 85 (3) ◽  
pp. 1157-1164 ◽  
Author(s):  
FLAVIA DE OLIVEIRA ◽  
LAURA B.M. MAIFRINO ◽  
GUSTAVO P.P. DE JESUS ◽  
JULIANA G. CARVALHO ◽  
CLAUDIA MARCHON ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
Exercise Training ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Cyclooxygenase 2 ◽  
Sedentary Control ◽  
Down Regulation ◽  
Ovariectomized Mice ◽  
Cox 2

Estrogen deprivation in postmenopausal women increases cardiovascular risk. Cardiovascular risk as a result of atherosclerosis is able to induce an inflammatory disease as far as cyclooxygenase-2 ( COX-2) expression. The purpose of the study was to investigate the role of COX-2 on exercise training in female mice low-density lipoprotein receptor knockout ( LDL-KO) with or without ovariectomy. A total of 15 female C57BL/6 mice and 15 female LDL-KO mice were distributed into 6 groups: sedentary control, sedentary control ovariectomized, trained control ovariectomized, LDL-KO sedentary, LDL-KO sedentary ovariectomized and LDL-KO trained ovariectomized. The ascending part of the aorta was stained with H&E and COX-2 expression was assessed by immunohistochemistry. Results revealed that ovariectomy as well as exercise training were not able to induce histopathological changes in mouse aorta for all groups investigated. LDL-KO mice demonstrated plaque containing cholesterol clefts, foamy histiocytes and mild inflammatory process for all groups indistinctly. Ovariectomy induced a strong immunoexpression in atherosclerosis lesion of LDL-KO mice. Nevertheless, a down-regulation of COX-2 expression was detected in LDL-KO trained ovariectomized when compared to LDL-KO sedentary. Our results are consistent with the notion that exercise training is able to modulate COX-2 expression in LDL-KO mice as a result of COX-2 down-regulation.

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