G-Protein Estrogen Receptor as a Regulator of Low-Density Lipoprotein Cholesterol Metabolism

Abstract

T he importance of estrogen as a regulator of plasma lipid metabolism has been most clearly demonstrated in settings of estrogen deficiency (eg, menopause). Bilateral ovariectomy in premenopausal women causes an increase in plasma levels of low-density lipoprotein (LDL) when compared with premenopausal women with preserved ovaries.1 Furthermore, LDL cholesterol levels increase after onset of menopause. 2Multiple mechanisms have been proposed by which estrogens regulate lipoprotein metabolism in humans, including induction of hepatic LDL receptor expression, 3,4 reduction of hepatic secretion of acyl-coenzyme A: cholesterol acyltransferase 2-derived cholesteryl esters in plasma lipoproteins, 5 reduction of hepatic lipase, 6 and reduction of levels of proprotein convertase subtilisin kexin type 9 (PCSK9), 7 a key regulator of LDL receptor metabolism. 8 The receptor(s) mediating estrogen's effects on LDL metabolism is unclear. Estrogen's effects are triggered via 2 main receptor types. Classic estrogen receptors (ERs) have been shown to have both nuclear and cytoplasmic/membraneassociated sites of effect.9,10 More recently, a G-proteincoupled receptor, G-protein ER (GPER; aka GPR30) has been shown to mediate some of the so-called rapid (nongenomic) effects of estrogen. 11 We have recently shown that GPER is also activated by aldosterone. Objective-Estrogen deficiency is linked with increased low-density lipoprotein (LDL) cholesterol. The hormone receptor mediating this effect is unknown. G-protein estrogen receptor (GPER) is a recently recognized G-protein-coupled receptor that is activated by estrogens. We recently identified a common hypofunctional missense variant of GPER, namely P16L. However, the role of GPER in LDL metabolism is unknown. Therefore, we examined the association of the P16L genotype with plasma LDL cholesterol level. Furthermore, we studied the role of GPER in regulating expression of the LDL receptor and proprotein convertase subtilisin kexin type 9. Approach and Results-Our discovery cohort was a genetically isolated population of Northern European descent, and our validation cohort consisted of normal, healthy women aged 18 to 56 years from London, Ontario. In addition, we examined the effect of GPER on the regulation of proprotein convertase subtilisin kexin type 9 and LDL receptor expression by the treatment with the GPER agonist, G1. In the discovery cohort, GPER P16L genotype was associated with a significant increase in LDL cholesterol (mean±SEM): 3.18±0.05, 3.25±0.08, and 4.25±0.33 mmol/L, respectively, in subjects with CC (homozygous for P16), CT (heterozygotes), and TT (homozygous for L16) genotypes (P<0.05). In the validation cohort (n=339), the GPER P16L genotype was associated with a similar increase in LDL cholesterol: 2.17±0.05, 2.34±0.06, and 2.42±0.16 mmol/L, respectively, in subjects with CC, CT, and TT genotypes (P<0.05). In the human hepatic carcinoma cell line, the GPER agonist, G1, mediated a concentration-dependent increase in LDL receptor expression, blocked by eith...

The G-protein coupled estrogen receptor, GPER: The inside and inside-out story

“…In a complementary set of experiments, these investigators elegantly demonstrated that chronic administration of G1 to ovariectomized GPER+/+ mice inhibited atherosclerosis and vascular inflammation without any measurable uterotrophic activity. A further interesting development in the role of GPER in atherosclerosis may be realized from the recent finding from a genome wide association study that demonstrated a direct genetic and pharmacological linkage between GPER and serum LDL receptor levels via a decrease in proprotein convertase subtilisin kexin type 9 (PCSK9) expression [Hussain et al, 2015]. Collectively, these data suggest a critical role for GPER-1 in anti-atherogenesis and the reduction of cardiovascular disease.…”

What have we learned about GPER function in physiology and disease from knockout mice?

“…Dyslipidemia in male GPER KO1 mice, as evidenced by increased serum levels of total cholesterol, LDL cholesterol and triglycerides, occurred as the mice aged (24 vs. 12 months) [101]; whereas in young female GPER KO1 mice, an atherogenic diet resulted in increased total and LDL cholesterol levels [124]. Consistent with these observations in mice, epidemiological evidence for the regulation of LDL cholesterol through GPER activity in humans derives from carriers of a hypofunctional GPER polymorphism that correlates with higher circulating levels of plasma LDL cholesterol, potentially through the regulation of LDL receptor expression in the liver [138]. …”

Recent Advances in the Genetics of Atherothrombotic Disease and Its Determinants

“…Studying the variant Y157C in a PAR4 expression construct, they found reduced PAR4 responses because of aberrant anterograde surface receptor trafficking, which validated the involvement of rare F2RL3 variants in altering PAR4 reactivity after treatment with therapeutic PAR1 antagonists. 19 In another study, Hussain et al 20 considered the unknown link between estrogen deficiency and increased LDL-C (low-density lipoprotein cholesterol). They analyzed the role of GPER (G-protein estrogen receptor) in the regulation of both the LDL receptor and PCSK9 (proprotein convertase subtilisin kexin type 9).…”

“…Taken together, these results suggest a role of GPER in LDL metabolism. 20 Additional studies pursued functional assessment of GWAS-identified SNPs, notably in relation to CAD. For instance, 1 group functionally investigated a coding variant, rs1051338, in LIPA, encoding lysosomal acid lipase and found that the risk allele leads to faster lysosomal acid lipase degradation, reduced protein levels, and decreased activity.…”