The calcium-sensing receptor R990G polymorphism is associated with increased risk of hypertriglyceridemia in obese Chinese.

BACKGROUND: We have demonstrated that the calcium-sensing receptor (CaSR) is involved in lipid metabolism; however, whether CaSR polymorphisms affect lipid metabolism in obesity is still unclear. The present study aimed to determine the effects of CaSR polymorphisms on HTG risk in obese Chinese. METHODS: A total of 972 subjects with HTG and 1197 with normal triglyceride (NTG) were stratified by body mass index (BMI) into normal weight, overweight or obesity subgroups. After 12-h fasting, CaSR polymorphisms in exon 7 were determined in the blood. Serum lipids and glucose, as well as height, body weight and waist circumference were measured. The anthropometric and metabolic characteristics of the NTG subjects were re-evaluated 3 years later. RESULTS: There were no genotypic or allelic distribution differences for the A986S or Q1011E polymorphisms between the NTG and HTG groups. However, the G/G genotypic and G allelic distributions of the CaSR R990G polymorphism in the HTG group were higher than the NTG group (p<0.001). After stratification, in obese subjects, the homozygous (G/G) distribution of the CaSR R990G polymorphism in the HTG group was significantly higher than in the NTG group (p=0.001), and showed an increased risk of HTG at baseline [OR=2.55, 95% CI=1.65-3.92, p<0.006]. Interaction of the CaSR R990G polymorphism with BMI was associated with increased risk of HTG (ß=0.927, p<0.001). Re-evaluation of the NTG subjects revealed significantly increased serum triglyceride levels in obese homozygous versus wildtype carriers (p<0.05). CONCLUSIONS: These results suggest that the CaSR R990G polymorphism is associated with increased risk of HTG, especially in obese Chinese, and may be a potential genetic predictor of diseases related to HTG.

Allosteric regulation of the calcium-sensing receptor in obese individuals.

We have previously reported that the calcium-sensing receptor (CaSR) plays an important role in modulating lipid metabolism under low calcium conditions. The aim of this study was to identify possible regulators of CaSR and the mechanisms of action of CaSR in obese individuals. Subcutaneous fat samples were obtained from 10 obese and 10 non-obese males undergoing elective abdominal surgery. Visceral fat pads were obtained from 12 obese and 12 non-obese male rats. Serum lipid, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) concentrations, as well as the gene and protein expression of CaSR in the white adipose tissue of obese subjects and rats were determined. Serum total calcium, vitamin D, parathyroid hormone (PTH) and amino acid levels in human subjects were measured. Intracellular calcium and cyclic adenosine monophosphate (cAMP) levels in rat adipocytes were measured by laser scanning confocal microscopy and ELISA, respectively. The results revealed that serum triglyceride (TG), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), TNF-α, IL-6 and PTH levels were significantly higher in the obese individuals versus the controls. By contrast, serum vitamin D and amino acid concentrations were lower in the obese individuals versus the controls. In addition, intracellular calcium levels were higher, while cAMP levels were lower in the obese rat adipocytes compared with the control group. However, the gene and protein expression of CaSR in white adipose tissue did not differ between the obese groups and the controls. Thus, these results suggest that CaSR functions not through its expression, but rather through allosteric regulation in obese individuals.

Calcium supplementation increases circulating cholesterol by reducing its catabolism via GPER and TRPC1-dependent pathway in estrogen deficient women.

BACKGROUND: Limited studies have addressed the effects of calcium supplementation (CaS) on serum total cholesterol (TC) in postmenopausal women and the results are inconclusive. Moreover, the potential mechanisms through which CaS regulates cholesterol metabolism in the absence of estrogen are still sealed for the limitation of human being study. METHODS: Cross-sectional survey, animal and in vitro experiments were conducted to investigate the effect of CaS on endogenous cholesterol metabolism in estrogen deficiency and identify its potential mechanisms. Ovariectomized rats were used to mimic estrogen deficiency. In vitro, HepG2 cell line was exposed to estradiol and/or calcium treatment. RESULTS: We demonstrated that CaS significantly increased serum TC and the risk of hypercholesterolemia and myocardial infarction in postmenopausal women. Increased serum TC in estrogen deficiency was caused mainly by decreased cholesterol catabolism rather than increased synthesis. This was mediated by reduced 7α-hydroxylase resulting from increased liver intracellular Ca(2+) concentrations, reduced intracellular basal cAMP and subsequent up-regulation of SREBP-1c and SHP expression. Estrogen had a protective role in preventing CaS-induced TC increase by activating the G-protein coupled estrogen receptor, which mediated the estrogen effect through the transient receptor potential canonical 1 cation channel. CONCLUSIONS: CaS increases endogenous serum TC via decreasing hepatic cholesterol catabolism in estrogen deficiency. G-protein coupled estrogen receptor is shown to be a key target in mediating CaS-induced TC increase. CaS should be monitored for the prevention of serum TC increase during menopause.