Antilipolytic effect of calcimimetics depends on the allelic variant of calcium-sensing receptor gene polymorphism rs1042636 (Arg990Gly)

Abstract

Calcium-sensing receptor polymorphism rs1042636 (Arg990Gly) affects the response to the calcimimetic cinacalcet, used to treat hypercalcemia in secondary hyperparathyroidism (sHPT) or parathyroid carcinoma. Carriers of the Arg allelle, show less parathyroid hormone secretion suppression in response to the drug. This effect was reproducible in transfected cultured human embryonic kidney cells, supporting a causal relationship on the protein level. We previously established that cinacalcet has an antilipolytic effect in isolated human adipocytes; however, there were a number of samples that did not respond to the treatment. The present work aimed to investigate whether the variable antilipolytic response to cinacalcet in adipocytes was consistent with the effect reported for the rs1042636 polymorphism. Lipolysis was assessed by measuring glycerol release after exposure to cinacalcet (10 lM) or vehicle in adipocytes isolated from 38 donors. Responsiveness was defined as lipolysis suppression (cinacalcet vs vehicle control) greater than 20%. Genotype analysis showed that 23 adipocyte donors were homozygous for Arg at position 990, 14 heterozygous and 1 homozygous Gly-Gly. Among the Arg homozygotes, one was responsive to cinacalcet, whereas five Gly carriers responded to the calcimimetic. In all, 83% of adipocytes showing response to cinacalcet carried the glycine allele, whereas in 96% of Arg-Arg individuals adipocytes did not respond to the calcimimetic (P¼0.027, Fisher's exact test). Confirming sHPT observations, adipocytes from rs1042636 Gly-allele carriers show higher sensitivity to the antilipolytic action of cinacalcet. The potential benefit of cinacalcet as a suppressor of basal lipolysis and free fatty acid release in uremic patients needs to consider the rs1042636 single-nucleotide polymorphism.

MEN1-related hyperparathyroidism: response to cinacalcet and its relationship with the calcium-sensing receptor gene variant Arg990Gly

“…In this study, patients bearing the 990Gly allele were more sensitive to cinacalcet compared with homozygotes for Arg at that location (16). This observation is consistent with in vitro functional data, showing increased sensitivity of HEK cells stably transfected with CASR 990Gly allele to the calcimimetic R-568 (17) and an increased antilipolytic effect of cinacalcet in primary cultures of normal adipocytes having 990Gly allele (18).…”

Calcium-sensing receptor gene (CASR) polymorphisms and CASR transcript level concerning dyslipidemia in hemodialysis patients: a cross-sectional study

“…Therefore, a suppressive action of cinacalcet on free fatty acid release may be less pronounced in the rs1042636 AA homozygotes. An analysis of the same study samples performed concerning the rs1801725 genotypes yielded no conclusive results [17]. In our study, CASR rs7652589 and rs1801725 correlated with dyslipidemia in HD patients but their simultaneous associations with calcimimetics need to be shown in future studies.…”

“…On the other hand, CaSR activation by calcimimetic cinacalcet decreased adipocyte TG content by 20% [14]. Antilipolytic effect of calcimimetics was attributed to the allelic variant of CASR polymorphism rs1042636 (Arg990Gly) [17]. Additionally, up-regulation of CaSR was found to activate the peroxisome proliferator-activated receptor ɣ (PPARɣ) which is a transcription factor involved in the regulation of adipogenesis [18].…”

Engendering biased signalling from the calcium‐sensing receptor for the pharmacotherapy of diverse disorders

“…Consistent with its effects on gut hormone release and gastric acid secretion, CaSRs expressed in hepatocytes promote bile flow (Canaff et al ., ) to facilitate digestion and absorption of fats and CaSRs expressed on adipocytes, in turn, facilitate fat storage by promoting adipocyte differentiation and adipogenesis (Cifuentes and Rojas, ; He et al ., 2011; 2012; Reyes et al ., ). CaSR activation in adipose tissue also elevates the production of cytokines and chemokines, including IL‐6, IL‐1β, TNF‐α and CC chemokine 2 (Cifuentes et al ., ) and pro‐inflammatory cytokines increase CaSR expression in adipocytes (Cifuentes et al ., ), suggesting the existence of a positive feedback loop.…”