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肠道钙转运基因通过不依赖维生素D受体的机制被雌激素和生殖周期上调。

Intestinal calcium transporter genes are upregulated by estrogens and the reproductive cycle through vitamin D receptor-independent mechanisms.

作者信息

Van Cromphaut S J, Rummens K, Stockmans I, Van Herck E, Dijcks F A, Ederveen A G H, Carmeliet P, Verhaeghe J, Bouillon R, Carmeliet G

机构信息

Laboratory of Experimental Medicine and Endocrinology (Legendo), Katholieke Universiteit Leuven, Leuven, Belgium.

出版信息

J Bone Miner Res. 2003 Oct;18(10):1725-36. doi: 10.1359/jbmr.2003.18.10.1725.

Abstract

UNLABELLED

1alpha,25(OH)2-vitamin D strongly regulates the expression of the epithelial calcium channel CaT1. CaT1 expression is reduced in ERKOalpha mice and induced by estrogen treatment, pregnancy, or lactation in VDR WT and KO mice. Estrogens and vitamin D are thus independent potent regulators of the expression of this calcium influx mechanism, which is involved in active intestinal calcium absorption.

INTRODUCTION

Active duodenal calcium absorption consists of three major steps: calcium influx into, transfer through, and extrusion out of the enterocyte. These steps are carried out by the calcium transport protein 1 (CaT1), calbindin-D9K, and the plasma membrane calcium ATPase (PMCA1b), respectively. We investigated whether estrogens or hormonal changes during the female reproductive cycle influence the expression of these genes, and if so, whether these effects are vitamin D-vitamin D receptor (VDR) dependent.

MATERIALS AND METHODS

We evaluated duodenal expression patterns in estrogen receptor (ER)alpha and -beta knockout (KO) mice, as well as in ovariectomized, estrogen-treated, pregnant, and lactating VDR wild-type (WT) and VDR KO mice.

RESULTS

Expression of calcium transporter genes was not altered in ERKObeta mice. CaT1 mRNA expression was reduced by 55% in ERKOalpha mice, while the two other calcium transporter genes were not affected. Ovariectomy caused no change in duodenal expression pattern of VDR WT and KO mice, whereas treatment with a pharmacologic dose of estrogens induced CaT1 mRNA expression in VDR WT (4-fold) and KO (8-fold) mice. Pregnancy enhanced CaTI expression equally in VDR WT and KO mice (12-fold). Calbindin-D9K and PMCA1b expression increased to a lesser extent and solely in pregnant VDR WT animals. In lactating VDR WT and KO mice, CaT1 mRNA expression increased 13 times, which was associated with a smaller increase in calbindin-D9K protein content and PMCA1b mRNA expression.

CONCLUSIONS

Estrogens or hormonal changes during pregnancy or lactation have distinct, vitamin D-independent effects at the genomic level on active duodenal calcium absorption mechanisms, mainly through a major upregulation of the calcium influx channel CaT1. The estrogen effects seem to be mediated solely by ERalpha.

摘要

未标记

1α,25(OH)₂-维生素D强烈调节上皮钙通道CaT1的表达。在ERKOα小鼠中CaT1表达降低,而在VDR野生型(WT)和敲除(KO)小鼠中,雌激素处理、怀孕或哺乳可诱导其表达。因此,雌激素和维生素D是这种钙内流机制表达的独立强效调节因子,该机制参与肠道主动钙吸收。

引言

十二指肠主动钙吸收包括三个主要步骤:钙流入肠上皮细胞、在细胞内转运以及排出细胞。这些步骤分别由钙转运蛋白1(CaT1)、钙结合蛋白-D9K和质膜钙ATP酶(PMCA1b)完成。我们研究了雌激素或雌性生殖周期中的激素变化是否会影响这些基因的表达,如果是,这些影响是否依赖维生素D-维生素D受体(VDR)。

材料与方法

我们评估了雌激素受体(ER)α和β敲除(KO)小鼠以及去卵巢、雌激素处理、怀孕和哺乳的VDR野生型(WT)和VDR KO小鼠十二指肠中的表达模式。

结果

ERKObeta小鼠中钙转运基因的表达未改变。ERKOα小鼠中CaT1 mRNA表达降低了55%,而其他两个钙转运基因未受影响。去卵巢对VDR WT和KO小鼠十二指肠表达模式无影响,而用药理剂量的雌激素处理可诱导VDR WT(4倍)和KO(8倍)小鼠中CaT1 mRNA表达。怀孕使VDR WT和KO小鼠中CaTI表达均同等增强(12倍)。钙结合蛋白-D9K和PMCA1b表达仅在怀孕的VDR WT动物中轻度增加。在哺乳的VDR WT和KO小鼠中,CaT1 mRNA表达增加了13倍,这与钙结合蛋白-D9K蛋白含量和PMCA1b mRNA表达的较小增加相关。

结论

雌激素或怀孕或哺乳期间的激素变化在基因组水平对十二指肠主动钙吸收机制具有独特的、不依赖维生素D的影响,主要是通过钙内流通道CaT1的显著上调。雌激素的作用似乎仅由ERα介导。

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