Does the absence of ABCC6 (multidrug resistance protein 6) in patients with Pseudoxanthoma elasticum prevent the liver from providing sufficient vitamin K to the periphery?
Does the absence of ABCC6 (multidrug resistance protein 6) in patients with Pseudoxanthoma elasticum prevent the liver from providing sufficient vitamin K to the periphery?
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DOI：
10.4161/cc.7.11.6005
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发表时间：
2008-06-01
期刊：
影响因子：
4.3
通讯作者：
Schlingemann, Reinier
中科院分区：
文献类型：
--
作者：
Borst, Piet;van de Wetering, Koen;Schlingemann, Reinier
弹性纤维性假黄瘤（PXE）是一种常染色体隐性遗传疾病，其特征是结缔组织进行性矿化，导致皮肤、动脉和眼部疾病。经典的PXE是由ABCC 6基因突变引起的，该基因编码有机阴离子转运蛋白的ABCC（MRP）家族的成员。最近对Abcc 6（-/-）小鼠的研究表明，肝脏中ABCC 6的缺失对PXE至关重要，并证实了PXE的“代谢病假说”，即组织钙化是由于缺乏从基底外侧肝细胞膜分泌的血浆因子。我们提出这种血浆因子是维生素K（前体）。我们提出，维生素K（前体）是由ABCC 6从肝脏分泌的谷胱甘肽（或葡萄糖醛酸苷）共轭物，这补充了外周组织的维生素K需要，从饮食中获得的维生素不足，因为饮食中的维生素K是有效地从血液中提取的肝脏。外周组织中的维生素K是谷氨酸残基的γ-羧化所必需的，而谷氨酸残基是抵抗全身结缔组织钙化所必需的，我们的假设解释了已知的PXE事实，也解释了为什么在γ-谷氨酰羧化酶基因（编码负责蛋白羧化酶的酶）突变的患者和用维生素K拮抗剂治疗的大鼠中会出现类似PXE的症状。这一假设意味着，通过向患者（静脉内）提供一种可被外周组织利用的血浆维生素K（前体）形式，可以预防或减轻PXE的症状。
Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by a progressive mineralization of connective tissue, resulting in skin, arterial and eye disease. Classical PXE is caused by mutations in the ABCC6 gene, which encodes a member of the ABCC (MRP) family of organic anion transporters. Recent studies on Abcc6(-/-) mice show that the absence of ABCC6 in the liver is crucial for PXE and confirm the "metabolic disease hypothesis" for PXE, which states that tissue calcification is due to the absence of a plasma factor secreted from the basolateral hepatocyte membrane.We propose that this plasma factor is vitamin K (precursor). We propose that vitamin K (precursor) is secreted by ABCC6 from the liver as a glutathione -(or glucuronide)- conjugate and that this supplements the vitamin K need of peripheral tissues that receive insufficient vitamin from the diet, because dietary vitamin K is effectively extracted from blood by the liver. Peripheral tissue vitamin K is needed for the gamma-carboxylation of glutamate residues in proteins known to be required for counteracting calcification of connective tissue throughout the body.Our hypothesis explains the known facts of PXE and also explains why PXE-like symptoms can occur in patients with mutations in the gamma-glutamyl carboxylase gene ( encoding the enzyme responsible for protein carboxylase) and in rats treated with vitamin K antagonists. The hypothesis implies that the symptoms of PXE can be prevented or mitigated by providing patients (intravenously) with a form of plasma vitamin K (precursor) that can be used by peripheral tissues.