Autotaxin is released from adipocytes, catalyzes lysophosphatidic acid synthesis, and activates preadipocyte proliferation -: Up-regulated expression with adipocyte differentiation and obesity
Autotaxin is released from adipocytes, catalyzes lysophosphatidic acid synthesis, and activates preadipocyte proliferation -: Up-regulated expression with adipocyte differentiation and obesity
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DOI：
10.1074/jbc.m301158200
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发表时间：
2003-05-16
影响因子：
4.8
通讯作者：
Saulnier-Blache, JS
中科院分区：
文献类型：
--
作者：
Ferry, G;Tellier, E;Saulnier-Blache, JS
我们小组最近已经证明(Gesta，S.，Simon，M.，Rey，A.，Sibrac，D.，Girard，A.，Lafontan，M.，Valet，P.和Saulnier-Blache，J.S.(2002)J.Lipid Res.43,904-910)脂肪细胞条件培养液中存在参与合成生物活性磷脂溶血磷脂酸(LPA)的可溶性溶血磷脂酶D活性(LPLDact)。本研究从3T3F442A型脂肪细胞条件培养液中分离纯化了LPLDact，鉴定其为II型外核苷酸焦磷酸二酯酶、自体趋化蛋白(ATX)。从3T3F442A型脂肪细胞中克隆了ATX基因，并在COS-7细胞中进行了重组表达，使LPLDact在细胞外释放。3T3F442A型前体脂肪细胞在脂肪细胞分化过程中ATX基因表达显著上调。这种上调与新分化的脂肪细胞释放LPLDact和LPA的能力平行。在小鼠前脂肪细胞的原代培养中也观察到ATX表达的分化依赖性上调。与ATX不表达的COS-7细胞的浓缩条件培养液相比，ATX表达的COS-7细胞用浓缩条件培养液处理3T3F442a前脂肪细胞后，细胞数增加。ATX对前体脂肪细胞增殖的特异性作用被LPA水解型磷脂酶B共同作用完全抑制。最后，ATX在从小鼠脂肪组织分离的成熟脂肪细胞中被发现表达，并且在遗传性肥胖糖尿病db/db小鼠中与其瘦兄弟姐妹相比显著增加。综上所述，目前的工作表明ATX负责脂肪细胞释放LPLDact，并通过LPA依赖的机制对前脂肪细胞的生长起旁分泌控制作用。ATX的表达上调与脂肪细胞分化和遗传性肥胖有关，提示这种释放的蛋白可能参与了脂肪组织的发展和肥胖相关的病理。
Our group has recently demonstrated (Gesta, S., Simon, M., Rey, A., Sibrac, D., Girard, A., Lafontan, M., Valet, P., and Saulnier-Blache, J. S. (2002) J. Lipid Res. 43, 904-910) the presence, in adipocyte conditioned-medium, of a soluble lysophospholipase D-activity (LPLDact) involved in synthesis of the bioactive phospholipid lysophosphatidic acid (LPA). In the present report, LPLDact was purified from 3T3F442A adipocyte-conditioned medium and identified as the type II ecto-nucleotide pyrophosphatase phosphodiesterase, autotaxin (ATX). A unique ATX cDNA was cloned from 3T3F442A adipocytes, and its recombinant expression in COS-7 cells led to extracellular release of LPLDact. ATX mRNA expression was highly up-regulated during adipocyte differentiation of 3T3F442A-preadipocytes. This up-regulation was paralleled by the ability of newly differentiated adipocytes to release LPLDact and LPA. Differentiation-dependent up-regulation of ATX expression was also observed in a primary culture of mouse preadipocytes. Treatment of 3T3F442A-preadipocytes with concentrated conditioned medium from ATX-expressing COS-7 cells led to an increase in cell number as compared with concentrated conditioned medium from ATX non-expressing COS-7 cells. The specific effect of ATX on preadipocyte proliferation was completely suppressed by co-treatment with a LPA-hydrolyzing phospholipase, phospholipase B. Finally, ATX expression was found in mature adipocytes isolated from mouse adipose tissue and was substantially increased in genetically obese-diabetic db/db mice when compared with their lean siblings. In conclusion, the present work shows that ATX is responsible for the LPLDact released by adipocytes and exerts a paracrine control on preadipocyte growth via an LPA-dependent mechanism. Up-regulations of ATX expression with adipocyte differentiation and genetic obesity suggest a possible involvement of this released protein in the development of adipose tissue and obesity-associated pathologies.