Shedding of syndecan-1 from human hepatocytes alters very low density lipoprotein clearance.
Shedding of syndecan-1 from human hepatocytes alters very low density lipoprotein clearance.
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DOI：
10.1002/hep.24626
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发表时间：
2012-01
期刊：
影响因子：
13.5
通讯作者：
Esko, Jeffrey D.
中科院分区：
文献类型：
--
作者：
Deng, Yiping;Foley, Erin M.;Gonzales, Jon C.;Gordts, Philip L.;Li, Yulin;Esko, Jeffrey D.
我们最近显示，基于多配体蛋白聚糖-1的系统性缺失和硫酸乙酰肝素生物合成中涉及的磺基转移酶的肝细胞特异性失活，硫酸乙酰肝素蛋白聚糖多配体蛋白聚糖-1介导小鼠中富含磷脂酰肌醇的脂蛋白的肝清除（麦克阿瑟等人（2007）J.Clin.Invest.2005）。117：153-164;斯坦福大学（Stanford）等人（2009）J. Clin. Invest. 119：3236-3245;斯坦福大学等人（2010）J. Biol. Chem. 285：286-294）。在这份报告中，我们表明，syndecan-1表达的原代人肝细胞和Hep 3B人肝癌细胞可以介导的结合和摄取极低密度脂蛋白。多配体蛋白聚糖-1还经历从原代人和鼠肝细胞和Hep 3B细胞的自发脱落。在人类细胞中，佛波醇肉豆蔻酸（PMA）诱导多配体蛋白聚糖-1脱落，导致多配体蛋白聚糖-1胞外域在培养基中积累。脱落通过A去整合素和金属蛋白酶-17的蛋白激酶C依赖性活化而发生。PMA刺激显著降低DiD-VLDL与细胞的结合，并且脱落的多配体蛋白聚糖-1胞外域与VLDL结合。虽然小鼠肝细胞在体外对诱导脱落有抗性，但将脂多糖注射到小鼠体内会导致肝多配体蛋白聚糖-1的丢失、胞外域在血浆中的积累、VLDL催化剂受损和高脂血症。这些发现表明，syndecan-1介导人类和小鼠的肝脏VLDL周转，并且脱落可能导致脓毒症患者的高脂血症。
We recently showed that the heparan sulfate proteoglycan syndecan-1 mediates hepatic clearance of triglyceride-rich lipoproteins in mice based on systemic deletion of syndecan-1 and hepatocyte-specific inactivation of sulfotransferases involved in heparan sulfate biosynthesis (MacArthur et al. (2007) J. Clin. Invest. 117:153–164; Stanford et al. (2009) J. Clin. Invest. 119:3236–3245; Stanford et al. (2010) J. Biol. Chem. 285:286–294). In this report we show that syndecan-1 expressed on primary human hepatocytes and Hep3B human hepatoma cells can mediate binding and uptake of VLDL. Syndecan-1 also undergoes spontaneous shedding from primary human and murine hepatocytes and Hep3B cells. In human cells, phorbol myristic acid (PMA) induces syndecan-1 shedding, resulting in accumulation of syndecan-1 ectodomains in the medium. Shedding occurs through a protein kinase C-dependent activation of A Disintegrin and Metalloproteinase-17. PMA-stimulation significantly decreases DiD-VLDL binding to cells, and shed syndecan-1 ectodomains bind to VLDL. Although mouse hepatocytes appear resistant to induced-shedding in vitro, injection of lipopolysaccharide into mice results in loss of hepatic syndecan-1, accumulation of ectodomains in the plasma, impaired VLDL catabolism, and hypertriglyceridemia. These findings suggest that syndecan-1 mediates hepatic VLDL turnover in humans as well as in mice and that shedding might contribute to hypertriglyceridemia in patients with sepsis.
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