Shedding of syndecan-1 from human hepatocytes alters very low density lipoprotein clearance

被引:34
作者
Deng, Yiping [1 ,3 ]
Foley, Erin M. [1 ,2 ]
Gonzales, Jon C. [1 ,2 ]
Gordts, Philip L. [1 ]
Li, Yulin [3 ]
Esko, Jeffrey D. [1 ,2 ]
机构
[1] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Biomed Sci Grad Program, La Jolla, CA 92093 USA
[3] Jilin Univ, Key Lab Pathobiol, Minist Educ, Norman Bethune Coll Med, Changchun 130023, Peoples R China
基金
美国国家卫生研究院;
关键词
HEPARAN-SULFATE PROTEOGLYCANS; TRIGLYCERIDE-RICH LIPOPROTEINS; NECROSIS-FACTOR-ALPHA; GROWTH-FACTOR-ALPHA; CHYLOMICRON REMNANTS; LDL-RECEPTOR; L-SELECTIN; STAPHYLOCOCCUS-AUREUS; LIGAND CATABOLISM; APOLIPOPROTEIN-E;
D O I
10.1002/hep.24626
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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. Here, we show that syndecan-1 expressed on primary human hepatocytes and Hep3B human hepatoma cells can mediate binding and uptake of very low density lipoprotein (VLDL). Syndecan-1 also undergoes spontaneous shedding from primary human and murine hepatocytes and Hep3B cells. In human cells, phorbol myristic acid induces syndecan-1 shedding, resulting in accumulation of syndecan-1 ectodomains in the medium. Shedding occurs through a protein kinase Cdependent activation of ADAM17 (a disintegrin and metalloproteinase 17). Phorbol myristic acid stimulation significantly decreases DiD (1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate)-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. Conclusion: 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. (HEPATOLOGY 2012;55:277-286)
引用
收藏
页码:277 / 286
页数:10
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