title: Shedding of syndecan-1 from human hepatocytes alters very low density lipoprotein clearance.
abstract: 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 C-dependent 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0687, USA.
authors: Yiping
authors: Y
authors: Deng
authors: Erin M
authors: EM
authors: Foley
authors: Jon C
authors: JC
authors: Gonzales
authors: Philip L
authors: PL
authors: Gordts
authors: Yulin
authors: Y
authors: Li
authors: Jeffrey D
authors: JD
authors: Esko
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D045744:Cell Line, Tumor; D006497:Heparan Sulfate / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D015228:Hypertriglyceridemia / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008079:Lipoproteins, VLDL / Q000493:pharmacokinetics*; D008113:Liver Neoplasms; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011493:Protein Kinase C / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism; D053668:Syndecan-1 / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood
chemical_list: D002273:Carcinogens; D006497:Heparan Sulfate; D008070:Lipopolysaccharides; D008079:Lipoproteins, VLDL; D011493:Protein Kinase C; D053668:Syndecan-1; D013755:Tetradecanoylphorbol Acetate; D014280:Triglycerides; C508241:SDC1 protein, human; C508242:Sdc1 protein, mouse