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 (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. 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.

Emerging Liver–Kidney Interactions in Nonalcoholic Fatty Liver Disease

“…Recently, the key role for the transmembrane heparan sulfate proteoglycan syndecan-1 in hepatic TRLP clearance has emerged [95]: syndecan-1 is constitutively bound to hepatocyte membrane, where it binds to lipoprotein lipase (LPL) and apolipoprotein E (APOE) through its negatively charged heparan sulfate chains, and internalizes APOE-containing lipoproteins [96]. Defective syndecan-1 sulfation by hepatocyte-specific inactivation of sulfotransferases involved in heparan sulfate biosynthesis, or accelerated syndecan-1 shedding from hepatocytes by activation of metalloproteinases, result in impaired TRLP clearance and dyslipidemia [95,96]. NAFLD patients have increased shedding of syndecan-1, as a result of increased hepatic metalloproteinase activation, and impaired syndecan-1 sulfation as a result of defective hepatic sulfotransferase activity [97,98], which may alter TRLP clearance and contribute to atherogenic dyslipidemia.…”

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

“…Syndecan-1 is another key mediator of hepatic clearance of triglyceride-rich lipoproteins (TRLPs) (113). It is a transmembrane heparan sulfate proteoglycan constitutively bound to hepatocyte membrane, where it binds lipoprotein lipase and apolipoprotein (apo) E through its heparan sulfate chains and internalizes apoE-containing lipoproteins (31).…”

Apolipoproteins E and AV mediate lipoprotein clearance by hepatic proteoglycans

“…Binding to cell surface HSPGs was assessed by incubation of the radiolabeled TRLs with Hep3B human hepatocarcinoma cells, a cell line expressing an HSPG profile similar to that of primary human and murine hepatocytes (13,34 Figure 1B). The residual binding presumably reflects other receptors (e.g., LDLR) or incomplete removal of heparan sulfate.…”

“…Finally, binding of TRLs to HSPGs was not affected in vitro by mAbs raised against different domains of ApoB. In these latter experiments, we took advantage of the observation that shed SDC1 ectodomains will form complexes with purified TRLs from human plasma, based on an assay in which 35 S-labeled HSPG ectodomains are mixed with human TRLs and subjected to ultracentrifugation (34). Under these conditions, complexes of human TRLs with [ 35 Figure 3C).…”