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. 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)