Submitted on September 3, 2003
Revised on April 20, 2004
Accepted on April 21, 2004
Association of hepatic lipase with proteoglycans stimulates the production of proteoglycans in vivo and in vitro
Sung-Joon Lee, Sujata Kadambi, Christopher David, Allen D. Cooper, and Sungshin Y. Choi
Department of Cardiovascular Biology, Palo Alto Medical Foundation, Palo Alto, CA 94301
Corresponding Author: chois{at}pamfri.org
Cell surface proteoglycans (PGs) are present in the space of Disse and play an important role in the sequestration of lipoproteins. Hepatic lipase (HL) is synthesized in hepatocytes, and functions while bound to heparan sulfate proteoglycans (HSPG) in sinusoidal endothelial cells. The HL-mediated uptake of lipoprotein requires cell-surface HSPG. The present study tested whether HL plays a role in the production of HSPG. The production of HSPG in CHO cells was determined by measuring the incorporation of 35S-SO4 (sulfate) into PGs. HL-producing CHO (HL-CHO) cells showed approximately 30% more cellular PG than did wild-type (WT) cells. In contrast, PG production in cells producing a membrane-anchored form (HL-GPI) of HL that was not bound to HSPG was virtually identical to that in WT cells. When purified HL was added to the WT or HL-GPI cells, PG production increased significantly to a level similar to that of the HL-secreting cells, suggesting that the binding of HL to HSPG, and not the production of HL, triggered the increased HSPG production. Heparin reduced PG production in HL-producing cells, confirming that PG production is stimulated only when HL is present as a ligand for HSPG. Real-time PCR and Northern blots, using liver RNA demonstrated that PG production was significantly reduced in animals deficient in HL in vivo. Together, these data suggest that the binding of HL to PG on the cell surface exerts a positive feedback on cellular PG production.
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