| Title | Heparan sulfate 2-O-sulfotransferase is required for triglyceride-rich lipoprotein clearance. | | Author(s) | Stanford KI, Wang L, Castagnola J, Song D, Bishop JR, Brown JR, Lawrence R, Bai X, Habuchi H, Tanaka M, Cardoso WV, Kimata K, Esko JD | | Institution | UCSD, United States; | | Source | J Biol Chem 2009 Nov 4. | | Abstract | Hepatic clearance of triglyceride-rich lipoproteins depends on heparan sulfate and low-density lipoprotein receptors expressed on the basal membrane of hepatocytes. Binding and uptake of the lipoproteins by way of heparan sulfate depends on the degree of sulfation of the chains based on accumulation of plasma triglycerides and delayed clearance of triglyceride-rich lipoproteins in mice bearing a hepatocyte-specific alteration of N-acetylglucosamine (GlcNAc) N-deacetylase/N-sulfotransferase 1 (Ndst1) (MacArthur et al (2007) J. Clin. Invest. 117:94). Inactivation of Ndst1 led to decreased overall sulfation of heparan sulfate due to coupling of uronyl 2-O- sulfation and glucosaminyl 6-O-sulfation to initial N-deacetylation and N-sulfation of GlcNAc residues. To determine if lipoprotein clearance depends on 2-O- and 6-O-sulfation, we evaluated plasma triglyceride levels in mice containing loxP-flanked conditional alleles of uronyl 2-O-sulfotransferase (Hs2stf/f) and glucosaminyl 6-O-sulfotransferase-1 (Hs6st1f/f) and the bacterial Cre recombinase expressed in hepatocytes from the rat albumin (Alb) promoter. We show that Hs2stf/fAlbCre+ mice accumulated plasma triglycerides and exhibited delayed clearance of intestinally derived chylomicrons and injected human VLDL to the same extent as observed in Ndst1f/fAlbCre+ mice. In contrast, Hs6st1f/fAlbCre+ mice did not exhibit any changes in plasma triglycerides. Chemically modified heparins lacking N-sulfate and 2-O-sulfate groups did not block VLDL binding and uptake in isolated hepatocytes, whereas heparin lacking 6-O-sulfate groups was as active as unaltered heparin. Our findings show that plasma lipoprotein clearance depends on specific subclasses of sulfate groups and not on overall charge of the chains. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19889634 |
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