Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members

Abstract

We examined the role of hepatic heparan sulfate in triglyceride-rich lipoprotein metabolism by inactivating the biosynthetic gene GlcNAc N-deacetylase/N-sulfotransferase 1 (Ndst1) in hepatocytes using the Cre-loxP system, which resulted in an approximately 50% reduction in sulfation of liver heparan sulfate. Mice were viable and healthy, but they accumulated triglyceride-rich lipoprotein particles containing apoB-100, apoB-48, apoE, and apoCI-IV. Compounding the mutation with LDL receptor deficiency caused enhanced accumulation of both cholesterol-and triglyceride-rich particles compared with mice lacking only LDL receptors, suggesting that heparan sulfate participates in the clearance of cholesterol-rich lipoproteins as well. Mutant mice synthesized VLDL normally but showed reduced plasma clearance of human VLDL and a corresponding reduction in hepatic VLDL uptake. Retinyl ester excursion studies revealed that clearance of intestinally derived lipoproteins also depended on hepatocyte heparan sulfate. These findings show that under normal physiological conditions, hepatic heparan sulfate proteoglycans play a crucial role in the clearance of both intestinally derived and hepatic lipoprotein particles.

Structure and Function of the Lipolysis Stimulated Lipoprotein Receptor

“…LSR therefore acts downstream of the lipolytic process as a hepatic receptor for the removal of TG-rich particles from the circulation (Figure 4). This conclusion is supported by a recent paper which reported that the removal of apoB-containing lipoproteins was inhibited in animals with reduced sulfation of heparan sulfate proteoglycans in the liver (MacArthur et al, 2007). Indeed, it was suggested that the removal of lipoproteins was mediated by a downstream pathway independent of the LDL-R or LRP1 (Mahley & Huang, 2007 Fig.…”

Systemic inactivation of Hs6st1 in mice is associated with late postnatal mortality without major defects in organogenesis

“…Lack of lethality during this period suggests that Hs6st12/2 pups can consume their mother's milk. During adult life Hs6st1 is expressed at high level in the liver, and there is recent evidence implicating liver heparan sulfates in lipoprotein metabolism (MacArthur et al, 2007). Thus, a metabolic defect could potentially affect postnatal weight gain, growth and, ultimately survival in the Hs6st1-deficient mouse model.…”

The Dominating Role of N-Deacetylase/N-Sulfotransferase 1 in Forming Domain Structures in Heparan Sulfate

“…Unlike other NDST isoforms, the absence of NDST-1 in mice led to respiratory distress, and subsequently neonatal death (15). Conditional knock-out of NDST-1 revealed a series of physiological and pathophysiolog-ical roles, including the clearance of lipoproteins (16), the development of lobuloalveolar of mammary gland (17), neutrophil trafficking (18), and inhibition of tumor angiogenesis (19). These in vivo effects of NDST-1 were attributed to the disruption of the N-sulfation, leading to dramatic changes in O-sulfations and epimerization of HS in genetically modified animals.…”