heparitin-sulfate and Hyperlipidemias

The heparan sulfate proteoglycan (HSPG)/low density lipoprotein (LDL) receptor-related protein (LRP) pathway plays a critical role in apolipoprotein (apo) E-containing lipoprotein metabolism in hepatocytes and other cells, including neurons. In this review, it will be shown that the HSPG sequestration step (i.e., the recruitment and trapping of remnant lipoproteins in the space of Disse in the liver) is an important component of remnant metabolism mediated by apo-E. In vitro studies indicate that the apo-E-containing lipoproteins must first interact with HSPG; only then does the LRP mediate lipoprotein uptake. The differential interaction of apo-EIII and the various mutant forms of apo-E with this pathway before internalization appears to be one factor that modulates the expression of recessive versus dominant type III hyperlipoproteinemia. Furthermore, it is now apparent that the HSPG/LRP pathway is involved in the delivery of apo-E to neurons, where apo-E alters neurite growth and cytoskeletal activity in these cells. Specifically, apo-EIV, which has been associated with the pathogenesis of Alzheimer's disease, inhibits neurite extension and microtubule formation subsequent to the interaction of apo-EIV with the HSPG/LRP pathway.

Topics: Alzheimer Disease; Apolipoproteins E; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Hyperlipidemias; Hyperlipoproteinemia Type III; Liver; Proteoglycans; Receptors, LDL

Hyperlipidemia accelerates the progression of glomerular disease, and lipoproteins bind glomerular mesangial cells (MC) and induce proliferation and cytokine expression. In the vessel wall, the binding of lipoproteins to endothelial cells is markedly enhanced by lipoprotein lipase (LpL), synthesized by the underlying smooth muscle cells. While it is known that LpL is localized to the glomerulus, it is not known if and how it modulates the lipoprotein-mesangial interaction.. Very low-density lipoprotein (VLDL) was isolated from rats and was used to treat cultured primary rat MCs. Binding studies were done with and without LpL and with/without pretreatment with heparanase, which degrades cell surface heparan sulfate proteoglycan (HSPG), known to modulate the LpL-lipoprotein interaction in blood vessels. VLDL/LpL was also used to assess MC proliferation and gene expression of the cytokine platelet-derived growth factor (PDGF).. LpL enhanced VLDL binding to MCs by as much as 200-fold, and most of this effect was blocked by pretreatment with heparanase. LpL amplified VLDL-driven MC proliferation and increased VLDL-induced PDGF expression. Heparanase pretreatment of cells eliminated both of these amplifications. LpL alone increased MC proliferation and PDGF gene expression.. As in the vessel wall, LpL enhances VLDL binding to MCs. MCs respond to LpL binding by proliferating and expressing cytokines such as PDGF. LpL may be a crucial paracrine mediator of the glomerular response to circulating lipoproteins, amplifying a response that includes cytokine elaboration, influx of circulating monocytes, and eventual sclerosis.

Topics: Animals; Cell Division; Cells, Cultured; Female; Gene Expression; Glomerular Mesangium; Glomerulonephritis; Glucuronidase; Heparitin Sulfate; Hyperlipidemias; Lipoprotein Lipase; Lipoproteins, VLDL; Paracrine Communication; Platelet-Derived Growth Factor; Rats; Rats, Sprague-Dawley; Rats, Zucker; RNA, Messenger