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Aspects on lipoprotein lipase and atherosclerosis
Umeå University, Faculty of Medicine, Medical Biosciences, Physiological chemistry. Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Clinical Physiology.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lipoprotein lipase (LPL) hydrolyses blood lipids at the vascular endothelium. This action makes fatty acids available for tissue metabolic requirements. LPL is anchored to the endothelium by electrostatic forces and may act as a bridge connecting lipoproteins to cell surfaces. Clusters of positively charged amino acid residues in LPL interact with anionic groups on oligosaccharides covering the cell surfaces. Heparin competes with cell surface oligosaccharides for binding to LPL. Interaction of LPL with soluble and cell surface- ound oligosaccharides influences the activity and catabolism of the enzyme. LPL has a dual role in the development of atherosclerosis. Hydrolysis of lipoproteins by LPL contributes to clearance of lipids from plasma, resulting in an anti-atherogenic lipid profile. On the other hand, trough its bridging function, LPL contributes to lipoprotein retention at the endothelium and in the connective tissue of the artery wall. Furthermore LPL may stimulate uptake of lipoproteins in cells, converting them to foam cells. In this way LPL is considered to be proatherogenic.

We have investigated the effects caused by a synthetic heparin analogue, RG-13577, developed for treatment of tumors by anti-angiogenesis theraphy (Paper I) and by heparin (Paper II) on the turnover and biological role of LPL. The variation of LPL activity in kidney among animal species was studied in Paper III. Localization of LPL in healthy and atherosclerotic human arteries in relation to two other heparin-binding proteins (extracellular superoxide dismutase and apolipoprotein B) was studied in Paper IV.

Place, publisher, year, edition, pages
2005. , 54 p.
National Category
Physiology
Identifiers
URN: urn:nbn:se:umu:diva-564ISBN: 91-7305-8998 OAI: oai:DiVA.org:umu-564DiVA: diva2:143807
Public defence
2005-09-07, sal E04, NUS, 09:00 (English)
Opponent
Available from: 2005-08-18 Created: 2005-08-18 Last updated: 2009-10-13Bibliographically approved
List of papers
1. Effects of the heparin-mimicking compound RG-13577 on lipoprotein lipase and on lipase mediated binding of LDL to cells
Open this publication in new window or tab >>Effects of the heparin-mimicking compound RG-13577 on lipoprotein lipase and on lipase mediated binding of LDL to cells
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2001 (English)In: Atherosclerosis, ISSN 0021-9150, Vol. 157, no 1, 13-21 p.Article in journal (Refereed) Published
Abstract [en]

Lipoprotein lipase (LPL) has high affinity for heparin and heparin-like compounds. In vivo the enzyme is attached to heparan sulfate proteoglycans on the endothelium of capillaries and larger blood vessels. The enzyme is released from these sites after intravenous injection of heparin. One has here investigated the effects of RG-13577 on LPL, both after intravenous injection to rats and under cell culture conditions. RG-13577 is a heparin-mimicking compound known to prevent angiogenesis by interference with binding of growth factors to cells. It has therefore been considered for use in cancer therapy as well as for prevention of atherosclerosis and restenosis. It was found that intravenously injected RG-13577 released both LPL and hepatic lipase (HL) to the blood. Binding of LPL in extrahepatic tissues was prevented and clearance of radiolabeled LPL from the circulation was delayed. Furthermore, RG-13577 released LPL from extracellular matrix (ECM) produced by endothelial cells and from THP-1 monocyte-derived macrophages. Lipase-mediated binding and uptake of human LDL in these cells was also prevented by RG-13577. Thus, in the test systems RG-13577 had the same effects as heparin, but on a molar basis RG-13577 was in all cases less effective.

Identifiers
urn:nbn:se:umu:diva-4621 (URN)10.1016/S0021-9150(00)00652-3 (DOI)11427199 (PubMedID)
Available from: 2005-08-18 Created: 2005-08-18Bibliographically approved
2. Lipoprotein lipase in the kidney: activity varies widely among animal species.
Open this publication in new window or tab >>Lipoprotein lipase in the kidney: activity varies widely among animal species.
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2004 (English)In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, Vol. 287, no 6, F1131-1139 p.Article in journal (Refereed) Published
Abstract [en]

Much evidence points to a relationship among kidney disease, lipoprotein metabolism, and the enzyme lipoprotein lipase (LPL), but there is little information on LPL in the kidney. The range of LPL activity in the kidney in five species differed by >500-fold. The highest activity was in mink, followed by mice, Chinese hamsters, and rats, whereas the activity was low in guinea pigs. In contrast, the ranges for LPL activities in heart and adipose tissue were less than six- and fourfold, respectively. The activity in the kidney (in mice) decreased by >50% on food deprivation for 6 h without corresponding changes in mRNA or mass. This decrease in LPL activity did not occur when transcription was blocked with actinomycin D. Immunostaining for kidney LPL in mice and mink indicated that the enzyme is produced in tubular epithelial cells. To explore the previously suggested possibility that the negatively charged glomerular filter picks up LPL from the blood, bovine LPL was injected into rats and mice. This resulted in decoration of the glomerular capillary network with LPL. This study shows that in some species LPL is produced in the kidney and is subject to nutritional regulation by a posttranscriptional mechanism. In addition, LPL can be picked up from blood in the glomerulus.

Keyword
Adipose Tissue/enzymology, Animal Nutrition Physiology, Animals, Cricetinae, Cricetulus, Female, Food Deprivation, Guinea Pigs, Kidney/*enzymology, Lipoprotein Lipase/genetics/*metabolism, Male, Mice, Mink, Myocardium/enzymology, RNA; Messenger/analysis, Rats, Rats; Sprague-Dawley, Species Specificity
Identifiers
urn:nbn:se:umu:diva-15203 (URN)10.1152/ajprenal.00089.2004 (DOI)15292043 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2009-10-13Bibliographically approved
3. Effects of heparin on the uptake of lipoprotein lipase in rat liver.
Open this publication in new window or tab >>Effects of heparin on the uptake of lipoprotein lipase in rat liver.
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2004 (English)In: BMC Physiology, ISSN 1472-6793, Vol. 4, no 1, 13- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Lipoprotein lipase (LPL) is anchored at the vascular endothelium through interaction with heparan sulfate. It is not known how this enzyme is turned over but it has been suggested that it is slowly released into blood and then taken up and degraded in the liver. Heparin releases the enzyme into the circulating blood. Several lines of evidence indicate that this leads to accelerated flux of LPL to the liver and a temporary depletion of the enzyme in peripheral tissues. RESULTS: Rat livers were found to contain substantial amounts of LPL, most of which was catalytically inactive. After injection of heparin, LPL mass in liver increased for at least an hour. LPL activity also increased, but not in proportion to mass, indicating that the lipase soon lost its activity after being bound/taken up in the liver. To further study the uptake, bovine LPL was labeled with 125I and injected. Already two min after injection about 33 % of the injected lipase was in the liver where it initially located along sinusoids. With time the immunostaining shifted to the hepatocytes, became granular and then faded, indicating internalization and degradation. When heparin was injected before the lipase, the initial immunostaining along sinusoids was weaker, whereas staining over Kupffer cells was enhanced. When the lipase was converted to inactive before injection, the fraction taken up in the liver increased and the lipase located mainly to the Kupffer cells. CONCLUSIONS: This study shows that there are heparin-insensitive binding sites for LPL on both hepatocytes and Kupffer cells. The latter may be the same sites as those that mediate uptake of inactive LPL. The results support the hypothesis that turnover of endothelial LPL occurs in part by transport to and degradation in the liver, and that this transport is accelerated after injection of heparin.

Keyword
Animals, Cattle, Heparin/administration & dosage/*pharmacology, Injections, Lipoprotein Lipase/analysis/*metabolism/pharmacokinetics, Liver/*enzymology, Male, Protein Transport, Rats, Rats; Sprague-Dawley
Identifiers
urn:nbn:se:umu:diva-15201 (URN)10.1186/1472-6793-4-13 (DOI)15544705 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2009-11-25Bibliographically approved
4. Distribution of lipoprotein lipase in human arteries: Relation to extracellular superoxide dismutase, apolipoprotein B and atherosclerosis
Open this publication in new window or tab >>Distribution of lipoprotein lipase in human arteries: Relation to extracellular superoxide dismutase, apolipoprotein B and atherosclerosis
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Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:umu:diva-4624 (URN)
Available from: 2005-08-18 Created: 2005-08-18Bibliographically approved

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Citation style
  • apa
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