Metabolism of Lp(a): assembly and excretion.
Lp(a) is one of the most atherogenic lipoproteins, and we know much more about the pathophysiology of Lp(a) than about its physiological function and metabolism. From our previous investigations and the new results reported here, we propose the following model of Lp(a) metabolism: apo(a) is biosynthesized in liver cells and the size of the isoform determines its rate of synthesis and excretion. Specific kringle-4 domains in apo(a), mainly T-6 and T-7, bind in a first step to circulating LDL, followed by the stabilization of the newly formed Lp(a) complex by a disulfide bridge. Circulating Lp(a) interacts specifically with kidney cells, or possibly other tissues, causing cleavage of 2/3-3/4 of the N-terminal part of apo(a) by a collagenase-type protease. Part of the apo(a) fragments is found in the urine, but there are indications that they in fact represent the biologically active form of apo(a). The core portion of Lp(a) in turn is cleared by the LDL-receptor or another specific binding system of the liver. Strategies for reducing plasma Lp(a) levels with medication should aim at interfering with the assembly of Lp(a) on one hand and the stimulation of apo(a) fragmentation on the other hand.
Kostner
G M
GM
Institute of Medical Biochemistry, University of Graz, Austria. gerhard.kostner@kfunigraz.ac.at
Wo
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Frank
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Kostner
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Zimmermann
R
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Steyrer
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D000818:Animals; D001054:Apolipoproteins A / Q000737:chemistry / Q000493:pharmacokinetics*; D017364:Collagenases / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D006364:Hedgehogs; D006801:Humans; D018082:Kringles / Q000502:physiology; D017270:Lipoprotein(a) / Q000378:metabolism* / Q000493:pharmacokinetics; D008077:Lipoproteins, LDL / Q000493:pharmacokinetics; D008954:Models, Biological; D010446:Peptide Fragments / Q000378:metabolism
D001054:Apolipoproteins A; D017270:Lipoprotein(a); D008077:Lipoproteins, LDL; D010446:Peptide Fragments; D010450:Endopeptidases; D017364:Collagenases