title: An apolipoprotein(a) peptide delays chylomicron remnant clearance and increases plasma remnant lipoproteins and atherosclerosis in vivo.
abstract: OBJECTIVE
  Humans with high expression of apolipoprotein(a) [apo(a)] and high plasma levels of lipoprotein(a) [Lp(a)] are at increased risk for atherosclerosis, but the mechanism is not known. We have previously shown that the KIV(5-8) domain of apo(a) has unique cell-surface binding properties, and naturally occurring fragments of apo(a) encompassing this domain are thought to be atherogenic in humans. To investigate the effect of KIV(5-8) on lipoprotein metabolism and atherosclerosis in vivo, we created several independent lines of liver-targeted KIV(5-8) transgenic mice.
  
  
  RESULTS
  The transgenic mice have plasma apo(a) peptide concentrations that are similar to Lp(a) concentrations in humans at risk for coronary artery disease. Remarkably, the transgenic mice had a 2- to 4-fold increase in cholesterol-rich remnant lipoproteins (RLPs) when fed a cholesterol-rich diet, and a 5- to 20-fold increase in atherosclerosis lesion area in the aortic root. Using an in vivo clearance study, we found only slight differences in the triglyceride and apolipoprotein B secretion rates between the 2 groups of mice, suggesting an RLP clearance defect. Using an isolated perfused mouse liver system, we showed that transgenic livers had a slower rate of RLP removal, which was retarded further when KIV(5-8), full-length apo(a), or Lp(a) were added to the perfusate. An apo(a) peptide that does not interact with cells, K(IV2)3, did not retard RLP removal, and low-density lipoprotein (LDL) had a much smaller effect than Lp(a).
  
  
  CONCLUSIONS
  We propose that high levels of apo(a)/Lp(a), perhaps acting via a specific cell-surface binding domain, inhibit hepatic clearance of remnants, leading to high plasma levels of RLPs and markedly enhanced atherosclerosis. We speculate that the KIV(5-8) region of apo(a) competes with one or more receptors for remnant clearance in the liver and that this process may represent one mechanism accounting for increased atherosclerosis in humans with high secretion levels of apo(a).
authors.affiliation: Department of Medicine, Columbia University, 630 W 168th St, New York, NY 10032, USA.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Devlin
authors.forename: Sung-Joon
authors.initials: SJ
authors.lastname: Lee
authors.forename: George
authors.initials: G
authors.lastname: Kuriakose
authors.forename: Craig
authors.initials: C
authors.lastname: Spencer
authors.forename: Lev
authors.initials: L
authors.lastname: Becker
authors.forename: Itamar
authors.initials: I
authors.lastname: Grosskopf
authors.forename: Carol
authors.initials: C
authors.lastname: Ko
authors.forename: Li-Shin
authors.initials: LS
authors.lastname: Huang
authors.forename: Marlys L
authors.initials: ML
authors.lastname: Koschinsky
authors.forename: Allen D
authors.initials: AD
authors.lastname: Cooper
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D053299:Apolipoprotein B-100; D053283:Apolipoprotein B-48; D001054:Apolipoproteins A / Q000097:blood* / Q000235:genetics* / Q000494:pharmacology; D001055:Apolipoproteins B / Q000097:blood / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism*; D015243:Cholesterol, VLDL / Q000097:blood; D053298:Chylomicron Remnants; D002914:Chylomicrons / Q000097:blood*; D005260:Female; D006801:Humans; D018082:Kringles / Q000235:genetics; D008074:Lipoproteins / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051381:Rats; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
chemical_list: D053299:Apolipoprotein B-100; D053283:Apolipoprotein B-48; D001054:Apolipoproteins A; D001055:Apolipoproteins B; D015243:Cholesterol, VLDL; D053298:Chylomicron Remnants; D002914:Chylomicrons; D008074:Lipoproteins; D014280:Triglycerides; C112017:remnant-like particle cholesterol; D002784:Cholesterol