An apolipoprotein(a) peptide delays chylomicron remnant clearance and increases plasma remnant lipoproteins and atherosclerosis in vivo

Cecilia M. Devlin, Sung-Joon Lee, George Kuriakose, Craig Spencer, Lev Becker, Itamar Grosskopf, Carol Ko, Li Shin Huang, Marlys L. Koschinsky, Allen D. Cooper, Ira Tabas

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 KIV5-8 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 KIV5-8 transgenic mice. Methods and 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 KIV5-8, 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 KIV5-8 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).

Original languageEnglish
Pages (from-to)1704-1710
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume25
Issue number8
DOIs
Publication statusPublished - 2005 Aug 1

Fingerprint

Chylomicron Remnants
Apoprotein(a)
Lipoproteins
Atherosclerosis
Lipoprotein(a)
Peptides
Liver
Transgenic Mice
Cholesterol
Surface Properties
Apolipoproteins B
LDL Lipoproteins
Coronary Artery Disease
Triglycerides
Diet

Keywords

  • Apolipoprotein(a)
  • Atherosclerosis
  • Hepatic clearance
  • Lipoprotein(a)
  • Remnant lipoproteins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

An apolipoprotein(a) peptide delays chylomicron remnant clearance and increases plasma remnant lipoproteins and atherosclerosis in vivo. / Devlin, Cecilia M.; Lee, Sung-Joon; Kuriakose, George; Spencer, Craig; Becker, Lev; Grosskopf, Itamar; Ko, Carol; Huang, Li Shin; Koschinsky, Marlys L.; Cooper, Allen D.; Tabas, Ira.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 25, No. 8, 01.08.2005, p. 1704-1710.

Research output: Contribution to journalArticle

Devlin, Cecilia M. ; Lee, Sung-Joon ; Kuriakose, George ; Spencer, Craig ; Becker, Lev ; Grosskopf, Itamar ; Ko, Carol ; Huang, Li Shin ; Koschinsky, Marlys L. ; Cooper, Allen D. ; Tabas, Ira. / An apolipoprotein(a) peptide delays chylomicron remnant clearance and increases plasma remnant lipoproteins and atherosclerosis in vivo. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2005 ; Vol. 25, No. 8. pp. 1704-1710.
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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 KIV5-8 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 KIV5-8 transgenic mice. Methods and 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 KIV5-8, 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 KIV5-8 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).",
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T1 - An apolipoprotein(a) peptide delays chylomicron remnant clearance and increases plasma remnant lipoproteins and atherosclerosis in vivo

AU - Devlin, Cecilia M.

AU - Lee, Sung-Joon

AU - Kuriakose, George

AU - Spencer, Craig

AU - Becker, Lev

AU - Grosskopf, Itamar

AU - Ko, Carol

AU - Huang, Li Shin

AU - Koschinsky, Marlys L.

AU - Cooper, Allen D.

AU - Tabas, Ira

PY - 2005/8/1

Y1 - 2005/8/1

N2 - 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 KIV5-8 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 KIV5-8 transgenic mice. Methods and 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 KIV5-8, 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 KIV5-8 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).

AB - 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 KIV5-8 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 KIV5-8 transgenic mice. Methods and 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 KIV5-8, 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 KIV5-8 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).

KW - Apolipoprotein(a)

KW - Atherosclerosis

KW - Hepatic clearance

KW - Lipoprotein(a)

KW - Remnant lipoproteins

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