PAPP-A negatively regulates ABCA1, ABCG1 and SR-B1 expression by inhibiting LXRα through the IGF-I-mediated signaling pathway

Atherosclerosis. 2012 Jun;222(2):344-54. doi: 10.1016/j.atherosclerosis.2012.03.005. Epub 2012 Mar 27.

Abstract

Pregnancy-associated plasma protein-A (PAPP-A) has been involved in the atherosclerotic process through regulation of local expression of IGF-1 that mediates the activation of the phosphatidylinositol-3 (PI3-K) and Akt kinase (Akt) signaling cascades which lead to constitutive nitric oxide formation, with its attending vasodilator, antiplatelet and insulin-sensitizing actions. In addition, IGF-1 may decreased cholesterol efflux through reductions of expression in ABCA1 and SR-B1 by the PI3-K/Akt signaling pathway. In the current study, we examined whether PAPP-A was involved in LXRα regulation and in expression of ABCA1, ABCG1 or SR-B1 through the IGF-I-mediated signaling pathway (IGF/PI3-K/Akt). Results showed that PAPP-A significantly decreased expression of ABCA1, ABCG1 and SR-BI at both transcriptional and translational levels in a dose-dependent and time-dependent manner. Cellular cholesterol content was increased while cholesterol efflux was decreased by PAPP-A treatment. Moreover, LXRα which can regulate the expression of ABCA1, ABCG1 and SR-B1, was also down-regulated by PAPP-A treatment. LXRα-specific activation by LXRα agonist almost rescued the down-regulation of ABCA1, ABCG1 and SR-B1 expression by PAPP-A. In addition, PAPP-A can induce the IGF-1/PI3-K/Akt pathway in macrophages. Furthermore, our results indicate that the decreased levels observed in LXRα, ABCA1, ABCG1 and SR-B1 mRNA and protein levels upon treating cells with PAPP-A were strongly impaired with the PI3-K inhibitors or IGF-1R siRNA while the MAPK cascade inhibitor did not execute this effect, indicating that the process of ABCA1, ABCG1 and SR-BI degradation by PAPP-A involves the IGF-1/PI3-K/Akt pathway. In conclusion, PAPP-A may first down-regulate expression of LXRα through the IGF-1/PI3-K/Akt signaling pathway and then decrease expression of ABCA1, ABCG1, SR-B1 and cholesterol efflux in THP-1 macrophage-derived foam cells. Therefore, our study provided one of the mechanisms for understanding the critical effect of PAPP-A in pathogenesis of atherosclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Atherosclerosis / etiology
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Cell Line
  • Cholesterol / metabolism
  • Down-Regulation
  • Foam Cells / drug effects
  • Foam Cells / metabolism*
  • Gene Expression Regulation
  • Humans
  • Insulin-Like Growth Factor I / metabolism*
  • Liver X Receptors
  • Orphan Nuclear Receptors / metabolism*
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Pregnancy-Associated Plasma Protein-A / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • RNA, Messenger / metabolism
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism
  • Scavenger Receptors, Class B / genetics
  • Scavenger Receptors, Class B / metabolism*
  • Signal Transduction*
  • Time Factors
  • Transcription, Genetic
  • Transfection

Substances

  • ABCA1 protein, human
  • ABCG1 protein, human
  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP-Binding Cassette Transporters
  • Liver X Receptors
  • NR1H3 protein, human
  • Orphan Nuclear Receptors
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • SCARB1 protein, human
  • Scavenger Receptors, Class B
  • Insulin-Like Growth Factor I
  • Cholesterol
  • Phosphatidylinositol 3-Kinase
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt
  • Pregnancy-Associated Plasma Protein-A