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

Shi-Lin Tang1, Wu-Jun Chen, Kai Yin

  • 1Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, Hunan 421001, China.

Atherosclerosis
|April 17, 2012
PubMed

Insights

Pregnancy-associated plasma protein-A (PAPP-A) reduces cholesterol efflux by down-regulating LXRα and key cholesterol transporters (ABCA1, ABCG1, SR-B1) via the IGF-1/PI3-K/Akt pathway, contributing to atherosclerosis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Pregnancy-associated plasma protein-A (PAPP-A) influences atherosclerosis by regulating insulin-like growth factor-1 (IGF-1).
  • IGF-1 signaling, via PI3-K/Akt, affects cholesterol efflux and nitric oxide formation.
  • The PI3-K/Akt pathway can decrease cholesterol efflux by reducing ABCA1 and SR-B1 expression.

Purpose of the Study:

  • To investigate PAPP-A's role in regulating liver X receptor alpha (LXRα) and cholesterol transporter expression (ABCA1, ABCG1, SR-B1).
  • To determine if the IGF-1-mediated signaling pathway (IGF/PI3-K/Akt) is involved in PAPP-A's effects.
  • To elucidate the mechanism by which PAPP-A contributes to the pathogenesis of atherosclerosis.

Main Methods:

  • Dose- and time-dependent experiments assessing PAPP-A's effect on ABCA1, ABCG1, and SR-B1 expression at transcriptional and translational levels.
  • Measurement of cellular cholesterol content and cholesterol efflux following PAPP-A treatment.
  • Investigation of LXRα regulation and the involvement of the IGF-1/PI3-K/Akt pathway using specific inhibitors and siRNA.
  • Analysis of PAPP-A's impact on the MAPK cascade.

Main Results:

  • PAPP-A significantly decreased ABCA1, ABCG1, and SR-B1 expression in a dose- and time-dependent manner.
  • PAPP-A treatment increased cellular cholesterol content and decreased cholesterol efflux.
  • PAPP-A down-regulated LXRα expression, which was partially rescued by LXRα agonist activation.
  • The IGF-1/PI3-K/Akt pathway, but not the MAPK cascade, was involved in PAPP-A-induced downregulation of LXRα, ABCA1, ABCG1, and SR-B1.

Conclusions:

  • PAPP-A down-regulates LXRα expression through the IGF-1/PI3-K/Akt signaling pathway.
  • This down-regulation leads to decreased expression of ABCA1, ABCG1, and SR-B1, impairing cholesterol efflux in macrophage-derived foam cells.
  • The study elucidates a key mechanism for PAPP-A's contribution to atherosclerosis pathogenesis.

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