Deletion of PARP-2 induces hepatic cholesterol accumulation and decrease in HDL levels

Magdolna Szántó, Attila Brunyánszki, Judit Márton, György Vámosi, Lilla Nagy, Tamás Fodor, Borbála Kiss, László Virág, Pál Gergely, Péter Bai

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Poly(ADP-ribose) polymerase-2 (PARP-2) is acknowledged as a DNA repair enzyme. However, recent investigations have attributed unique roles to PARP-2 in metabolic regulation in the liver. We assessed changes in hepatic lipid homeostasis upon the deletion of PARP-2 and found that cholesterol levels were higher in PARP-2-/- mice as compared to wild-type littermates. To uncover the molecular background, we analyzed changes in steady-state mRNA levels upon the knockdown of PARP-2 in HepG2 cells and in murine liver that revealed higher expression of sterol-regulatory element binding protein (SREBP)-1 dependent genes. We demonstrated that PARP-2 is a suppressor of the SREBP1 promoter, and the suppression of the SREBP1 gene depends on the enzymatic activation of PARP-2. Consequently, the knockdown of PARP-2 enhances SREBP1 expression that in turn induces the genes driven by SREBP1 culminating in higher hepatic cholesterol content. We did not detect hypercholesterolemia, higher fecal cholesterol content or increase in serum LDL, although serum HDL levels decreased in the PARP-2-/- mice. In cells and mice where PARP-2 was deleted we observed decreased ABCA1 mRNA and protein expression that is probably linked to lower HDL levels. In our current study we show that PARP-2 impacts on hepatic and systemic cholesterol homeostasis. Furthermore, the depletion of PARP-2 leads to lower HDL levels which represent a risk factor to cardiovascular diseases.

Original languageEnglish
Pages (from-to)594-602
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1842
Issue number4
DOIs
Publication statusPublished - Apr 1 2014

Keywords

  • ABCA1
  • Cholesterol
  • HDL
  • Lipoprotein
  • PARP-2
  • SREBP1

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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