title: Deletion of PARP-2 induces hepatic cholesterol accumulation and decrease in HDL levels.
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.
authors.affiliation: MTA-DE Cell Biology and Signaling Research Group of the Hungarian Academy of Sciences, 4032 Debrecen, Hungary; Department of Medical Chemistry, University of Debrecen, 4032 Debrecen, Hungary.
authors.forename: Magdolna
authors.initials: M
authors.lastname: Szántó
authors.affiliation: MTA-DE Cell Biology and Signaling Research Group of the Hungarian Academy of Sciences, 4032 Debrecen, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Brunyánszki
authors.affiliation: Department of Medical Chemistry, University of Debrecen, 4032 Debrecen, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Márton
authors.affiliation: Department of Biophysics and Cell Biology, University of Debrecen, 4032 Debrecen, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Vámosi
authors.affiliation: Department of Medical Chemistry, University of Debrecen, 4032 Debrecen, Hungary.
authors.forename: Lilla
authors.initials: L
authors.lastname: Nagy
authors.affiliation: Department of Medical Chemistry, University of Debrecen, 4032 Debrecen, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Fodor
authors.affiliation: Department of Dermatology, Medical and Health Science Center, University of Debrecen, 4032 Debrecen, Hungary.
authors.forename: Borbála
authors.initials: B
authors.lastname: Kiss
authors.affiliation: MTA-DE Cell Biology and Signaling Research Group of the Hungarian Academy of Sciences, 4032 Debrecen, Hungary; Department of Medical Chemistry, University of Debrecen, 4032 Debrecen, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Virág
authors.affiliation: Department of Medical Chemistry, University of Debrecen, 4032 Debrecen, Hungary.
authors.forename: Pál
authors.initials: P
authors.lastname: Gergely
authors.affiliation: MTA-DE Cell Biology and Signaling Research Group of the Hungarian Academy of Sciences, 4032 Debrecen, Hungary; Department of Medical Chemistry, University of Debrecen, 4032 Debrecen, Hungary. Electronic address: baip@med.unideb.hu.
authors.forename: Péter
authors.initials: P
authors.lastname: Bai
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000502:physiology
chemical_list: D008075:Lipoproteins, HDL; D051780:Sterol Regulatory Element Binding Protein 1; D002784:Cholesterol; C483041:PARP2 protein, human; D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse
keywords: ABCA1; Cholesterol; HDL; Lipoprotein; PARP-2; SREBP1