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

• Published in: Biochimica et biophysica acta 2014-04, Vol.1842 (4), p.594-602
• Main Authors: Szántó, Magdolna, Brunyánszki, Attila, Márton, Judit, Vámosi, György, Nagy, Lilla, Fodor, Tamás, Kiss, Borbála, Virág, László, Gergely, Pál, Bai, Péter
• Format: Article
• Language: English
• Subjects: ABCA1; Animals; Cholesterol; Cholesterol - metabolism; HDL; Hep G2 Cells; Humans; Lipoprotein; Lipoproteins, HDL - blood; Liver - metabolism; Male; Mice; PARP-2; Poly(ADP-ribose) Polymerases - physiology; SREBP1; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - physiology
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2013.12.006

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. [Display omitted] •Deletion of PARP-2 leads to hepatic cholesterol accumulation and reduced HDL level.•Knockdown of PARP-2 enhances the expression of SREBP1 and SREBP1-dependent genes.•The suppression of SREBP1 expression depends on the enzymatic activation of PARP-2.•The deletion of PARP-2 decreases the expression of ABCA1.•Lower ABCA1 protein level is a likely explanation for reduced HDL levels.