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.

A genome-wide association analysis for porcine serum lipid traits reveals the existence of age-specific genetic determinants

“…For instance, SNPs within the SSC13 TAR for LDL45 were also associated with PARP2 mRNA expression (nominal P -value = 1.50 × 10e-07). Interestingly, the deletion of this gene leads to an increase in the accumulation of cholesterol in the liver by enhancing SREBP1 expression [47]. Other genes of interest were SLC19A1 , that in humans is associated with HDL levels [48]; SYCP3 , whose knockdown affects the expression of genes related to lipid metabolism [49]; CISD2 , that inhibits muscle fat infiltration [50]; and DPP4 , a gene that is overexpressed in the visceral fat of severely obese individuals [51].…”

Biology of Poly(ADP-Ribose) Polymerases: The Factotums of Cell Maintenance

“…Out of the novel PARPs, PARP-2, -7, -10, and -14 were shown to regulate transcription. PARP-2 is mostly a positive cofactor in transcription that regulates $600-1,000 genes (Farré s et al, 2013;Szá ntó et al, 2014). Positive effects of PARP-2 on transcription are exerted through facilitating the activity of transcription (co)factors, while negative effects are due to the attraction of cofactors promoting chromatin compaction and the consequent inhibition of transcription (Szá ntó et al, 2014).…”

“…PARP-2 is mostly a positive cofactor in transcription that regulates $600-1,000 genes (Farré s et al, 2013;Szá ntó et al, 2014). Positive effects of PARP-2 on transcription are exerted through facilitating the activity of transcription (co)factors, while negative effects are due to the attraction of cofactors promoting chromatin compaction and the consequent inhibition of transcription (Szá ntó et al, 2014). PARP-7 is a cofactor for aryl-hydrocarbon receptor (Diani-Moore et al, 2013), which suggests its importance combating environmental toxins, PARP-10 interacts with c-Myc (Feijs et al, 2013), while…”

Poly(ADP) ribose polymerase-1 ablation alters eicosanoid and docosanoid signaling and metabolism in a murine model of contact hypersensitivity

“…FABP7 has preference towards n-3, as compared with n-6, PUFAs (33), this may be a plausible explanation for the accumulation of EPA-derived metabolites, and increased ratios of PUFA-metabolites (DHA/AA MET, EPA/AA MET) in the PARP-1 +/+ mice. The results of the present study widen the spectrum of altered lipid metabolism upon PARP-1 expression ablation (34,35), by implicating skin eicosanoid and docosanoid metabolism and signaling. A reduction in PARP-1 expression results in a reduced pro-inflammatory and increased pro-resolving or anti-inflammatory environment in the skin.…”