Role Of Poly (ADP-ribose) Polymerase1in The Transcriptional Regulation Of Metabolic Nuclear Receptors

Part I Crucial role of PARP1in high cholesterol diet induced abnormalities in cholesterol metabolism in miceChronic high cholesterol diet (HCD) is one major cause of hypercholesterolemia. To explore whether or not hepatic poly(ADP-ribose) polymerase (PARP)1is involved in the HCD-induced abnormalities in cholesterol metabolism, we employed the rodent model of HCD-induced hypercholesterolemia, and biochemically studied the role of PARP1in cholesterol metabolism. HCD-feeding promoted hepatic PARP1activation. Treatment with PARP inhibitor prevented HCD-induced hypercholesterolemia and hepatic lipid accumulation. Further studies revealed that inhibition of PARP activity stimulated the hepatic expression of liver X receptor (LXR) a target genes involved in cholesterol metabolism, and enhanced the LXRa-LXR response element complex formation in nuclear extracts from liver tissues. Knockout of PARP1failed to prevent HCD-induced abnormalities in cholesterol metabolism, and inhibited LXRa target gene expression in liver. Moreover, the effects of PARP inhibitor on the HCD induced hypercholesterolemia, hepatic lipid accumulation and expression of LXRa target genes were also diminished in PARP1knock out (PKO) mice. These results illustmicee that activation of PARP1plays a crucial role in HCD-induced abnormalities in cholesterol metabolism. Part II Control of liver X receptor a mediated transcription by poly(ADP-ribosyI)ationLiver X receptor a (LXRa) functions importantly in lipid metabolism, cell proliferation and differentiation, reproduction, growth and development, immune and inflammation. In the absence of ligand, LXRa binds to target promoter and inhibits transcription by recruiting nuclear co-repressors. Ligand binding causes an exchange of co-repressor with co-activator, thus stimulating transcription. Here, we report that poly(ADP-ribosyl)ation plays an essential role in the control of LXRa mediated transcription. PARP1mediated poly(ADP-ribosyl)ation of LXRa and itself prevents LXRa binding to the target promoter, thus inhibiting transcription. Un-poly(ADP-ribosyl)ated PARP1assists LXRa binding to target promoter through direct association with LXRa, thereby promoting transcription. We further demonstrate that LXR ligands are potent PARP1inhibitors. Inhibition of poly(ADP-ribosyl)ation mediates the ligand-induced LXRa activation. Thus, the strength and duration of LXRa dependent transcription is controlled by poly(ADP-ribosyl)ation levels. Part III PARP1Promotes Oxidative Stress-Induced hepatocyte death via suppressing FXRFarnesoid X receptor a (FXR) is highly expressed in liver and regulates the expression of various genes involved in liver repair. In this study, we demonstrated that activated poly(ADP-ribose) polymerase1(PARP1) promoted cell death by inhibiting the expression of FXR dependent hepatoprotective genes. PARP1could bind to and poly(ADP-ribosyl)ated FXR. Poly(ADP-ribosyl)ation dissociated FXR from FXR response element (FXRE) present in the promoter of target genes, and blocked FXR mediated gene transcription. Moreover, FXR agonist treatment attenuated poly(ADP-ribosyl)ation of FXR and promoted FXR dependant gene expression in cultured hepatic cells. Thus, our results identified poly(ADP-ribosyl)ation of FXR by PARP1as a key step in oxidative stress-induced cell death. The molecular cooperation between PARP1and FXR in transcription activation provided a new insight into the mechanism underlying the inhibition of PARPl prevents liver injury.