PARP1-mediated PPARα poly(ADP-ribosyl)ation suppresses fatty acid oxidation in non-alcoholic fatty liver disease

Background & Aims: PARP1 is a key mediator of cellular stress responses and critical in multiple physiological and pathophysiological processes of cells. However, whether it is involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) remains elusive. Methods: We analysed PARP1 activity in the liver of mice on a high fat diet (HFD), and samples from NAFLD patients. Gain- or loss-of-function approaches were used to investigate the roles and mechanisms of hepatic PARP1 in the pathogenesis of NAFLD. Results: PARP1 is activated in fatty liver of HFD-fed mice. Pharmacological or genetic manipulations of PARP1 are sufficient to alter the HFD-induced hepatic steatosis and inflammation. Mechanistically we identified peroxisome proliferator-activated receptor alpha (PPAR alpha) as a substrate of PARP1-mediated poly (ADP-ribosyl) ation. This poly(ADP-ribosyl) ation of PPAR alpha inhibits its recruitment to target gene promoters and its interaction with SIRT1, a key regulator of PPAR alpha signaling, resulting in suppression of fatty acid oxidation upregulation induced by fatty acids. Moreover, we show that PARP1 is a transcriptional repressor of PPAR alpha gene in human hepatocytes, and its activation suppresses the ligand (fenofibrate)-induced PPARa transactivation and target gene expression. Importantly we demonstrate that liver biopsies of NAFLD patients display robust increases in PARP activity and PPAR alpha poly(ADP-ribosyl) ation levels. Conclusions: Our data indicate that PARP1 is activated in fatty liver, which prevents maximal activation of fatty acid oxidation by suppressing PPAR alpha signaling. Pharmacological inhibition of PARP1 may alleviate PPARa suppression and therefore have therapeutic potential for NAFLD. Lay summary: PARP1 is activated in the non-alcoholic fatty liver of mice and patients. Inhibition of PARP1 activation alleviates lipid accumulation and inflammation in fatty liver of mice. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.