title: PARP1-mediated PPARα poly(ADP-ribosyl)ation suppresses fatty acid oxidation in non-alcoholic fatty liver disease.
abstract: 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.
  
  
  
  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.
  
  
  
  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 α (PPARα) as a substrate of PARP1-mediated poly(ADP-ribosyl)ation. This poly(ADP-ribosyl)ation of PPARα inhibits its recruitment to target gene promoters and its interaction with SIRT1, a key regulator of PPARα signaling, resulting in suppression of fatty acid oxidation upregulation induced by fatty acids. Moreover, we show that PARP1 is a transcriptional repressor of PPARα gene in human hepatocytes, and its activation suppresses the ligand (fenofibrate)-induced PPARα transactivation and target gene expression. Importantly we demonstrate that liver biopsies of NAFLD patients display robust increases in PARP activity and PPARα poly(ADP-ribosyl)ation levels.
  
  
  
  Our data indicate that PARP1 is activated in fatty liver, which prevents maximal activation of fatty acid oxidation by suppressing PPARα signaling. Pharmacological inhibition of PARP1 may alleviate PPARα suppression and therefore have therapeutic potential for NAFLD.
  
  
  
  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.
authors.affiliation: Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
authors.affiliation: Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Du
authors.affiliation: Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Tan
authors.affiliation: Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Division of Gastroenterology, Department of Internal Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Xiangrao
authors.initials: X
authors.lastname: Li
authors.affiliation: Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Fengxiao
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Min
authors.initials: M
authors.lastname: Cheng
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, AL, USA.
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, MD, USA.
authors.forename: Liqing
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Huang
authors.affiliation: Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China. Electronic address: huangkai1@hust.edu.cn.
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D005227:Fatty Acids / Q000378:metabolism*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000502:physiology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000502:physiology*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D056564:Sirtuin 1 / Q000502:physiology
chemical_list: D005227:Fatty Acids; D047493:PPAR alpha; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011064:Poly Adenosine Diphosphate Ribose; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: High fat diet; Non-alcoholic fatty liver disease; PPARα; Poly(ADP-ribose) polymerase 1; Transcriptional regulation