Kun Huang1, Meng Du1, Xin Tan1, Ling Yang2, Xiangrao Li1, Yuhan Jiang1, Cheng Wang1, Fengxiao Zhang1, Feng Zhu1, Min Cheng1, Qinglin Yang3, Liqing Yu4, Lin Wang5, Dan Huang1, Kai Huang6. 1. 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. 2. 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. 3. Department of Nutrition Sciences, University of Alabama at Birmingham, AL, USA. 4. Department of Animal and Avian Sciences, University of Maryland, MD, USA. 5. Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China. 6. 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.
Abstract
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 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. CONCLUSIONS: 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. 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.
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 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. CONCLUSIONS: 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. 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.
Authors: Michal Pawlak; Eric Baugé; William Bourguet; Karolien De Bosscher; Fanny Lalloyer; Anne Tailleux; Corinna Lebherz; Philippe Lefebvre; Bart Staels Journal: Hepatology Date: 2014-10-01 Impact factor: 17.425
Authors: Mara Artibani; Kenta Masuda; Zhiyuan Hu; Pascal C Rauher; Garry Mallett; Nina Wietek; Matteo Morotti; Kay Chong; Mohammad KaramiNejadRanjbar; Christos E Zois; Sunanda Dhar; Salma El-Sahhar; Leticia Campo; Sarah P Blagden; Stephen Damato; Pubudu N Pathiraja; Shibani Nicum; Fergus Gleeson; Alexandros Laios; Abdulkhaliq Alsaadi; Laura Santana Gonzalez; Takeshi Motohara; Ashwag Albukhari; Zhen Lu; Robert C Bast; Adrian L Harris; Christer S Ejsing; Robin W Klemm; Christopher Yau; Tatjana Sauka-Spengler; Ahmed Ashour Ahmed Journal: JCI Insight Date: 2021-06-08
Authors: Meng Du; Lin Yuan; Xin Tan; Dandan Huang; Xiaojing Wang; Zhe Zheng; Xiaoxiang Mao; Xiangrao Li; Liu Yang; Kun Huang; Fengxiao Zhang; Yan Wang; Xi Luo; Dan Huang; Kai Huang Journal: Nat Commun Date: 2017-12-11 Impact factor: 14.919
Authors: Sandra M Martín-Guerrero; José A Muñoz-Gámez; María-Carmen Carrasco; Javier Salmerón; María Martín-Estebané; Miguel A Cuadros; Julio Navascués; David Martín-Oliva Journal: PLoS One Date: 2017-10-26 Impact factor: 3.240