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

Kun Huang, Meng Du, Xin Tan, Ling Yang, Xiangrao Li, Yuhan Jiang, Cheng Wang, Fengxiao Zhang, Feng Zhu, Min Cheng, Qinglin Yang, Liqing Yu, Lin Wang, Dan Huang, Kai Huang

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)962-977
Number of pages16
JournalJournal of Hepatology
Volume66
Issue number5
DOIs
StatePublished - May 2017
Externally publishedYes

Keywords

  • High fat diet
  • Non-alcoholic fatty liver disease
  • PPARα
  • Poly(ADP-ribose) polymerase 1
  • Transcriptional regulation

ASJC Scopus subject areas

  • Hepatology

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