Targeting NFATc4 attenuates non-alcoholic steatohepatitis in mice

Meng Du, Xiaojing Wang, Lin Yuan, Bing Liu, Xiaoxiang Mao, Dandan Huang, Liu Yang, Kun Huang, Fengxiao Zhang, Yan Wang, Xi Luo, Cheng Wang, Jiangtong Peng, Minglu Liang, Dan Huang, Kai Huang

Research output: Contribution to journalArticlepeer-review

Abstract

Background & Aims: The nuclear factor of activated T-cells (NFAT) family was first recognised to play an important role in the differentiation of T cells, but has since been shown to regulate multiple pathophysiological processes. However, whether it is involved in the pathogenesis of non-alcoholic steatohepatitis (NASH) remains unknown. Methods: Hepatic NFATc expression and localisation were analysed in C57BL/6 mice on a methionine–choline-deficient diet, as well as in samples from non-alcoholic fatty liver disease patients. Gain- or loss-of-function approaches were used to investigate the role of NFATc4 in NASH. Results: NFATc4 translocates from the cytoplasm to the nucleus in hepatocytes of both humans and rodents with NASH. NFATc4 knockdown resulted in decreased hepatic steatosis, inflammation, and fibrosis during NASH progression. Mechanistically, we found that activated NFATc4 directly bound to peroxisome proliferator-activated receptor α (PPARα) in the nucleus and negatively regulated its transcriptional activity, thereby impairing the hepatic fatty acid oxidation pathway and increasing lipid deposition in the liver. Moreover, NFATc4 activation increased the production and secretion of osteopontin (OPN) from hepatocytes, which subsequently enhanced the macrophage-mediated inflammatory response and hepatic stellate cell-mediated fibrosis progression via paracrine signalling. Conclusions: Hepatic NFATc4 activation accelerates the progression of NASH by suppressing PPARα signalling and increasing OPN expression. Genetic or pharmacological inhibition of NFATc4 may have potential for future therapy of NASH. Lay summary: NFATc4 is activated in the non-alcoholic steatohepatitis of mice and patients. Inhibition of NFATc4 activation alleviates lipid deposition, inflammatory response, and fibrosis progression in the liver.

Original languageEnglish (US)
Pages (from-to)1333-1346
Number of pages14
JournalJournal of Hepatology
Volume73
Issue number6
DOIs
StatePublished - Dec 2020
Externally publishedYes

Keywords

  • Lipid metabolism
  • NFATc
  • Non-alcoholic steatohepatitis
  • Paracrine

ASJC Scopus subject areas

  • Hepatology

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