Targeting NFATc4 attenuates non-alcoholic steatohepatitis in mice

Abstract Background & Aims The Nuclear Factor of Activated T-cells (NFAT) family was first recognized 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 nonalcoholic steatohepatitis (NASH) remains unknown. Methods Hepatic NFATc expression and localization were analysed in C57BL/6 mice on a methionine-choline-deficient (MCD) diet, as well as in samples from non-alcoholic fatty liver disease (NAFLD) 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 (KD) 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 (FAO) 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 (HSC)-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.