The proteolytic cleavage of Fibronectin type III domain-containing 5 (FNDC5) 
generates soluble irisin. Initially described as being mainly produced in muscle 
during physical exercise, irisin mediates adipose tissue thermogenesis and also 
regulates carbohydrate and lipid metabolism. The aim of this study was to 
evaluate the hepatic expression of FNDC5 and its role in hepatocytes in 
Non-Alcoholic Fatty Liver (NAFL). Here we report that hepatic expression of 
FNDC5 increased with hepatic steatosis and liver injury without impacting the 
systemic level of irisin in mouse models of NAFLD (HFD and MCDD) and in obese 
patients. The increased Fndc5 expression in fatty liver resulted from its 
upregulation in hepatocytes and non-parenchymal cells in mice. The local 
production of Fndc5 in hepatocytes was influenced by genotoxic stress and 
p53-dependent pathways. The down-regulation of FNDC5 in human HepG2 cells and in 
primary mouse hepatocytes increased the expression of PEPCK, a key enzyme 
involved in gluconeogenesis associated with a decrease in the expression of 
master genes involved in the VLDL synthesis (CIDEB and APOB). These alterations 
in FNDC5-silenced cells resulted to increased steatosis and insulin resistance 
in response to oleic acid and N-acetyl glucosamine, respectively. The 
downregulation of Fndc5 also sensitized primary hepatocytes to apoptosis in 
response to TNFα, which has been associated with decreased hepatoprotective 
autophagic flux. In conclusion, our human and experimental data strongly suggest 
that the hepatic expression of FNDC5 increased with hepatic steatosis and its 
upregulation in hepatocytes could dampen the development of NAFLD by negatively 
regulating steatogenesis and hepatocyte death.