Fibronectin type III domain-containing protein 5 rs3480 A>G polymorphism, irisin, and liver fibrosis in patients with Nonalcoholic fatty liver disease

Context: Contrasting data have been reported on the role of irisin, a novel myokine encoded by the FNDC5 gene, in NAFLD pathogenesis. We tested in patients with suspected NASH the association of FNDC5 variants, hepatic expression and circulating irisin with liver damage(F2-F4 fibrosis as main outcome). We also investigated whether irisin modulates hepatocellular fat accumulation and stellate cell activation in experimental models. Methods: We considered 593 consecutive patients, who underwent liver biopsy for suspected NASH and 192 patients with normal liver enzymes and without steatosis. FNDC5 rs3480 and rs726344 genotypes were assessed by 5’nuclease assays. Hepatic irisin expression was evaluated in mice fed high-fat diet(HFD) or treated with CCl4. The effect of irisin was evaluated in fat-loaden HepG2 hepatocytes and in hepatic stellate cells (HSC). Results: In patients at risk of NASH(OR 0.64,95%CI 0.47-0.87;P=0.005), and more so in the high-risk subgroup of those with impaired fasting glucose/diabetes(OR 0.44,95%CI 0.26-0.74;P=0.002) the rs3480 A➔G variant was independently associated with protection from F2-F4 fibrosis. Irisin is expressed in human activated HSC, where mediates fibrogenic actions and collagen synthesis, and is over-expressed in NAFLD patients with F2-F4 fibrosis and CCl4-treated mice. However, Irisin does not affect fat accumulation in HepG2, and is not induced by HFD inducing NAFLD, but no fibrosis. Conclusions: The FNDC5 rs3480 variant is associated with protection from clinically significant fibrosis in patients with NAFLD, while irisin expression is correlated with the severity of NAFLD, and my be involved in extracellular matrix deposition. These data suggest that irisin is involved in regulation of hepatic fibrogenesis.