Salvatore Petta1, Luca Valenti2, Gianluca Svegliati-Baroni3,4, Massimiliano Ruscica5, Rosaria Maria Pipitone1, Paola Dongiovanni2, Chiara Rychlicki3,4, Nicola Ferri6, Calogero Cammà1, Anna Ludovica Fracanzani2, Irene Pierantonelli3,4, Vito Di Marco1, Marica Meroni2, Debora Giordano3,4, Stefania Grimaudo1, Marco Maggioni7, Daniela Cabibi8, Silvia Fargion2, Antonio Craxì1. 1. Section of Gastroenterology, Di.Bi.M.I.S., University of Palermo, 90100 Palermo, Italy. 2. Department of Pathophysiology and Transplantation, Università degli Studi, Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, 20100 Milan, Italy. 3. Department of Gastroenterology, Polytechnic University of Marche, 60100 Ancona, Italy. 4. Obesity Center, Polytechnic University of Marche, 60100 Ancona, Italy. 5. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20100 Milan, Italy. 6. Department of Pharmacological Sciences, Padova University, 35100 Padua, Italy. 7. Pathology, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, 20100 Milan, Italy. 8. Department of Science for Promotion of Health and Mother and Child Care, Section of Human Pathology, University of Palermo, 90127 Palermo, Italy.
Abstract
Context: Contrasting data have been reported on the role of irisin, a novel myokine encoded by the fibronectin type III domain-containing protein 5 (FNDC5) gene, in nonalcoholic fatty liver disease (NAFLD) pathogenesis. We tested in patients with suspected nonalcoholic steatohepatitis (NASH) the association of FNDC5 variants, hepatic expression, and circulating irisin with liver damage (F2 to 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 a high-fat diet or treated with CCl4. The effect of irisin was evaluated in fat-laden HepG2 hepatocytes and in hepatic stellate cells (HSCs). Results: In patients at risk for NASH [odds ratio (OR) = 0.64, 95% confidence interval (CI), 0.47 to 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 to 0.74; P = 0.002), the rs3480 A>G variant was independently associated with protection from F2 to F4 fibrosis. Irisin is expressed in human activated HSC, where it mediated fibrogenic actions and collagen synthesis, and is overexpressed in NAFLD patients with F2 to F4 fibrosis and CCl4-treated mice. However, Irisin does not affect fat accumulation in HepG2 and is not induced by high-fat-diet-inducing NAFLD. 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 may be involved in extracellular matrix deposition. These data suggest that irisin is involved in regulation of hepatic fibrogenesis.
Context: Contrasting data have been reported on the role of irisin, a novel myokine encoded by the fibronectin type III domain-containing protein 5 (FNDC5) gene, in nonalcoholic fatty liver disease (NAFLD) pathogenesis. We tested in patients with suspected nonalcoholic steatohepatitis (NASH) the association of FNDC5 variants, hepatic expression, and circulating irisin with liver damage (F2 to 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. FNDC5rs3480 and rs726344 genotypes were assessed by 5' nuclease assays. Hepatic irisin expression was evaluated in mice fed a high-fat diet or treated with CCl4. The effect of irisin was evaluated in fat-laden HepG2 hepatocytes and in hepatic stellate cells (HSCs). Results: In patients at risk for NASH [odds ratio (OR) = 0.64, 95% confidence interval (CI), 0.47 to 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 to 0.74; P = 0.002), the rs3480 A>G variant was independently associated with protection from F2 to F4 fibrosis. Irisin is expressed in human activated HSC, where it mediated fibrogenic actions and collagen synthesis, and is overexpressed in NAFLD patients with F2 to F4 fibrosis and CCl4-treated mice. However, Irisin does not affect fat accumulation in HepG2 and is not induced by high-fat-diet-inducing NAFLD. Conclusions: The FNDC5rs3480 variant is associated with protection from clinically significant fibrosis in patients with NAFLD, while irisin expression is correlated with the severity of NAFLD and may be involved in extracellular matrix deposition. These data suggest that irisin is involved in regulation of hepatic fibrogenesis.