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

Salvatore Petta, Luca Valenti, Gianluca Svegliati-Baroni, Massimiliano Ruscica, Rosaria Maria Pipitone, Paola Dongiovanni, Chiara Rychlicki, Nicola Ferri, Calogero Cammà, Anna Ludovica Fracanzani, Irene Pierantonelli, Vito Di Marco, Marica Meroni, Debora Giordano, Stefania Grimaudo, Marco Maggioni, Daniela Cabibi, Silvia Fargion, Antonio Craxì

Research output: Contribution to journalArticle

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 50 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 associatedwith protection fromclinically 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.

Original languageEnglish
Pages (from-to)2660-2669
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume102
Issue number8
DOIs
Publication statusPublished - Aug 1 2017

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ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Petta, S., Valenti, L., Svegliati-Baroni, G., Ruscica, M., Pipitone, R. M., Dongiovanni, P., Rychlicki, C., Ferri, N., Cammà, C., Fracanzani, A. L., Pierantonelli, I., Di Marco, V., Meroni, M., Giordano, D., Grimaudo, S., Maggioni, M., Cabibi, D., Fargion, S., & Craxì, A. (2017). Fibronectin type III domain-containing protein 5 rs3480 A>G polymorphism, irisin, and liver fibrosis in patients with nonalcoholic fatty liver disease. Journal of Clinical Endocrinology and Metabolism, 102(8), 2660-2669. https://doi.org/10.1210/jc.2017-00056