Peptides 88 (2017) 62–66 Contents lists available at ScienceDirect Peptides j ourna l ho me pa g e: www.elsevier.com/locate/peptides Increased FNDC5/Irisin expression in human hepatocellular carcinoma Melania Gaggini a,1 , Manuela Cabiati a,1 , Serena Del Turco a , Teresa Navarra a , Paolo De Simone b , Franco Filipponi b , Silvia Del Ry a , Amalia Gastaldelli a , Giuseppina Basta a,∗ a Institute of Clinical Physiology, CNR, Pisa, Italy b Hepatobiliary surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy a r t i c l e i n f o Article history: Received 8 September 2016 Received in revised form 20 December 2016 Accepted 20 December 2016 Available online 21 December 2016 Keywords: Hepatocellular carcinoma Fibronectin type III domain containing 5 Irisin De novo lipogenesis Cancer a b s t r a c t The fibronectin type III domain containing 5 (FNDC5)/Irisin, a novel energy-regulating hormone, is asso- ciated with lipid and carbohydrate metabolism. It is produced in low amounts by normal hepatic tissue, while in human hepatocellular carcinoma (HCC), in which aberrant de novo lipogenesis (DNL) occurs, the hepatic expression of FNDC5/Irisin is still unknown. The gene expression of FNDC5/Irisin, associated to key regulators of DNL, inflammation and cancer progression was evaluated in liver tissue of 18 patients with HCC undergoing liver transplantation and of 18 deceased donors. Hepatic mRNA expression of FNDC5/Irisin and stearoyl-CoA desaturase (SCD-1), main enzymatic regulator of DNL, were significantly higher in HCC patients than in donors (p < 0.0001 and p = 0.015, respectively). The hepatic mRNA expression of the neurogenic locus notch homolog protein 1 (NOTCH1) tended to be higher in HCC patients than in donors (p = 0.06). Only in HCC patients, hepatic FNDC5/Irisin strongly correlated with the transcription factor sterol regulatory element–binding factor 1, SCD- 1, NOTCH1, tumor necrosis factor- and Interleukin-6 mRNA expression. Further, in HCC patients, FNDC5/Irisin mRNA tended to correlate to plasma lipid profile namely triglycerides, palmitic/linoleic acid and polyunsaturated fatty acid/saturated fatty acid ratios. In conclusion, HCC-liver tissue over-expressed FNDC5/Irisin in association with gene expression of mediators involved in lipogenesis, inflammation and cancer, suggesting a possible protective role of the hormone from the liver damage. © 2016 Elsevier Inc. All rights reserved. 1. Introduction The Irisin is a novel metabolism-regulating hormone resulting from the proteolytic cleavage of the fibronectin type III domain- containing protein 5 (FNDC5) [1–3]. Although initially found in skeletal muscle [4], afterwards Irisin revealed its ubiquitous nature since it was found also in brain, heart, stomach, pancreas, spleen, testis, liver, adipose and skin [5]. Since it regulates fat metabolism, Irisin is involved in obesity, non-alcoholic fatty liver disease, ther- Abbreviations: FNDC5, fibronectin type III domain containing 5; DNL, de novo lipogenesis; HCC, human hepatocellular carcinoma; SCD-1, stearoyl-CoA desat- urase; NOTCH-1, Neurogenic locus notch homolog protein 1; SREBF-1, sterol regulatory element–binding factor 1; SFA, saturated fatty acid; PUFA, polyunsat- urated fatty acid; CAR, constitutive androstane receptor; TNF-, tumor necrosis factor-; IL-6, interleukin-6. ∗ Corresponding author at: CNR, Institute of Clinical Physiology, San Cataldo Research Area, Via Moruzzi, 1, 56124 Pisa, Italy. E-mail address: lapina@ifc.cnr.it (G. Basta). 1 Both authors contributed equally to this work. mogenesis, diabetes, and other metabolic diseases [2,5,6]. Irisin is produced in low amounts by hepatocytes, Kupffer cells and sinu- soidal endothelial cells, but its role in the liver is still unknown [7]. In a recent in vitro study, the hepatocyte treatment with recombinant Irisin significantly inhibited the palmitic acid-induced expression of lipogenic and inflammatory markers, and of the transcriptional regulators of lipogenesis [8]. Although this study suggests that Irisin could be useful toward hepatic lipid accumula- tion and oxidative stress, further studies are needed to corroborate these findings. The tumor cells exhibit adaptive responses to hypoxia and hypo-nutrient conditions, a phenomenon of changes, known as “metabolic reprogramming”, which is one of main hallmarks of cancer including the constitutive activation of the fatty acid biosynthetic pathway [9–12]. De novo lipogenesis (DNL) produces saturated fatty acids (SFA) that are converted into monounsatu- rated fatty acids by Stearoyl-CoA desaturase 1 (SCD-1), to sustain the increasing demand of new membrane phospholipids with appropriate acyl composition [10,13]. Since DNL is difficult to mea- http://dx.doi.org/10.1016/j.peptides.2016.12.014 0196-9781/© 2016 Elsevier Inc. All rights reserved.