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Hepatology
Original research
Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker
  1. Guido Alessandro Baselli1,2,
  2. Paola Dongiovanni3,
  3. Raffaela Rametta3,
  4. Marica Meroni3,
  5. Serena Pelusi1,2,
  6. Marco Maggioni4,
  7. Sara Badiali5,
  8. Piero Pingitore6,
  9. Samantha Maurotti6,
  10. Tiziana Montalcini7,
  11. Alice Emma Taliento2,
  12. Daniele Prati2,
  13. Giorgio Rossi1,8,
  14. Anna Ludovica Fracanzani1,3,
  15. Rosellina Margherita Mancina9,
  16. Stefano Romeo6,10,
  17. Luca Valenti1,2
  1. 1 Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Milano, Lombardia, Italy
  2. 2 Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Lombardia, Italy
  3. 3 General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Lombardia, Italy
  4. 4 Pathology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Lombardia, Italy
  5. 5 Surgery, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Lombardia, Italy
  6. 6 Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Calabria, Italy
  7. 7 Department of Clinical and Experimental Medicine, Nutrition Unit, Magna Graecia University of Catanzaro, Catanzaro, Calabria, Italy
  8. 8 Liver Transplantation Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy
  9. 9 Department of Molecular and Clinical Medicine, Goteborgs Universitet, Goteborg, Sweden
  10. 10 Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Laboratory, Cardiology Department, University of Gothenburg, Goteborg, Sweden
  1. Correspondence to Professor Luca Valenti, Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Milano, Lombardia 20122, Italy; luca.valenti{at}unimi.it; Professor Stefano Romeo, Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Bruna Stråket 16, SE-413 45, Göteborg, Sweden; stefano.romeo{at}wlab.gu.se

Abstract

Objective Efforts to manage non-alcoholic fatty liver disease (NAFLD) are limited by the incomplete understanding of the pathogenic mechanisms and the absence of accurate non-invasive biomarkers. The aim of this study was to identify novel NAFLD therapeutic targets andbiomarkers by conducting liver transcriptomic analysis in patients stratified by the presence of the PNPLA3 I148M genetic risk variant.

Design We sequenced the hepatic transcriptome of 125 obese individuals. ‘Severe NAFLD’ was defined as the presence of steatohepatitis, NAFLD activity score ≥4 or fibrosis stage ≥2. The circulating levels of the most upregulated transcript, interleukin-32 (IL32), were measured by ELISA.

Results Carriage of the PNPLA3 I148M variant correlated with the two major components of hepatic transcriptome variability and broadly influenced gene expression. In patients with severe NAFLD, there was an upregulation of inflammatory and lipid metabolism pathways. IL32 was the most robustly upregulated gene in the severe NAFLD group (adjusted p=1×10−6), and its expression correlated with steatosis severity, both in I148M variant carriers and non-carriers. In 77 severely obese, and in a replication cohort of 160 individuals evaluated at the hepatology service, circulating IL32 levels were associated with both NAFLD and severe NAFLD independently of aminotransferases (p<0.01 for both). A linear combination of IL32-ALT-AST showed a better performance than ALT-AST alone in NAFLD diagnosis (area under the curve=0.92 vs 0.81, p=5×10−5).

Conclusion Hepatic IL32 is overexpressed in NAFLD, correlates with hepatic fat and liver damage, and is detectable in the circulation, where it is independently associated with the presence and severity of NAFLD.

  • nonalcoholic steatohepatitis
  • genetics
  • rna expression
  • cytokines
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/gutjnl-2019-319226

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    Footnotes

    • SR and LV are joint senior authors.

    • Twitter @lucavalenti75

    • GAB and PD contributed equally.

    • Contributors GAB, PD, SR, LV: study design and manuscript drafting; GAB, PD, SR, LV: data analysis and interpretation; RR, MM, PP: data generation; SP, MM, SB, TM, GR, ALF, DP: patient recruitment and characterisation; LV, SR: study supervision.

    • Funding The study was supported by myFIRST AIRC grant no.16888 for the EPIDEMIC-NAFLD project (LV), Ricerca Finalizzata 2016 Ministero della Salute - RF-2016-02364358 (LV), Ricerca Corrente Fondazione IRCCS Ca’ Granda (LV, SF). SR was supported by the Swedish Research Council (Vetenskapsrådet (VR), 2016-01527), the Swedish state under the Agreement between the Swedish government and the county councils (the ALF-agreement) (SU 2018-04276), the Novonordisk Foundation Grant for Excellence in Endocrinology (Excellence Project, 9321-430), Wallenberg Academy Fellows from the Knut and Alice Wallenberg Foundation (KAW 2017.0203) (SR).

    • Competing interests LV reports having received speaking fees from MSD, Gilead, AlfaSigma and AbbVie; having served as a consultant of Gilead, Pfizer, Astra Zeneca and Novo Nordisk; and received research grants from Gilead.

    • Patient consent for publication Not required.

    • Ethics approval Informed consent was obtained from each patient and the study protocol was approved by the Ethical Committee of the Fondazione IRCCS Ca’ Granda and University of Catanzaro and conformed to the ethical guidelines of the 1975 Declaration of Helsinki.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Deidentified gene expression data are available on request to the corresponding authors.