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Liver Transcriptomics Highlights Interleukin-32 As Novel NAFLD

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Liver Transcriptomics Highlights Interleukin-32 As Novel NAFLD Hepatology ORIGINAL RESEARCH Gut: first published as 10.1136/gutjnl-2019-319226 on 30 January 2020. Downloaded from Liver transcriptomics highlights interleukin-32 as novel NAFLD- related cytokine and candidate biomarker Guido Alessandro Baselli,1,2 Paola Dongiovanni ,3 Raffaela Rametta,3 Marica Meroni,3 Serena Pelusi,1,2 Marco Maggioni,4 Sara Badiali,5 Piero Pingitore,6 Samantha Maurotti,6 Tiziana Montalcini,7 Alice Emma Taliento,2 Daniele Prati,2 Giorgio Rossi,1,8 Anna Ludovica Fracanzani,1,3 Rosellina Margherita Mancina,9 Stefano Romeo ,6,10 Luca Valenti 1,2 ► Additional material is ABSTRact published online only. To view Objective Efforts to manage non- alcoholic fatty Significance of this study please visit the journal online liver disease (NAFLD) are limited by the incomplete (http:// dx. doi. org/ 10. 1136/ What is already known on this subject? gutjnl- 2019- 319226). understanding of the pathogenic mechanisms and the absence of accurate non- invasive biomarkers. The aim ► Non- alcoholic fatty liver disease (NAFLD) is the For numbered affiliations see leading cause of advanced liver diseases in the end of article. of this study was to identify novel NAFLD therapeutic targets andbiomarkers by conducting liver transcriptomic Western countries. ► Incomplete knowledge of NAFLD pathogenic Correspondence to analysis in patients stratified by the presence of the Professor Luca Valenti, PNPLA3 I148M genetic risk variant. mechanisms results in a lack of effective Department of Pathophysiology Design We sequenced the hepatic transcriptome of strategies for early diagnosis and treatment. and Transplantation, Universita 125 obese individuals. ’Severe NAFLD’ was defined as degli Studi di Milano, Milano, What are the new findings? the presence of steatohepatitis, NAFLD activity score Lombardia 20122, Italy; ► The PNPLA3 I48M variant was a major modifier luca. valenti@ unimi. it and ≥4 or fibrosis stage ≥2. The circulating levels of the of the liver transcriptome. Professor Stefano Romeo, most upregulated transcript, interleukin-32 (IL32), were ► Interleukin-32 (IL32) was the most strongly Wallenberg Laboratory, measured by ELISA. upregulated transcript in severe NAFLD. Department of Molecular and Results Carriage of the PNPLA3 I148M variant Clinical Medicine, University of ► IL32 circulating levels correlate with hepatic http://gut.bmj.com/ Gothenburg, Bruna Stråket 16, correlated with the two major components of hepatic expression and are increased in patients with SE-413 45, Göteborg, Sweden; transcriptome variability and broadly influenced gene NAFLD. stefano. romeo@ wlab. gu. se expression. In patients with severe NAFLD, there was an upregulation of inflammatory and lipid metabolism How might it impact on clinical practice in the GAB and PD contributed pathways. IL32 was the most robustly upregulated gene foreseeable future? equally. −6 in the severe NAFLD group (adjusted p=1×10 ), and ► IL32 is a candidate for non- invasive assessment SR and LV are joint senior its expression correlated with steatosis severity, both in of NAFLD presence/severity and for targeted on September 26, 2021 by guest. Protected copyright. authors. I148M variant carriers and non- carriers. In 77 severely therapy. obese, and in a replication cohort of 160 individuals Received 4 June 2019 Revised 5 December 2019 evaluated at the hepatology service, circulating IL32 Accepted 22 December 2019 levels were associated with both NAFLD and severe individuals progress to advanced liver fibrosis and/ NAFLD independently of aminotransferases (p<0.01 or hepatocellular carcinoma. The factors driving for both). A linear combination of IL32-­ALT-­AST liver damage progression are only partially under- showed a better performance than ALT-­AST alone in stood, but genetic predisposition plays an important NAFLD diagnosis (area under the curve=0.92 vs 0.81, role.4 p=5×10−5). A common genetic variant, the rs738409 C>G Conclusion Hepatic IL32 is overexpressed in NAFLD, single nucleotide polymorphism encoding for the correlates with hepatic fat and liver damage, and is p.Ile148Met (I148M) aminoacidic substitution in detectable in the circulation, where it is independently the patatin- like phospholipase domain- containing © Author(s) (or their associated with the presence and severity of NAFLD. employer(s)) 2020. Re- use 3 (PNPLA3), is the major genetic determinant of permitted under CC BY-­NC. No hepatic fat content and progressive NAFLD.5–7 commercial re- use. See rights and permissions. Published PNPLA3 is an enzyme expressed in hepatocytes and by BMJ. INTRODUCTION hepatic stellate cells and it is upregulated by insulin Non- alcoholic fatty liver disease (NAFLD) is signalling.8 9 The 148M mutant protein predis- To cite: Baselli GA, rapidly becoming a leading cause of advanced liver poses to NAFLD by interfering in the remodelling Dongiovanni P, Rametta R, 1 et al. Gut Epub ahead of disease worldwide. NAFLD is highly prevalent in of triglycerides and phospholipids at the surface of 10–12 print: [please include Day the population and is associated with dysmetab- lipid droplets, resulting in the accumulation Month Year]. doi:10.1136/ olism and qualitative alterations of the diet and of neutral fat due to reduced turnover.13 Further- gutjnl-2019-319226 microbiota.2 3 However, only a subset of affected more, the I148M variant impairs retinol disposal Baselli GA, et al. Gut 2020;0:1–12. doi:10.1136/gutjnl-2019-319226 1 Hepatology following activation of hepatic stellate cells, resulting in a proin- research network.18 Liver biopsies scoring was performed by an 14–17 19 20 flammatory and fibrogenic phenotype. However, to what expert pathologist unaware of patients’ status and genotype. Gut: first published as 10.1136/gutjnl-2019-319226 on 30 January 2020. Downloaded from extent the mechanism of liver disease progression in carriers of NASH was defined as the concomitant presence of steatosis, the I148M variant differs from those of patients not carrying lobular inflammation and ballooning. We arbitrarily defined the mutation is presently unknown. As no effective therapy and ‘Severe NAFLD’ as the presence of NASH, and/or NAS≥4, and/ accurate non-invasive biomarkers are yet available for progres- or fibrosis stage F2 or higher. sive NAFLD, this question may have an immediate clinical impli- In Metabolic unit cohort, liver steatosis was estimated by cation. Indeed, stratification by the I148M variant may identify assessing the controlled attenuation parameter (CAP). Median a distinct subset of patients amenable to specific screening and CAP value (244 db/m2) was used as cut- off to stratify patients as treatment strategies, enabling a framework of precision medicine. ‘low CAP’ (CAP<median) or ‘high CAP’ (CAP≥median). The aim of this study was therefore to identify new poten- tial therapeutic targets and biomarkers for progressive NAFLD Genotyping by highlighting and validating the most upregulated hepatic The rs58542926 C>T (E167K, TM6SF2) and rs738409 C>G transcripts in patients with fibrosing NAFLD (either NAS≥4, (I148M, PNPLA3) genetic variants were assessed in duplicate by NASH or significant liver fibrosis stage F≥2, hereafter defined TaqMan 5'‐nuclease assays (Life Technologies, Carlsbad, Cali- as ‘severe NAFLD’), stratified by the presence of the PNPLA3 fornia, USA). I148M variant. The study workflow is presented in online supplementary figure S1. Transcriptomic and bioinformatic analysis The detailed protocol for the transcriptomic and bioinformatic PTIA ENTS AND METHODS analysis is reported in the Supplementary Methods. Briefly, Patients total RNA was isolated using RNeasy mini-kit (Qiagen, Huls- The study was conducted in 125 obese individuals (‘Tran- terweg, Germany). RNA was sequenced in paired-end mode scriptomic cohort’) who underwent percutaneous liver biopsy (read length 150nt) using the Illumina HiSeq 4000 (Novogene, performed during bariatric surgery, and for whom sufficient Hong Kong, China). Reads were mapped by a custom pipe- material for extraction of high- quality RNA was available. Indi- line,21 encompassing reads quality check (FastQC software, viduals with at-risk alcohol intake (>30/20 g/day in M/F), viral Babraham Bioinformatics, Cambridge, UK), low-quality reads and autoimmune hepatitis or other causes of liver disease were trimming and mapping on GRCh37 reference genome by STAR excluded. Interleukin-32 (IL32) plasma levels were retrospec- mapper.22 Reads count (ENSEMBL human transcript reference tively assessed in 71 obese patients, who underwent percuta- assembly v75) was performed using RSEM package.23 Counts neous liver biopsy performed during bariatric surgery (‘Bariatric were normalised using DESeq2 package.24 IL32 transcripts surgery cohort’). The intersection of the Transcriptomic and were grouped and reconducted to isoforms described in the the Bariatric surgery cohorts was represented by 16 patients literature.25 matching both the inclusion criteria. The association between For principal components analysis (PCA), gene-level expres- circulating IL32 and liver damage was replicated in an inde- sion data were normalised under the null model through DESeq2 http://gut.bmj.com/ pendent cohort of 160 individuals made up of patients with standard pipeline, and variance stabilising transformation func- histological NAFLD from the general medicine (n=148), and tion was applied. of healthy blood donors without NAFLD, ruled out by non- To identify differentially expressed pathways, pre-ranked gene invasive assessment (n=12), who presented on a single
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