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Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker.

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.

SUBMITTER: Baselli GA

PROVIDER: S-EPMC7497582 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker.

Baselli Guido Alessandro GA Dongiovanni Paola P Rametta Raffaela R Meroni Marica M Pelusi Serena S Maggioni Marco M Badiali Sara S Pingitore Piero P Maurotti Samantha S Montalcini Tiziana T Taliento Alice Emma AE Prati Daniele D Rossi Giorgio G Fracanzani Anna Ludovica AL Mancina Rosellina Margherita RM Romeo Stefano S Valenti Luca L

Gut 20200130 10

<h4>Objective</h4>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 <i>PNPLA3</i> I148M genetic risk variant.<h4>Design</h4>We sequenced the hepatic transcriptome of 125 obese individuals. ' ...[more]

PMID: 32001554

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Project description:Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder due to increased accumulation of fat in the liver and in many cases to enhanced inflammation. Although the contribution of inflammation in the pathogenesis of NAFLD is well established, the cytokines that are involved and how they influence liver transformation are still poorly characterized. In addition, with other modifiers, inflammation influences NAFLD progression to liver cirrhosis and hepatocellular carcinoma, demonstrating the need to find new molecular targets with potential future therapeutic applications. We investigated gene signatures in 38 liver biopsies from patients with NAFLD and obesity who had received bariatric surgery and compared these to 10 control patients who had received a cholecystectomy, using DNA microarray technology. A subset of differentially expressed genes was then validated on a larger cohort of 103 patients who had received bariatric surgery for obesity; data were thoroughly analyzed in terms of correlations with NAFLD pathophysiological parameters. Finally, the impact of a specific cytokine, interleukin-32 (IL32), was addressed on primary human hepatocytes (PHHs). Transcript analysis revealed an up-regulation of proinflammatory cytokines IL32, chemokine (C-X-C motif) ligand 9 (CXCL9), and CXCL10 and of ubiquitin D (UBD), whereas down-regulation of insulin-like growth factor-binding protein 2 (IGFBP2) and hypoxanthine phosphoribosyltransferase 1 (HPRT1) was reported in patients with NAFLD. Moreover, IL32, which is the major deregulated gene, correlated with body mass index (BMI), waist circumference, NAFLD activity score (NAS), aminotransferases (alanine aminotransferase [ALAT] and aspartate aminotransferase [ASAT]), and homeostasis model assessment of insulin resistance (HOMA-IR) index in patients. Consistent with an instrumental role in the pathophysiology of NAFLD, treatment of control human hepatocytes with recombinant IL32 leads to insulin resistance, a hallmark metabolic deregulation in NAFLD hepatocytes. Conclusion: IL32 has a critical role in the pathogenesis of NAFLD and could be considered as a therapeutic target in patients.

Dataset Information

Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker.

Publications

Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker.

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