Interleukin‐32 Contributes to Human Nonalcoholic Fatty Liver Disease and Insulin Resistance

Abstract

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.

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

“…UBD encodes for ubiquitin D, which is implicated in the formation of Mallory-Denk bodies during steatohepatitis and is also upregulated in liver cancer 44. Supporting our findings, while this manuscript was under revision, Dali-Youcef et al also reported upregulation of hepatic expression of IL32 and UBD in obese individuals with NASH, providing initial evidence consistent with a role of IL32 in inducing hepatic insulin resistance 45…”

“… 44 Supporting our findings, while this manuscript was under revision, Dali-Youcef et al also reported upregulation of hepatic expression of IL32 and UBD in obese individuals with NASH, providing initial evidence consistent with a role of IL32 in inducing hepatic insulin resistance. 45 …”

Molecular interactions and functions of IL-32

“…Hepatocytes Il-32 is increased in nonalcoholic fatty liver disease and steatohepatitis 84 Correlated with liver steatosis, inflammation, and fibrosis in hepatitis C virus infected patients 84,125 Gastric tissue Found in cytoplasm of gastric epithelial cells 68 Elevated in gastritis and positively correlated with gastric inflammation and Helicobacter pylori 68,69 Helicobacter pylori 68,69 Pancreatic islets Coxsackie B virus 13 Gastric cancer/ cell lines Up-regulated compared to healthy controls 128 Associated with poorer prognosis, metastasis and clinicopathologic features 129 Correlated with tumor progression and poor prognosis, increased migration, and invasive properties 106 Induced by Helicobacter pylori, activates pro-inflammatory signaling and transcription 68 Helicobacter pylori 68,69…”

“…83 Another study looking at NAFLD patients found a similar up-regulation of IL-32 and also noted an inhibition of insulin signaling in primary human hepatocytes pretreated with IL-32, suggesting a role for IL-32 in insulin resistance. 84 The exact role of IL-32 in relation to metabolic disorders is unclear, and it is possible that IL-32 initially is up-regulated as a protective mechanism against accumulation of fatty acids. However, over longer time periods, the pro-inflammatory effects of IL-32 and its potential effects on insulin resistance could play an important role in the pathogenesis of metabolic disorders.…”

Toxicity of Zirconia oxide Nanoparticles: Liver Biodistribution and Liver Damages

“…The overexpression of Igfbp2 has been shown to reverse diabetes and steatosis in obese mice [37]. Downregulation of Igfbp2 was reported to be the maker of NAFLD [38]. As a symptom of metabolic disorders, hepatic lipid accumulation is strongly associated with insulin resistance [39].…”