PPAR Signaling Pathway and Cancer-Related Proteins Are Involved in Celiac Disease-Associated Tissue Damage

Maria Paola Simula,Vincenzo Canzonieri,Stefania Maiero,Renato Cannizzaro,Alessandro Pavan,Giuseppe Toffoli,Valli De Re

doi:10.2119/molmed.2009.00173

Abstract

Celiac disease (CD) is an immune-mediated disorder triggered by the ingestion of wheat gliadin and related proteins in genetically predisposed individuals. To find a proteomic CD diagnostic signature and to gain a better understanding of pathogenetic mechanisms associated with CD, we analyzed the intestinal mucosa proteome alterations using two dimensional difference gel electrophoresis (2D-DIGE) coupled with matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF ms) of CD patients with varying degrees of histological abnormalities defined by Marsh criteria and controls. Our results clearly evidenced the presence of two groups of patients: Group A, including controls and Marsh 0-I CD patients; and Group B, consisting of CD subjects with grade II-III Oberhuber-Marsh classification. Differentially expressed proteins were involved mainly in lipid, protein and sugar metabolism. Interestingly, in Group B, several downregulated proteins (FABP1, FABP2, APOC3, HMGCS2, ACADM and PEPCK) were implicated directly in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Moreover, Group B patients presented a deregulation of some proteins involved in apoptosis/survival pathways: phosphatidylethanolamine-binding protein 1 (PEBP1), Ras-related nuclear protein (Ran) and peroxiredoxin 4 (PRDX4). PEBP1 downregulation and RAN and PRDX4 upregulation were associated with more severe tissue damage. Likewise, IgMs were found strongly upregulated in Group B. In conclusion, our results indicate that a downregulation of proteins involved in PPAR signaling and the modulation of several cancer-related proteins are associated with the highest CD histological score according to Oberhuber-Marsh classification.

Highlights

Celiac disease (CD) is caused by an immune reaction to gliadin, a gluten protein found in wheat gluten and related derivatives, in genetically predisposed individuals
Following the differential expression analysis, we created a set comprised of proteins present in more than 80% of spot maps and with a one-way analysis of variance (ANOVA) P < 0.01
Its diagnosis requires abnormalities on laboratory tests that might be caused by malabsorption, the presence of high antigliadin titers, antitissue transglutaminase and antiendomysial antibodies, the presence of an HLA DQ2/8 variant, a duodenal biopsy that shows the characteristic findings of intraepithelial lymphocytosis, crypt hyperplasia, villous atrophy and, above all, a positive response to a gluten free diet (GFD)

Summary

Introduction

Celiac disease (CD) is caused by an immune reaction to gliadin, a gluten protein found in wheat gluten and related derivatives, in genetically predisposed individuals. Most individuals respond to treatment, a minority of them (≤5%) may have persistent symptoms and villous atrophy despite scrupulous adherence to a GFD: this disorder is called refractory CD (RF-CD). The prognosis of this subgroup of patients is poor, and they show a higher risk of developing an overt lymphoma and uncontrolled malabsorption. Overall CD patients present a higher risk of developing cancer [4,5]. Cancers include T- and B-cell nonHodgkin lymphoma, oropharyngeal, esophageal and intestinal adenocarcinomas and pancreas tumors [6]

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