PNPLA3 variant and portal/periportal histological pattern in patients with biopsy-proven non-alcoholic fatty liver disease: a possible role for oxidative stress

Guido Carpino,Roberto Carnevale,Licia Polimeni,Marcello Arca,Maria Del Ben,Eugenio Gaudio,Giancarlo Labbadia,Francesco Angelico,Daniele Pastori,Francesco Baratta,Gaetano Pannitteri,Diletta Overi,Alessia Di Costanzo,Francesco Violi

doi:10.1038/s41598-017-15943-z

Abstract

Pathogenesis of non-alcoholic fatty liver disease (NAFLD) is influenced by predisposing genetic variations, dysmetabolism, systemic oxidative stress, and local cellular and molecular cross-talks. Patatin-like phospholipase domain containing 3 (PNPLA3) gene I148M variant is a known determinant of NAFLD. Aims were to evaluate whether PNPLA3 I148M variant was associated with a specific histological pattern, hepatic stem/progenitor cell (HpSC) niche activation and serum oxidative stress markers. Liver biopsies were obtained from 54 NAFLD patients. The activation of HpSC compartment was evaluated by the extension of ductular reaction (DR); hepatic stellate cells, myofibroblasts (MFs), and macrophages were evaluated by immunohistochemistry. Systemic oxidative stress was assessed measuring serum levels of soluble NOX2-derived peptide (sNOX2-dp) and 8-isoprostaglandin F2α (8-iso-PGF2α). PNPLA3 carriers showed higher steatosis, portal inflammation and HpSC niche activation compared to wild-type patients. DR was correlated with NAFLD activity score (NAS) and fibrosis score. Serum 8-iso-PGF2α were significantly higher in I148M carriers compared to non-carriers and were correlated with DR and portal inflammation. sNox2-dp was correlated with NAS and with HpSC niche activation. In conclusion, NAFLD patients carrying PNPLA3 I148M are characterized by a prominent activation of HpSC niche which is associated with a more aggressive histological pattern (portal fibrogenesis) and increased oxidative stress.

Highlights

Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease worldwide[1]
patatin-like phospholipase domain containing 3 (PNPLA3) variants have been associated with a worse histological depict in NAFLD6; no studies investigated the potential influence of PNPLA3 I148M variant in the development of specific histological pattern and in the intricate cross-talks between different cellular compartments activated by the regenerative response to liver damage in NAFLD
The main findings of the study indicate that NAFLD patients carrying PNPLA3 variant, compared to WT subjects, showed: i) a more prominent portal/periportal pattern in liver damage, ii) a higher activation of Hepatic stem/progenitor cell (HpSC) niche, and iii) increased serum oxidative stress levels

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease worldwide[1]. The single nucleotide polymorphism in residue 148 (I148M, rs738409) in human patatin-like phospholipase domain containing 3 (PNPLA3) gene, which exhibits a C-to-G transition resulting in an amino acid substitution of isoleucine to methionine, is one of the strongest genetic determinants of NAFLD3–5. This mutation was suggested to impair triglyceride hydrolysis and potentially explain the increased triglyceride accumulation in www.nature.com/scientificreports/. The aims of the present study have been to evaluate whether NAFLD patients carrying PNPLA3 I148M variant: i) showed a specific histological pattern at liver biopsy; ii) were characterized by a prominent activation of HpSC niche; iii) presented increased levels of serum systemic oxidative stress markers

Methods

Results

Conclusion