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

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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 F _2α (8-iso-PGF _2α). 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-PGF _2α 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.

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Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.

Silvia Sookoian, Carlos Pirola (2011)

Our objective was to estimate the strength of the effect of the I148M (rs738409 C/G) patatin-like phospholipase domain containing 3 (PNPLA3) variant on nonalcoholic fatty liver (NAFLD) and disease severity across different populations. We performed a systematic review by a meta-analysis; literature searches identified 16 studies. Our results showed that rs738409 exerted a strong influence not only on liver fat accumulation (GG homozygous showed 73% higher lipid fat content when compared with CC ones, data from 2,937 subjects; P < 1 × 10(-9) ), but also on the susceptibility of a more aggressive disease (GG homozygous had 3.24-fold greater risk of higher necroinflammatory scores and 3.2-fold greater risk of developing fibrosis when compared with CC homozygous; P < 1 × 10(-9) ; data from 1,739 and 2,251 individuals, respectively). Nonalcoholic steatohepatitis (NASH) was more frequently observed in GG than CC homozygous (odds ratio [OR] 3.488, 95% confidence interval [CI] 1.859-6.545, random model; P < 2 × 10(-4) ; data from 2,124 patients). Evaluation of the risk associated with heterozygosity for the variant suggests that the additive genetic model best explains the effect of rs738409 on the susceptibility to develop NAFLD. Nevertheless, carrying two G alleles does not seem to increase the risk of severe histological features. Meta-regression showed a negative correlation between male sex and the effect of rs738409 on liver fat content (slope: -2.45 ± 1.04; P < 0.02). The rs738409 GG genotype versus the CC genotype was associated with a 28% increase in serum alanine aminotransferase levels. By summarizing the amount of evidence, this study provided unequivocal evidence of rs738409 as a strong modifier of the natural history of NAFLD in different populations around the world. Copyright © 2011 American Association for the Study of Liver Diseases.

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Liver regeneration - mechanisms and models to clinical application.

Stuart Forbes, Philip N. Newsome (2016)

Liver regeneration has been studied for many decades and the mechanisms underlying regeneration of the normal liver following resection or moderate damage are well described. A large number of factors extrinsic (such as bile acids and circulating growth factors) and intrinsic to the liver interact to initiate and regulate liver regeneration. Less well understood, and more clinically relevant, are the factors at play when the abnormal liver is required to regenerate. Fatty liver disease, chronic scarring, prior chemotherapy and massive liver injury can all inhibit the normal programme of regeneration and can lead to liver failure. Understanding these mechanisms could enable the rational targeting of specific therapies to either reduce the factors inhibiting regeneration or directly stimulate liver regeneration. Although animal models of liver regeneration have been highly instructive, the clinical relevance of some models could be improved to bridge the gap between our in vivo model systems and the clinical situation. Likewise, modern imaging techniques such as spectroscopy will probably improve our understanding of whole-organ metabolism and how this predicts the liver's regenerative capacity. This Review describes briefly the mechanisms underpinning liver regeneration, the models used to study this process, and discusses areas in which failed or compromised liver regeneration is clinically relevant.

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The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease.

T. Liang, Joseph M. Zmuda, … (2010)

Genome-wide association studies identified single-nucleotide polymorphisms (SNPs) that are associated with increased hepatic fat or elevated liver enzymes, presumably reflecting nonalcoholic fatty liver disease (NAFLD). To investigate whether these SNPs are associated with histological severity of NAFLD, 1117 (894 adults/223 children) individuals enrolled in the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network and National Institutes of Health Clinical Center studies with histologically confirmed NAFLD were genotyped for six SNPs that are associated with hepatic fat or liver enzymes in genome-wide association studies. In adults, three SNPs on chromosome 22 showed associations with histological parameters of NASH. After adjustment for age, sex, diabetes, and alcohol consumption, the minor allele of rs738409 C/G, a nonsynonymous coding SNP in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) (adiponutrin) gene encoding an Ile148Met change, was associated with steatosis (P = 0.03), portal inflammation (P = 2.5 x 10(-4)), lobular inflammation (P = 0.005), Mallory-Denk bodies (P = 0.015), NAFLD activity score (NAS, P = 0.004), and fibrosis (P = 7.7 x 10(-6)). Two other SNPs in the same region demonstrated similar associations. Three SNPs on chromosome 10 near the CHUK (conserved helix-loop-helix ubiquitous kinase) gene were independently associated with fibrosis (P = 0.010). In children, no SNP was associated with histological severity. However, the rs738409 G allele was associated with younger age at the time of biopsy in multivariate analysis (P = 0.045). In this large cohort of histologically proven NAFLD, we confirm the association of the rs738409 G allele with steatosis and describe its association with histological severity. In pediatric patients, the high-risk rs738409 G allele is associated with an earlier presentation of disease. We also describe a hitherto unknown association between SNPs at a chromosome 10 locus and the severity of NASH fibrosis.

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Author and article information

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Francesco Angelico: francesco.angelico@uniroma1.it

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 17 November 2017

Publication date PMC-release: 17 November 2017

Publication date Collection: 2017

Volume: 7

Electronic Location Identifier: 15756

Affiliations

[1 ]ISNI 0000 0000 8580 6601, GRID grid.412756.3, Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, ; Rome, Italy

[2 ]GRID grid.7841.a, Department of Internal Medicine and Medical Specialties, I Clinica Medica, Sapienza University of Rome, ; Rome, Italy

[3 ]GRID grid.7841.a, Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University, ; Rome, Italy

[4 ]GRID grid.7841.a, Department of Cardiovascular, Respiratory, Nephrologic, Anaesthesiologic and Geriatric Sciences, Sapienza University of Rome, ; Rome, Italy

[5 ]GRID grid.7841.a, Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, ; Latina, Italy

[6 ]GRID grid.7841.a, Department of Public Health and Infectious Diseases, Sapienza University, ; Rome, Italy

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Daniele Pastori http://orcid.org/0000-0001-6357-5213

Diletta Overi http://orcid.org/0000-0003-3561-8903

Article

Publisher ID: 15943

DOI: 10.1038/s41598-017-15943-z

PMC ID: 5693899

PubMed ID: 29150621

SO-VID: 8b37dca9-2749-44af-8771-e4e9be48fa88

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 28 July 2017

Date accepted : 5 November 2017

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

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Most cited references 30

Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.

Liver regeneration - mechanisms and models to clinical application.

The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease.

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Cited by 26

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