Z Gastroenterol 2019; 57(01): e50
DOI: 10.1055/s-0038-1677179
3. Metabolism (incl. NAFLD)
Georg Thieme Verlag KG Stuttgart · New York

The NLRP3 inflammasome rs10754558 is associated with increased serum ALT activities: analysis of a prospective NAFLD cohort

M Rau
3   Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
,
M Krawczyk
1   Department of Medicine II, Saarland University, Germany
2   Laboratory of Metabolic Liver Diseases, Center for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
,
K Paukstat
3   Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
,
F Lammert
1   Department of Medicine II, Saarland University, Germany
,
A Geier
3   Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

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    Background:

    Non-alcoholic fatty liver disease (NAFLD) is becoming the most frequent liver disorder, however its pathogenesis is only partially understood. Multiple factors, including metabolic and inflammatory mechanisms, have been associated with the progression of NAFLD. Lately NLRP3 inflammasome, an intracellular multiprotein complex involved in metabolic (sterile) inflammation has been implicated in NAFLD pathogenesis. Here we investigate if common genetic NLRP3 variations modulate liver injury and immune phenotypes in NAFLD.

    Patients and methods:

    In total, 160 NAFLD patients (113 women, age 45 ± 12 years, 64 with biopsy-proven NASH) were recruited in this study. The control cohort compromised 42 healthy controls (31 women). The rs10754588 and rs35829419 variants of NLRP3 were genotyped using TaqMan assays. PBMC were isolated and CD4 effector T cells (Th1, Th2 and Th17) were characterized by FACS analysis.

    Results:

    Genotype distributions did not deviate from Hardy-Weinberg equilibrium (both P > 0.05). NAFLD patients presented with higher serum ALT activities as compared to controls (P < 0.001). In the analysis of the entire study cohort, we detected an association between the NLRP3 rs10754558 variant and serum ALT activities: individuals carrying the [CC] genotype presented more frequently with elevated serum ALT levels (> 0.8 ULN) compared to patients carrying the [CG] or [GG] genotypes (P = 0.024). We also detected a trend (P = 0.06) for the association of the [CC] genotype with higher serum ALT in the analysis restricted to patients with NAFLD. Moreover NAFLD patients who carried the NLRP3 rs10754558 [CC] genotype had significant (P = 0.015) higher serum AP levels compared with [CG] and [GG] carriers. Serum AP and GGT levels did not differ in NAFL and NASH patients, and no association between serum GGT and rs10754558 [CC] genotype was observed. Further immunological analysis of peripheral immune cells revealed that individuals who tested positive for the [CG] or [GG] genotypes presented with higher peripheral CD4 Th1 cell counts compared to carriers of the [CC] genotype. No significant associations with histological phenotypes was observed for rs10754558. Interestingly, the NLRP3 rs35829419 minor allele was present only in NAFLD patients (n = 21), but absent in all healthy controls.

    Conclusions:

    The genetic variant rs10754558 in the NLRP3 inflammasome might modulate liver injury in patients with fatty liver disease. The pathomechanism could be related to changes in NLRP3 mRNA expression with differential effects in liver and peripheral blood.


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