β-Klotho gene variation is associated with liver damage in children with NAFLD.
Adolescent
Alleles
Carcinoma, Hepatocellular
/ metabolism
Case-Control Studies
Child
Down-Regulation
/ genetics
Female
Fibroblast Growth Factors
/ metabolism
Hep G2 Cells
Humans
Inflammation
/ blood
Klotho Proteins
Liver
/ pathology
Liver Cirrhosis
/ blood
Liver Neoplasms
/ metabolism
Male
Membrane Proteins
/ blood
Non-alcoholic Fatty Liver Disease
/ blood
Polymorphism, Single Nucleotide
Receptor, Fibroblast Growth Factor, Type 4
/ metabolism
Rome
/ epidemiology
Ballooning
Inflammation
NAFLD
SNPs
β-Klotho
Journal
Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
04
06
2019
revised:
17
09
2019
accepted:
11
10
2019
pubmed:
28
10
2019
medline:
15
9
2021
entrez:
27
10
2019
Statut:
ppublish
Résumé
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in adults and children. Along with obesity, diabetes and insulin resistance, genetic factors strongly impact on NAFLD development and progression. Dysregulated bile acid metabolism and the fibroblast growth factor 19 (FGF19) pathway play a pivotal role in NAFLD pathogenesis. However, the mechanism through which the FGF19 receptor system is associated with liver damage in NAFLD remains to be defined. We evaluated the impact of the rs17618244 G>A β-Klotho (KLB) variant on liver damage in 249 pediatric patients with biopsy-proven NAFLD and the association of this variant with the expression of hepatic and soluble KLB. In vitro models were established to investigate the role of the KLB mutant. The KLB rs17618244 variant was associated with an increased risk of ballooning and lobular inflammation. KLB plasma levels were lower in carriers of the rs17618244 minor A allele and were associated with lobular inflammation, ballooning and fibrosis. In HepG2 and Huh7 hepatoma cell lines, exposure to free fatty acids caused a severe reduction of intracellular and secreted KLB. Finally, KLB downregulation obtained by the expression of a KLB mutant in HepG2 and Huh7 cells induced intracellular lipid accumulation and upregulation of p62, ACOX1, ACSL1, IL-1β and TNF-α gene expression. In conclusion, we showed an association between the rs17618244 KLB variant, which leads to reduced KLB expression, and the severity of NAFLD in pediatric patients. We can speculate that the KLB protein may exert a protective role against lipotoxicity and inflammation in hepatocytes. Genetic and environmental factors strongly impact on the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD). The FGF19/FGFR4/KLB pathway plays a pivotal role in the pathogenesis of NAFLD. The aim of the study was to investigate the impact of a genetic variant in the KLB gene on the severity of liver disease. Our data suggest that the KLB protein plays a protective role against lipotoxicity and inflammation in hepatocytes.
Sections du résumé
BACKGROUND & AIM
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in adults and children. Along with obesity, diabetes and insulin resistance, genetic factors strongly impact on NAFLD development and progression. Dysregulated bile acid metabolism and the fibroblast growth factor 19 (FGF19) pathway play a pivotal role in NAFLD pathogenesis. However, the mechanism through which the FGF19 receptor system is associated with liver damage in NAFLD remains to be defined.
METHODS
We evaluated the impact of the rs17618244 G>A β-Klotho (KLB) variant on liver damage in 249 pediatric patients with biopsy-proven NAFLD and the association of this variant with the expression of hepatic and soluble KLB. In vitro models were established to investigate the role of the KLB mutant.
RESULTS
The KLB rs17618244 variant was associated with an increased risk of ballooning and lobular inflammation. KLB plasma levels were lower in carriers of the rs17618244 minor A allele and were associated with lobular inflammation, ballooning and fibrosis. In HepG2 and Huh7 hepatoma cell lines, exposure to free fatty acids caused a severe reduction of intracellular and secreted KLB. Finally, KLB downregulation obtained by the expression of a KLB mutant in HepG2 and Huh7 cells induced intracellular lipid accumulation and upregulation of p62, ACOX1, ACSL1, IL-1β and TNF-α gene expression.
CONCLUSION
In conclusion, we showed an association between the rs17618244 KLB variant, which leads to reduced KLB expression, and the severity of NAFLD in pediatric patients. We can speculate that the KLB protein may exert a protective role against lipotoxicity and inflammation in hepatocytes.
LAY SUMMARY
Genetic and environmental factors strongly impact on the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD). The FGF19/FGFR4/KLB pathway plays a pivotal role in the pathogenesis of NAFLD. The aim of the study was to investigate the impact of a genetic variant in the KLB gene on the severity of liver disease. Our data suggest that the KLB protein plays a protective role against lipotoxicity and inflammation in hepatocytes.
Identifiants
pubmed: 31655133
pii: S0168-8278(19)30613-0
doi: 10.1016/j.jhep.2019.10.011
pii:
doi:
Substances chimiques
FGF19 protein, human
0
KLB protein, human
0
Membrane Proteins
0
Fibroblast Growth Factors
62031-54-3
FGFR4 protein, human
EC 2.7.10.1
Receptor, Fibroblast Growth Factor, Type 4
EC 2.7.10.1
Klotho Proteins
EC 3.2.1.31
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
411-419Informations de copyright
Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.