https://www.ncbi.nlm.nih.gov/pubmed/31655133 NAFLD
J Hepatol. 2019 Oct 23. pii: S0168-8278(19)30613-0. doi: 10.1016/j.jhep.2019.10.011.
β-Klotho gene variation is associated with liver damage in children with NAFLD.
Dongiovanni P1, Crudele A2, Panera N3, Romito I4, Meroni M5, De Stefanis C6, Palma A7, Comparcola D8, Fracanzani AL9, Miele L10, Valenti L11, Nobili V12, Alisi A13.

Abstract

BACKGROUND AND AIM:
Nonalcoholic 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, it remains to be defined the mechanism through which the FGF19 receptor system is associated with liver damage in NAFLD.

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 KLB mutant.

RESULTS:
The KLB rs17618244 variant was associated with 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 down-regulation obtained by the expression of KLB mutant in HepG2 and Huh7 cells induced intracellular lipid accumulation and up-regulation 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 KLB protein may exert a protective role against lipotoxicity and inflammation in hepatocytes.

LAY SUMMARY:
Genetic and environmental factors strongly impact on NAFLD pathogenesis and progression. The FGF19/FGFR4/KLB pathway plays a pivotal role in NAFLD pathogenesis, thus, it has been identified as a therapeutic target. Therefore, the aim of the study was to investigate the impact of the KLB rs17618244 G>A genetic variant on liver damage severity in pediatric patients with NAFLD, and the effect of KLB mutant on hepatocellular damage.