Abstract
Klotho beta (KLB) mediates binding of fibroblast growth factor (FGF) 21 to the FGF receptor (FGFR). FGF21-KLB-FGFR signaling regulates multiple metabolic systems in the liver, and we hypothesized that FGF21, KLB and FGFR single-nucleotide polymorphisms (SNPs) are involved in hepatic lipid accumulation. The SNPs were detected in 1688 individuals divided into four groups: non-obese without non-alcoholic fatty liver disease (NAFLD), obese without NAFLD, non-obese with NAFLD, and obese with NAFLD. The A-allele of KLB SNP rs7670903 correlated with higher body mass index (P = 0.0005), and the A-allele frequency was higher in the obese than non-obese group (P = 0.003). The G-allele frequency of KLB rs7674434 and T-allele frequency of rs12152703 were higher in the obese with NAFLD than obese without NAFLD group (P = 0.004 and P = 0.006), but the genotype distribution between two non-obese groups did not differ. KLB rs7674434 and rs12152703 had associations with alanine aminotransferase (ALT) (P = 0.03 and P = 0.04, respectively) and gamma-glutamyltransferase (P = 0.03 and P = 0.02, respectively) levels in all subjects, but the associations were especially strong with ALT in the NAFLD group (P = 0.005 and P = 0.008, respectively). These findings suggest that KLB SNPs are related to obesity and hepatic inflammation and that they may be involved in the pathogenesis of NAFLD.
Highlights
The klotho family protein klotho beta (KLB) is a single transmembrane protein that serves as a co-receptor with fibroblast growth factor receptor (FGFR) [1]
Comparison of the clinical and biochemical characteristics of the subjects revealed no significant difference between the non-alcoholic fatty liver disease (NAFLD) and non-NAFLD groups (Table 2)
The results showed that KLB single-nucleotide polymorphisms (SNPs) rs7674434 and rs12152703 had significant associations with Alanine aminotransferase (ALT) (P = 0.030 and P = 0.041, respectively) and γ-GT (P = 0.032 and P = 0.024, respectively) levels, while SNP rs7670903 correlated with γ-GT levels (P = 0.034) (Table 5)
Summary
The klotho family protein klotho beta (KLB) is a single transmembrane protein that serves as a co-receptor with fibroblast growth factor receptor (FGFR) [1]. By mediating FGF21 binding to FGFR, KLB plays key roles in the regulation of metabolism [2]. Under fasting and some stress conditions, expression of FGF21 rises in the liver, adipose tissue, pancreas and brain [3, 4], where signaling via the FGF21-KLB-FGFR1 complex exerts effects impacting multiple metabolic systems [5]. NAFLD is thought to be a hepatic manifestation of metabolic syndrome caused by an underlying disorder of energy utilization and storage [6]. In mice decreased KLB expression appears to result in FGF21 resistance [8]. This suggests FGF21-KLB-FGFR signaling may be involved in the pathogenesis of NAFLD
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