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2016 ; 15
(12
): 2745-55
Nephropedia Template TP
Karanth S
; Zinkhan EK
; Hill JT
; Yost HJ
; Schlegel A
Cell Rep
2016[Jun]; 15
(12
): 2745-55
PMID27292639
show ga
A SNP (rs8004664) in the first intron of the FOXN3 gene is associated with human
fasting blood glucose. We find that carriers of the risk allele have higher
hepatic expression of the transcriptional repressor FOXN3. Rat Foxn3 protein and
zebrafish foxn3 transcripts are downregulated during fasting, a process
recapitulated in human HepG2 hepatoma cells. Transgenic overexpression of
zebrafish foxn3 or human FOXN3 increases zebrafish hepatic gluconeogenic gene
expression, whole-larval free glucose, and adult fasting blood glucose and also
decreases expression of glycolytic genes. Hepatic FOXN3 overexpression suppresses
expression of mycb, whose ortholog MYC is known to directly stimulate expression
of glucose-utilization enzymes. Carriers of the rs8004664 risk allele have
decreased MYC transcript abundance. Human FOXN3 binds DNA sequences in the human
MYC and zebrafish mycb loci. We conclude that the rs8004664 risk allele drives
excessive expression of FOXN3 during fasting and that FOXN3 regulates fasting
blood glucose.
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