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Hypoxia reduces HNF4?/MODY1 protein expression in pancreatic ?-cells by
activating AMP-activated protein kinase
#MMPMID28364040
Sato Y
; Tsuyama T
; Sato C
; Karim MF
; Yoshizawa T
; Inoue M
; Yamagata K
J Biol Chem
2017[May]; 292
(21
): 8716-8728
PMID28364040
show ga
Hypoxia plays a role in the deterioration of ?-cell function. Hepatocyte nuclear
factor 4? (HNF4?) has an important role in pancreatic ?-cells, and mutations of
the human HNF4A gene cause a type of maturity-onset diabetes of the young
(MODY1). However, it remains unclear whether hypoxia affects the expression of
HNF4? in ?-cells. Here, we report that hypoxia reduces HNF4? protein expression
in ?-cells. Hypoxia-inducible factor was not involved in the down-regulation of
HNF4? under hypoxic conditions. The down-regulation of HNF4? was dependent on the
activation of AMP-activated protein kinase (AMPK), and the reduction of HNF4?
protein expression by metformin, an AMPK activator, and hypoxia was inhibited by
the overexpression of a kinase-dead (KD) form of AMPK?2. In addition, hypoxia
decreased the stability of the HNF4? protein, and the down-regulation of HNF4?
was sensitive to proteasome inhibitors. Adenovirus-mediated overexpression of
KD-AMPK?2 improved insulin secretion in metformin-treated islets, hypoxic islets,
and ob/ob mouse islets. These results suggest that down-regulation of HNF4? could
be of importance in ?-cell dysfunction by hypoxia.
|*Down-Regulation
[MESH]
|AMP-Activated Protein Kinases/genetics/*metabolism
[MESH]
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