Hypoxia reduces HNF4α/MODY1 protein expression in pancreatic β-cells by activating AMP-activated protein kinase

Abstract

Hypoxia plays a role in the deterioration of β-cell function. Hepatocyte nuclear factor 4α (HNF4α) has an important role in pancreatic β-cells, and mutations of the human gene cause a type of maturity-onset diabetes of the young (MODY1). However, it remains unclear whether hypoxia affects the expression of HNF4α in β-cells. Here, we report that hypoxia reduces HNF4α protein expression in β-cells. Hypoxia-inducible factor was not involved in the down-regulation of HNF4α under hypoxic conditions. The down-regulation of HNF4α was dependent on the activation of AMP-activated protein kinase (AMPK), and the reduction of HNF4α protein expression by metformin, an AMPK activator, and hypoxia was inhibited by the overexpression of a kinase-dead (KD) form of AMPKα2. In addition, hypoxia decreased the stability of the HNF4α protein, and the down-regulation of HNF4α was sensitive to proteasome inhibitors. Adenovirus-mediated overexpression of KD-AMPKα2 improved insulin secretion in metformin-treated islets, hypoxic islets, and/ mouse islets. These results suggest that down-regulation of HNF4α could be of importance in β-cell dysfunction by hypoxia.

Lipid metabolism in cancer progression and therapeutic strategies

“…In addition, the nuclear receptor HNF4 alpha (HNF4α), a key regulator in mitochondrial FA β‐oxidation, cholesterol and bile acid metabolism, and lipoprotein metabolism, 141 is also phosphorylated by AMPK. AMPK‐induced phosphorylation in the HNF4α protein reduces its ability to form homodimers, a process needed for binding to DNA, and thus enhancing the turnover of HNF4α 142 . In astrocytic tumors, AMPK was shown to contribute to lipid metabolic reprogramming by reducing energy expenditure, through reduced de novo fatty synthesis and increased extracellular lipid internalization 143 .…”

AMPK: Regulation of Metabolic Dynamics in the Context of Autophagy

“…In addition to its direct activity, AMPK is able to modulate lipid metabolism by regulating the activity of several transcription factors involved in lipid synthesis and associated processes. Specifically, AMPK phosphorylation inhibits the transcriptional activity of SREBP1 (sterol regulatory element binding protein 1), ChREBP (carbohydrate-responsive element binding protein) or HNF4α (hepatocyte nuclear factor 4α) [33,34,35,36]. Thus, by inhibiting phosphorylation of these transcription factors, AMPK negatively regulates lipogenic processes through the modulation of lipid-specific transcriptional programs.…”

Bioinformatics-Based Analysis of the lncRNA-miRNA-mRNA Network and TF Regulatory Network to Explore the Regulation Mechanism in Spinal Cord Ischemia/Reperfusion Injury

“…SP1 expression was also increased in cortex subjected to brain I/R insult and in primary neurons subjected to OGD/R treatment ( Sun et al, 2015 ). Hnf4a is a TF belonging to the nuclear receptor superfamily and is expressed in the intestine, kidney, liver, and pancreas (including β-cells) ( Yamanishi et al, 2015 ; Sato et al, 2017 ). It has been proved that Hnf4a was a key TF which showed specific binding at enhancer and super-enhancer sites during ischemic acute kidney injury ( Wilflingseder et al, 2020 ).…”

“…A study demonstrated that the increase of an acute-phase response from the concomitant action of IL-6, TNF-α, and IL-1β inhibited the expression of Hnf4a -dependent APR genes in HepG2 cells ( Wang and Burke, 2008 ). Besides, in pancreatic β-cells, hypoxia reduced Hnf4a/MODY1 protein expression by activating AMPK ( Sato et al, 2017 ). In the present study, we explored the TFs correlated with the mRNAs of the ceRNA-Pathway network.…”