Heme-Regulated eIF2α Kinase Modulates Hepatic FGF21 and Is Activated by PPARß/δ Deficiency.
Diabetes
; 65(10): 3185-99, 2016 10.
Article
em En
| MEDLINE
| ID: mdl-27486236
ABSTRACT
Fibroblast growth factor 21 (FGF21), a peptide hormone with pleiotropic effects on carbohydrate and lipid metabolism, is considered a target for the treatment of diabetes. We investigated the role of peroxisome proliferator-activated receptor (PPAR) ß/δ deficiency in hepatic FGF21 regulation. Increased Fgf21 expression was observed in the livers of PPARß/δ-null mice and in mouse primary hepatocytes when this receptor was knocked down by small interfering RNA (siRNA). Increased Fgf21 was associated with enhanced protein levels in the heme-regulated eukaryotic translation initiation factor 2α (eIF2α) kinase (HRI). This increase caused enhanced levels of phosphorylated eIF2α and activating transcription factor (ATF) 4, which is essential for Fgf21-induced expression. siRNA analysis demonstrated that HRI regulates Fgf21 expression in primary hepatocytes. Enhanced Fgf21 expression attenuated tunicamycin-induced endoplasmic reticulum stress, as demonstrated by using a neutralizing antibody against FGF21. Of note, increased Fgf21 expression in mice fed a high-fat diet or hepatocytes exposed to palmitate was accompanied by reduced PPARß/δ and activation of the HRI-eIF2α-ATF4 pathway. Moreover, pharmacological activation of HRI increased Fgf21 expression and reduced lipid-induced hepatic steatosis and glucose intolerance, but these effects were not observed in Fgf21-null mice. Overall, these findings suggest that HRI is a potential target for regulating hepatic FGF21 levels.
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Base de dados:
MEDLINE
Assunto principal:
EIF-2 Quinase
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PPAR beta
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PPAR delta
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Fatores de Crescimento de Fibroblastos
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Fígado
Limite:
Animals
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article