Glucose regulates the expression of the apolipoprotein A5 gene.
The apolipoprotein A5 gene (APOA5) is a key player in determining triglyceride concentrations in humans and mice. Since diabetes is often associated with hypertriglyceridemia, this study explores whether APOA5 gene expression is regulated by alteration in glucose homeostasis and the related pathways. d-Glucose activates APOA5 gene expression in a time- and dose-dependent manner in hepatocytes, and the glycolytic pathway involved was determined using d-glucose analogues and metabolites. Together, transient transfections, electrophoretic mobility shift assays and chromatin immunoprecipitation assays show that this regulation occurs at the transcriptional level through an increase of USF1/2 binding to an E-box in the APOA5 promoter. We show that this phenomenon is not due to an increase of mRNA or protein expression levels of USF. Using protein phosphatases 1 and 2A inhibitor, we demonstrate that d-glucose regulates the APOA5 gene via a dephosphorylation mechanism, resulting in an enhanced USF1/2-promoter binding. Last, subsequent suppressions of USF1/2 and phosphatases mRNA through siRNA gene silencing abolished the regulation. We demonstrate that the APOA5 gene is up regulated by d-glucose and USF through phosphatase activation. These findings may provide a new cross-talk between glucose and lipid metabolism.
Institut Pasteur de Lille, Département d'Athérosclérose, Lille, France.
Maxime
M
Nowak
Audrey
A
Helleboid-Chapman
Heidelinde
H
Jakel
Emmanuelle
E
Moitrot
Corinne
C
Rommens
Len A
LA
Pennacchio
Jamila
J
Fruchart-Najib
Jean-Charles
JC
Fruchart
D000818:Animals; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology*; D006019:Glycolysis; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054645:Protein Phosphatase 1 / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014158:Transcription, Genetic; D051720:Upstream Stimulatory Factors / Q000378:metabolism
C437704:APOA5 protein, human; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; C497181:USF1 protein, human; C497184:USF2 protein, human; D051720:Upstream Stimulatory Factors; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D005947:Glucose