In vitro transcriptional induction of the human apolipoprotein A-II gene by glucose.
Type 2 diabetic patients present high triglyceride and low HDL levels, significant determinants for the risk of atherosclerosis. Transgenic mice overproducing human apolipoprotein (apo)A-II, one of the two major apos of HDLs, display the same lipid disorders. Here, we investigated the possible regulation of apoA-II gene expression by glucose. In primary rat hepatocytes and in HepG2 cells, the transcription of the human apoA-II gene was upregulated by glucose. This response was mediated by a hormone-responsive element within the enhancer of the apoA-II promoter and was dependent on hepatocyte nuclear factor-4alpha. Accordingly, in transgenic mice, the human apoA-II gene is stimulated by a high-carbohydrate diet after fasting and at weaning. By contrast, the apoA-II mRNA level is not modified in streptozotocin-induced diabetic rats. In transgenic mice overexpressing the human apoA-II gene, plasma human apoA-II concentration was positively correlated with blood glucose levels. These mice displayed a marked delay in plasma glucose tolerance as compared with control mice. We hypothesize that the following pathogenic pathway might occur in the course of type 2 diabetes: increased apoA-II level causes a rise in plasma triglyceride level and glucose intolerance, resulting in hyperglycemia, which in turn might further increase apoA-II gene transcription.
Institut National de la Santé et de la Recherche Médicale (INSERM) U505, Institut Biomédical des Cordeliers, Paris, France.
Dominique
D
Sauvaget
Valérie
V
Chauffeton
Sonia
S
Dugué-Pujol
Athina-Despina
AD
Kalopissis
Isabelle
I
Guillet-Deniau
Fabienne
F
Foufelle
Jean
J
Chambaz
Armelle
A
Leturque
Philippe
P
Cardot
Agnès
A
Ribeiro
D000818:Animals; D016633:Apolipoprotein A-II / Q000235:genetics*; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*
D016633:Apolipoprotein A-II; D001786:Blood Glucose; D017931:DNA Primers; D012333:RNA, Messenger; D005947:Glucose