Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia.
Overexpression of plasma apolipoprotein CIII (apo CIII) causes hypertriglyceridemia in transgenic mice. A genetically variant form of the human apo CIII promoter, containing five single base pair changes, has been shown to be associated with severe hypertriglyceridemia in a patient population. In animals and in cultured cells the apo CIII gene is transcriptionally downregulated by insulin. In this study we demonstrate that, unlike the wild-type promoter, the variant promoter was defective in its response to insulin treatment, remaining constitutively active at all concentrations of insulin. The loss of insulin regulation was mapped to polymorphic sites at -482 and -455, which fall within a previously identified insulin response element. Loss of insulin regulation could result in overexpression of the apo CIII gene and contribute to the development of hypertriglyceridemia. The variant apo CIII promoter is common in the human population and may represent a major contributing factor to the development of hypertriglyceridemia.
Li
W W
WW
Department of Signal Transduction, Parke-Davis Co., Ann Arbor, Michigan 48105, USA.
Dammerman
M M
MM
Smith
J D
JD
Metzger
S
S
Breslow
J L
JL
Leff
T
T
D000483:Alleles; D000818:Animals; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics*; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000032:analysis / Q000096:biosynthesis; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D014644:Genetic Variation; D015698:Genomic Library; D006801:Humans; D006953:Hyperlipoproteinemia Type IV / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology* / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008156:Luciferases / Q000032:analysis / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015183:Restriction Mapping; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D007328:Insulin; D008156:Luciferases; D015500:Chloramphenicol O-Acetyltransferase