Transcriptional regulation of the apoC-III gene by insulin in diabetic mice: correlation with changes in plasma triglyceride levels.
Insulin-dependent diabetes mellitus (IDDM) is associated with elevated plasma triglyceride levels that normalize after insulin administration. The observation that overexpression of the apoC-III gene in transgenic mice can cause hypertriglyceridemia and other evidence implicating apoC-III in the regulation of triglyceride levels prompted us to examine whether apoC-III might be involved in the hypertriglyceridemia associated with IDDM. To this end, the regulation of apoC-III gene expression was studied in the streptozotocin-treated mouse model of IDDM. In the insulin-deficient diabetic state, these mice have elevated glucose and triglyceride levels and a 1.4- to 1.5-fold increase in hepatic apoC-III mRNA levels, by Northern analysis as well as quantitative solution hybridization RNase protection assay. Insulin treatment normalized the glucose and triglyceride levels and diminished hepatic apoC-III mRNA levels by 59%. Analysis of transcription rates using the nuclear run-on technique demonstrated that the changes in hepatic apoC-III mRNA levels were the results of changes in the transcriptional activity of the gene. To determine the role of insulin in the regulation of apoC-III transcription, HepG2 cells were transfected with an apoC-III reporter construct, and treated with different insulin concentrations. The results demonstrated that insulin treatment induced a dose-dependent down-regulation of apoC-III transcriptional activity. These data suggest that the apoC-III transcriptional changes seen in animals are caused by differences in insulin concentrations. Assuming that apoC-III mRNA levels reflect the synthesis and secretion of the protein, these results present the possibility that overexpression of the apoC-III gene could contribute to the hypertriglyceridemia observed in IDDM.
Chen
M
M
Department of Biotechnology, Parke-Davis, Ann Arbor, MI 48105.
Breslow
J L
JL
Li
W
W
Leff
T
T
D000818:Animals; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000235:genetics*; D001786:Blood Glucose / Q000378:metabolism; D015152:Blotting, Northern; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007328:Insulin / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014280:Triglycerides / Q000097:blood*
D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D014280:Triglycerides