Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia.

Abstract

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 Cm promoter is common in the human population and may represent a major contributing factor to the development of hypertriglyceridemia. (J. Clin. Invest. 1995. 96:2601-2605

Why there is an IRS.

“…This major action of the hormone is important for normal metabolism but gains added significance in view of the fact that insulin resistance is the cornerstone of genetic diseases such as noninsulin-dependent diabetes mellitus and obesity. The possibility that faulty regulation of gene expression by insulin could result in disease is now given credence by the observations reported by Li et al (2) in this issue of The Journal.…”

“…Recently, Dammerman et al (3) identified five polymorphisms in this region of the apo CIII promoter. Li et al (2) now show that single base pair changes at either of two of the five variant sites (at -482 and -455) abolish the repression of apo CIII gene transcription by insulin, an observation that reveals why these mutations lead to apo CIII overexpression. The functional significance of the nucleotide changes in the other three variant sites is unclear but is not related to regulation of apo CIII gene expression by insulin.…”

Population prevalence of APOE, APOC3 and PPAR-α mutations associated to hypertriglyceridemia in French Canadians

“…In vitro studies showed that the simultaneous presence of the rare alleles of APOC3 C-482T and T-455C SNPs located in the IRE results in the up-regulation of the APOC3 gene in transfected HepG2 cells and could induce the over-expression of plasma apoCIII and the development of HTG (Li et al 1995). However, an association study between the presence of two APOC3 SNPs haplotypes, such as the T-482 and G3238 alleles, and HTG did not strengthen the association observed solely between the G3238 allele and HTG (Shoulders et al 1996;Surguchov et al 1996).…”

The SstI polymorphism of the apo C-III gene is associated with insulin sensitivity in young men

“…In contrast, the S2 allele, identified by the restriction enzyme Sst-I, is in disequilibrium with two mutations located in the promoter region of the apo C-III gene [9]. The presence of these two mutations determines the absence of regulation by the insu- lin and the decrease of apo-CIII, which is physiologically produced by the hormone, resulting in an increase in plasma concentrations of apoprotein CIII [19]. Apo C-III modulates the metabolism of triglyceride rich particles [20], so its overexpression could interfere in the plasmatic clearance of the triglyceride rich lipoproteins, resulting in its subsequent increase.…”