Abstract
We have generated transgenic mice carrying wild-type promoters of the human apolipoprotein A-I (apoA-I)-apoCIII gene cluster or promoters mutated in their hormone response elements. The wild-type cluster directed high levels of apoA-I gene expression in liver and intestine, moderate expression in kidney, and low to minimal expression in other tissues. It also directed high levels of chloramphenicol acetyltransferase (CAT) expression (used as a reporter for the apoCIII gene) in liver, low levels in intestine and kidney, and no expression in other tissues. Mutations in the apoCIII promoter and enhancer abolished the intestinal and renal expression of the apoA-I gene, reduced hepatic apoA-I expression by 80%, and abolished CAT expression in all tissues. A similar pattern of expression was obtained by mutations in the apoCIII enhancer alone. Mutations in the proximal apoA-I promoter reduced by 85% hepatic and intestinal apoA-I expression and did not affect CAT expression. The findings suggest that a hormone response element within the apoCIII enhancer is essential for intestinal and renal expression of apoA-I and apoCIII genes and also enhances hepatic expression. The hormone response elements of the proximal apoA-I promoter or the apoCIII enhancer can promote independently low levels of hepatic and intestinal expression of the apoA-I gene in vivo.
Highlights
ApoA-I1 is the major protein component of HDL and is responsible for its biological functions
The findings suggest that a hormone response element within the apoCIII enhancer is essential for intestinal and renal expression of apoA-I and apoCIII genes and enhances hepatic expression
The findings indicate that the hormone response elements (HREs) present on element I4 of the apoCIII enhancer (which, as shown previously, binds HNF-4 [18, 19]) is essential for the intestinal and renal expression of the apoCIII gene
Summary
ApoA-I1 is the major protein component of HDL and is responsible for its biological functions. ApoCIII has been shown to modulate the catabolism of triglyceride-rich lipoproteins in vitro (6 – 8) This concept was further supported by in vivo studies, which showed that transgenic mice overexpressing the human apoCIII gene develop severe hypertriglyceridemia [9, 10]. Other transcription factors bind to proximal promoters of the apoA-I/apoCIII genes and may affect their overall activity and tissue specificity (16 –18, 21–22). Which regulatory elements control the tissue-specific expression of the human apoA-I and apoCIII gene in vivo? How do mutations in the HREs of the enhancer affect the tissue-specific expression of the two genes in vivo?. When the proximal HREs are mutated, the apoCIII enhancer alone may independently direct the expression of the apoA-I gene at lower levels in liver, intestine, and other tissues. Mutations in the HRE of the apoCIII enhancer abolished the intestinal and renal expression and reduced the hepatic expression of the two closely linked genes in vivo
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