A hormone response element in the human apolipoprotein CIII (ApoCIII) enhancer is essential for intestinal expression of the ApoA-I and ApoCIII genesand contributes to the hepatic expression of the two linked genes in transgenic mice

We have generated transgenic mice carrying wildtype promoters of the human apolipoprotein A-I (apoA-I)-apoCIII gene cluster or promoters mutated in th eir hormone response elements. The wild-type cluster directed high levels o f apoA-I gene expression in liver and intestine, moderate expression in kid ney, and low to minimal expression in other tissues. It also directed high levels of chloramphenicol acetyltransferase (CAT) expression (used as a rep orter for the apoCIII gene) in liver, low levels in intestine and kidney, a nd no expression in other tissues. Mutations in the apoCIII promoter and en hancer abolished the intestinal and renal expression of the apoA-I gene, re duced 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 b y 85% hepatic and intestinal apoA-I expression and did not affect CAT expre ssion, The findings suggest that a hormone response element within the apoC III enhancer is essential for intestinal and renal expression of apoA-I and apoCIII genes and also enhances hepatic expression. The hormone response e lements of the proximal apoA-I pro meter or the apoCIII enhancer can promot e independently low levels of hepatic and intestinal expression of the apoA -I gene in vivo.