DISTINCT PROMOTERS INDUCE APOBEC-1 EXPRESSION IN RAT-LIVER AND INTESTINE

The expression of apolipoprotein (apo) B can be modulated by mRNA edit ing, a unique posttranscriptional base change in the apo B mRNA. Apo B -48, the translation product of edited apo B mRNA, is not a precursor of the atherogenic low density lipoproteins and lipoprotein(a). In hum ans and various other mammals, the apo B mRNA is edited in the intesti ne but not in the liver, which exclusively secretes apo B-100-containi ng lipoproteins as precursors for low density lipoprotein formation. I n species such as the rat, mouse, dog, and horse, apo B mRNA is also e dited in the liver, resulting in low plasma levels of low density lipo protein. Editing of the apo B mRNA is mediated by the apo B mRNA-editi ng enzyme complex, of which the catalytic subunit APOBEC-1 is not expr essed in the liver of species without hepatic editing. To understand t he molecular basis for liver-specific expression of APOBEC-1 and the e diting of hepatic apo B mRNA, the expression pattern and genomic organ ization of the rat APOBEC-1 gene have been characterized. The rat APOB EC-1 gene contains 6 exons and 2 promoters with distinct activities. T he expression of APOBEC-1 in the rat liver is the result of a promoter located upstream, with tissue-specific exon use and alternate splicin g within the 5'-untranslated region of APOBEC-1 mRNA encoded by exon 2 . In addition to the liver, this promoter also induces APOBEC-1 expres sion in the spleen, lung, kidney, heart, and skeletal muscle. The prom oter located downstream belongs to a new class of TATA-less promoters and is responsible for the abundant expression of APOBEC-1 in the inte stine. Mapping of the transcriptional start sites and deletion analysi s of the promoter regions by using luciferase as the reporter gene hav e defined the regulatory elements of both promoters. The downstream, i ntestine-specific promoter contains a negative regulatory element betw een -1100 and -500, which appears to restrict its activity to the inte stine. The upstream, liver-specific promoter of the rat APOBEC-1 gene induces APOBEC-1 expression and editing of apo B mRNA in human hepatom a HuH-7 and Hep G2 cells. Understanding the molecular basis for the li ver-specific expression of APOBEC-1 in the rat promises new strategies to induce APOBEC-1 expression in the human liver for the reduction of atherogenic lipoprotein levels by hepatic apo B mRNA editing.