Transcriptional regulation of the human apolipoprotein genes

This review provides experiments and putative mechanisms which underlie the transcription of the human apolipoprotein genes in vitro and in vivo. Summarized below are the key findings for individual genes and gene clusters. ApoA-II 1- The –911/+29 promoter is sufficient to direct expression of a reporter gene exclusively in the liver and thus represents a liver-specific promoter. 2- Important factors for the activity of this promoter are hormone nuclear receptors and the ubiquitous factor USF. 3- SREBP-1 and SREBP-2 bind to five and four sites respectively and transactivate the apoA-II promoter. Their role in the in vivo transcription of the apoA-II gene has not been established. ApoB 1- Regulatory sequence extending 5 Kb upstream and 1.5 Kb downstream of the apoB promoter are sufficient to direct hepatic expression of the apoB gene. The intestinal expression of the apoB gene requires in addition a 315 bp intestinal enhancer located 56 Kb upstream of the apoB gene. 2- Important factors for apoB gene transcription appear to be C/EBP, HNF-3, HNF-4 and other nuclear receptors which bind both on the proximal promoter and the intestinal enhancer. ApoE/ApoCI/ApoCIV/ApoCII Cluster 1- The expression of the genes of the apoE/apoCI/apoCII/apoE cluster are controlled by two homologous hepatic control regions designated HCR-1 and HCR-2 of approximately 600 bp located 15 and 27 Kb 3′ of the apoE gene. Either region is sufficient to direct gene expression in vivo, although HCR-1 appears to have a dominant effect on apoE and apoCI and HCR-2 has a dominant effect on apoCIV and apoCII gene expression. 2- Two other homologous regulatory regions designated ME-1 and ME-2 located 3.3 and 15.9 Kb downstream of the apoE gene can direct independently the expression of the apoE gene in macrophages and adipocytes. 3- Important factors for apoE gene regulation appear to be SP1 on the proximal promoter, and possibly HNF-3, C/EBP and hormone nuclear receptors on the enhancers. 4- Important factors for apoCII gene transcription appear to be HNF-4 and RXR-alpha/T3R-beta which binds to a thyroid response element of the proximal promoter. ApoA-I/ApoCIII/ApoA-IV Gene Cluster 1- The transcription of the apoA-I/apoCIII/apoA-IV gene cluster is controlled by a common enhancer located 590 to 790 nucleotides upstream of the apoCIII gene. 2- Important factors for the activity of the enhancer are SP1, HNF-4 and possibly other nuclear receptors. Important factors for the activity of the proximal promoters are HNF-4, and possibly other nuclear receptors. 3- The HNF-4 binding site of the apoCIII enhancer is required for the intestinal expression of apoA-I and apoCIII gene and enhances synergistically the hepatic transcription of the two genes and possibly of apoA-IV in vivo. The three SP1 sites of the enhancer are also required for the intestinal expression of apoA-I and apoCIII genes in vivo and for the enhancement of the hepatic transcription. 4- Pro-inflammatory cytokines such as TNF-alpha and IL-1 repress, and TGF-beta stimulates the apoCIII promoter activity. The TGF-beta pathway activates SMAD3/4 proteins which interact with HNF-4 bound to the apoCIII promoter and enhancer and increase its activity. 5- It appears that other factors activated by different signaling pathways (NF-kappa-B, Jun and others) interact with HNF-4 bound to the enhancer and thus repress the activity of apoCIII promoter. Understanding the transcriptional regulatory mechanism of the apolipoprotein genes may allow, in the long run, selective increase of anti-atherogenic lipoproteins and thus reduce the risk of cardiovascular disease.