Transcriptional regulatory mechanisms of the human apolipoprotein genes in vitro and in vivo Vassilis I. Zannis a,b , Horng-Yuan Kan a , Aristidis Kritis b,c , Eleni E. Zanni a and Dimitris Kardassis b The present review summarizes recent advances in the transcriptional regulation of the human apolipoprotein genes, focusing mostly, but not exclusively, on in-vivo studies and signaling mechanisms that affect apolipoprotein gene transcription. An attempt is made to explain how interactions of transcription factors that bind to proximal promoters and distal enhancers may bring about gene transcription. The experimental approaches used and the transcriptional regulatory mechanisms that emerge from these studies may also be applicable in other gene systems that are associated with human disease. Understanding extracellular stimuli and the specific mechanisms that underlie apolipoprotein gene transcription may in the long run allow us to selectively switch on antiatherogenic genes, and switch off proatherogenic genes. This may have beneficial effects and may confer protection from atherosclerosis to humans. Curr Opin Lipidol 12:181±207. # 2001 Lippincott Williams & Wilkins. a Section of Molecular Genetics, Whitaker Cardiovascular Institute, Departments of Medicine and Biochemistry, Boston University School of Medicine, Boston, Massachusetts, b University of Crete, Department of Biochemistry, and Institute of Molecular Biology & Biotechnology, Crete, and c (Current address) Democritus University of Thrace, Alexandroupolis, Greece Correspondence to Vassilis I. Zannis, Section of Molecular Genetics, Whitaker Cardiovascular Institute, Departments of Medicine and Biochemistry, Boston University School of Medicine, Boston, MA 02118-2394, USA Tel: +1 617 638 5085; fax: +1 617 638 5141; e-mail: vzannis@bu.edu Current Opinion in Lipidology 2001, 12:181±207 Abbreviations AdML adenovirus major late promoter ARP apoA-I regulatory protein ATF activating transcription factor CAT chloramphenicol acetyltransferase C/EBP CCAAT enhancer binding protein EGR early growth response factor HCR hepatic control region HNF hepatic nuclear factor HRE hormone response element MAPK mitogen-activated protein kinase Erk1/2 extracellular signal-regulated kinases 1/2 MEKK1 MAPK/Erk1/2 kinase 1 NF-kB nuclear factor-kB PPAR peroxisome proliferator-activating receptor RXR retinoid X receptor SP1 specificity protein 1 SREBP sterol regulatory element binding protein T3Rb thyroid hormone receptor b TGF transforming growth factor USF upstream stimulatory factor # 2001 Lippincott Williams & Wilkins 0957-9672 Introduction The transcription of eukaryotic genes is a complex biologic event that involves numerous proteins, includ- ing the RNA polymerase II, the factors of the basal transcription initiation complex, the transcription factors, and numerous coactivators, corepressors and auxiliary factors. Earlier research provided extensive maps of the regulatory elements that control gene transcription and their relative importance for the function of a speci®c promoter in cell cultures. Parallel studies in transgenic mice identi®ed the long-distance regulatory elements that control the hepatic expression of apoE and apoCI genes (for review [1]). Advances have been made in the structural and functional characterization of several liver-speci®c and ubiquitous factors that are involved in apolipoprotein gene transcription. Impressive progress has also been made in the structural and functional characterization of the proteins of the basal transcription complex, coacti- vators, corepressors, and auxiliary proteins that bridge the gap between transcription factors and the basal transcription complex. The present review highlights our current understanding of the regulatory mechanisms that underlie the transcrip- tion of the human apolipoprotein genes and of means to in¯uence their transcription. In this regard, the in-vitro and in-vivo studies established that, similar to other systems, the apolipoprotein regulatory sequences are recognized by a multitude of factors that bind to promoter and enhancer regions. As highlighted in the present review, the in-vitro mutagenesis and the transgenic studies indicate that perhaps a few of these factors are essential and that transcription can be modulated by in¯uencing the activity of a single transcription factor, such as hepatic nuclear factor-4 (HNF-4) or other factors. The activity of these factors may be in¯uenced by ligands or by interaction with other transcription factors that are induced by signaling mechanisms. Proteins participating in gene transcription This section addresses the basal transcription complex: auxiliary factors, transcription factors, coactivators, co- repressors. 181