Alterations in apolipoprotein gene transcription may cause changes in plasma lipid and lipoprotein levels and in some instances may increase the risk of cardiovascular disease. The long-term objective of the proposed studies is to understand the mechanisms of transcriptional regulation of the human apolipoprotein genes in vivo. The rationale of our approach and our hypothesis is that if we understand the molecular events and the signal transduction pathway(s) which lead to gene activation, then we may be able to selectively regulate apolipoprotein and lipoprotein synthesis and thus regulate plasma lipids and lipoprotein levels for optimal health. As a model system for understanding gene regulation in cell cultures and in experimental animals, we will utilize the human apoA-I/apoCIII gene cluster. Key observations during the last five years have established that the -800/-590 apoCIII regulatory region is an intestinal enhancer and that nuclear receptors and SP1 play an important role in the regulation of the apoA-I and apoCIII genes.
Our specific aims are: 1) To elucidate how activation of cJun and ATF-2 and HNF-4 cascades, via specific signal transduction, affect the expression of the human apoCIII gene in cell cultures. 2) To elucidate what combinations of promoter and enhancer elements determine the tissue-specific expression of the apoA-I and apoCIII genes in vivo using transgenic and knock-in mouse models. 3) To elucidate the contribution of different nuclear receptors as well as the transcription factors such as SP1 and C/EBP to the hepatic and intestinal expression of the human apoA- I and apoCIII genes in vivo using existing animal models, antisense methodologies and adenovirus mediated gene transfer. It is expected that the proposed studies will provide new insights into the mechanism of transcriptional regulation of the apoA-I and apo-CIII genes as well as general insights into hepatic and intestinal gene regulation. Increases in plasma apoA-I and HDL levels are associated with protection from cardiovascular disease. Alteration in apoCIII has been shown to affect the catabolism of triglyceride-rich lipoproteins. Thus the information obtained from this project may provide rational approaches towards correcting low plasma HDL levels and reducing hypertriglyceridemia in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL033952-19
Application #
6638249
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Applebaum-Bowden, Deborah
Project Start
1984-09-01
Project End
2005-04-30
Budget Start
2003-05-01
Budget End
2005-04-30
Support Year
19
Fiscal Year
2003
Total Cost
$372,088
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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Drosatos, Konstantinos; Sanoudou, Despina; Kypreos, Kyriakos E et al. (2007) A dominant negative form of the transcription factor c-Jun affects genes that have opposing effects on lipid homeostasis in mice. J Biol Chem 282:19556-64
Zannis, Vassilis I; Chroni, Angeliki; Krieger, Monty (2006) Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL. J Mol Med 84:276-94
Chroni, Angeliki; Duka, Adelina; Kan, Horng-Yuan et al. (2005) Point mutations in apolipoprotein A-I mimic the phenotype observed in patients with classical lecithin:cholesterol acyltransferase deficiency. Biochemistry 44:14353-66
Chroni, Angeliki; Kan, Horng-Yuan; Shkodrani, Adelina et al. (2005) Deletions of helices 2 and 3 of human apoA-I are associated with severe dyslipidemia following adenovirus-mediated gene transfer in apoA-I-deficient mice. Biochemistry 44:4108-17
Chroni, Angeliki; Kan, Horng-Yuan; Kypreos, Kyriakos E et al. (2004) Substitutions of glutamate 110 and 111 in the middle helix 4 of human apolipoprotein A-I (apoA-I) by alanine affect the structure and in vitro functions of apoA-I and induce severe hypertriglyceridemia in apoA-I-deficient mice. Biochemistry 43:10442-57
Kan, Horng-Yuan; Georgopoulos, Spiros; Zanni, Markella et al. (2004) Contribution of the hormone-response elements of the proximal ApoA-I promoter, ApoCIII enhancer, and C/EBP binding site of the proximal ApoA-I promoter to the hepatic and intestinal expression of the ApoA-I and ApoCIII genes in transgenic mice. Biochemistry 43:5084-93
Chroni, Angeliki; Liu, Tong; Gorshkova, Irina et al. (2003) The central helices of ApoA-I can promote ATP-binding cassette transporter A1 (ABCA1)-mediated lipid efflux. Amino acid residues 220-231 of the wild-type ApoA-I are required for lipid efflux in vitro and high density lipoprotein formation in vivo. J Biol Chem 278:6719-30
Zannis, Vassilis I; Liu, Tong; Zanni, Markella et al. (2003) Regulatory gene mutations affecting apolipoprotein gene expression: functions and regulatory behavior of known genes may guide future pharmacogenomic approaches to therapy. Clin Chem Lab Med 41:411-24
Kardassis, Dimitris; Roussou, Anastasia; Papakosta, Paraskevi et al. (2003) Synergism between nuclear receptors bound to specific hormone response elements of the hepatic control region-1 and the proximal apolipoprotein C-II promoter mediate apolipoprotein C-II gene regulation by bile acids and retinoids. Biochem J 372:291-304

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