Hormonal regulation of ATP binding cassette transporters

Although the knowledge of ATP-binding cassette of lipid transport had grown substantially over the last few years, the detailed molecular mechanisms and the exact functions of these transporters were still awaiting clarification. In this thesis, analysis of the actions of human steroid and non-steroid hormones on cholesterol and phospholipid effluxes and on ABC transporters gene expression in two cell types (human monocytes derived macrophages and HepG2 cells) were performed. Human macrophages are the source of foam cells involved in the pathogenesis of atherosclerosis, and liver cells are the major site for cholesterol biosynthesis and catabolism by converting cholesterol to bile acids. Some of these hormones had promoted ApoA-1 dependent cholesterol and phospholipid effluxes and others had suppressed these effluxes depending on their influences on the expression of ATP binding cassette transporters. Beta-Estradiol enhanced ApoA-1 dependent cholesterol and phospholipids effluxes in human macrophages through upregulation of ABCA1 and ABCG1 gene expression. In HepG2 cells, beta-estradiol had little or reversed effect on ApoA-1 dependent cholesterol and phospholipids effluxes and sterol sensitive ABC transporters, which presumbly related to estrogen receptors gene expression. Estrogen receptor-beta was high expressed in human macrophages but not in HepG2 cells. Upregulations of ABCA1 and ABCG1 genes expression by beta-estadiol in human macrophages were time dependent where they started early and lasted for few hours. Progesterone augmented ApoA-1 dependent cholesterol and phospholipids effluxes in human macrophages through upregulation of ABCA1 and ABCG1 gene expressions. Luteinizing hormone increased ApoA-1 dependent phospholipid efflux in HepG2 cells through augmentation of ABCA7 mRNA. Somatostatin hormone also enhanced ApoA-1 dependent phospholipid efflux in HepG2 cells by enhancing ABCA7 gene expression. Human insulin promoted ApoA-1 dependent cholesterol and phospholipid effluxes in both human macrophages and HepG2 cells. These actions could be associated with an upregulation of ABCA1 and ABCG1 mRNA. The ABCA1 upregulation of human insulin was time, concentration and tissue dependent. In human macrophages, ABCA1 and ABCG1 induction started early and extended over hours. The same occurred in HepG2 cells but with a more extended effect. The maximum concentration of insulin that could upregulate ABCA1 gene expression was 150 nM in human macrophages. Above this concentration, ABCA1 gene expression declined. Posttransscription influence of insulin was more pronounced than its influence on ABCA1 transcription. ABCA1 gene expression in human macrophages was induced by insulin via a MAP kinase signaling pathway. Furthermore, we speculate that activation of PPAR-gamma and SDP1 were involved in this process. Some hormones had suppressed ApoA-1 dependent cholesterol and phospholipid effluxes. Hydrocortisone suppressed cholesterol efflux in human macrophages presumbly by downregulation of ABCA1 gene expression. Triiodothyroxin decreased cholesterol efflux in both human macrophages and HepG2 cells through downregulation of ABCA1 and ABCG1 genes in human macrophages, and ABCA7 and ABCG1 genes in HepG2 cells. Glucagon declined ApoA-1 dependent cholesterol and phospholipid effluxes in human macrophages by supression of ABCA1, ABCA7 and ABCG1 gene expressions. Dexamethasone suppressed ApoA-1 dependent cholesterol and phospholipids effluxes in HepG2 cells through downregulation of ABCA1 and especially ABCA7 and ABCG1 genes expressions.