PPARγ 와 LXRα 기능억제보조자로서 고아핵수용체 DAX-1 의 새로운 기능동정 = Identification of Novel Function of Orphan Nuclear Receptor DAX-1 as a Corepressor of PPARγ and LXRα

다국어 초록 (Multilingual Abstract)

Nuclear receptors (NRs) activate the transcription of target genes through its direct interactions with diverse transcriptional coactivator complexes. Dosage-sensitive sex reversal (DSS), Adrenal Hypoplasia Congenita (AHC)-critical region on the X chromosome, gene 1 (DAX-1;NR0B1), is an atypical NR which functions primarily as a transcriptional corepressor of other NRs via heterodimerization. Peroxisome proliferator-activated receptor (PPAR; NR1C3) γ is a ligand-dependent NR which performs a key function in lipid metabolism, inflammation, and adipogenesis. In this first study, I evaluated a novel cross-talk mechanism between DAX-1 and PPARγ, and elucidated a role for DAX-1 in adipocyte differentiation. Transient transcription assays demonstrated that DAX-1 inhibits the transactivity of PPARγ in a dose-dependent manner. DAX-1 directly interacted with the DNA binding domain (DBD)/hinge region of PPARγ in a ligand-independent manner, and competed with the PPARγ coactivator (PGC)-1α for binding to PPPRγ. Endogenous levels of DAX-1 were significantly lower in differentiated 3T3-L1 adipocytes and primary adipocytes, as compared to preadipocytes or stromal vascular cells. Using a retroviral expression system, I demonstrated that DAX-1 overexpression downregulates the expression of PPARγ target genes, resulting in an attenuation of adipogenesis in 3T3-L1 cells.
In addition to PPARγ, I further investigated relationship between DAX-1 and Liver X receptor (LXR;NR1H3) α. LXRα have been shown to regulate cholesterol metabolism and hepatic fatty acid biosynthesis. Here I show that DAX-1 also inhibits the transactivity of LXRα and mainly interacted with ligand binding domain (LBD) of LXRα in a ligand-dependent manner. DAX-1 competed with the steroid receptor coactivator (SRC)-1 for binding to LXRα.
These results suggest that DAX-1 acts as a corepressor of PPARγ and LXRα and performs a potential function in the regulation of PPARγ-mediated cellular differentiation and LXRα-driven fatty acid biosynthesis.

목차 (Table of Contents)

• Introduction 1
• 1. Nuclear receptors 1
• 2. Orphan nuclear receptor DAX-1 3
• 3. Peroxisome proliferator-activated receptor γ 4
• 4. Liver X receptor α 6
• Materials and Methods 8
• Results 17
• Chapter 1. The orphan nuclear receptor DAX-1 acts a transcriptional corepressor of PPARγ 17
• Chapter 2. The DAX-1 also interacts with LXRα and represses its transcriptional activity 43
• Discussion 56
• References 63
• Abstract in Korean 75