• 한국동물학회:뉴스레터
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• 제18권2호
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• pp.6-11
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• 2001

Peroxisome proliferator-activated receptor $\alpha$ (PPAR$\alpha$)에 대한 본격적인 연구는 고지혈증 치료제인 fibrate류의 약물들이 PPAR$\alpha$ activator로 작용한다는 사실이 밝혀짐으로써 크게 증대되었다. PPAR$\alpha$는 fibrate를 포함한 다양한 종류의 peroxisome proiferator (PP)에 의해 활성화되는데 이들을 쥐에 단기간 투여할 경우 간의 peroxisome수와 지 방산 산화효소의 유전자발현이 증가되고 장기간 투여 할 경우 간암을 발생시키지만, fibrate류의 약물들을 고지혈증 환자에게 투여 할 경우 간암을 발생시키지 않으므로써 PP에 대한 반응성에 있어서 species difference를 나타낸다 PPAR$\alpha$는 핵에 존재하는 orphan receptor로서 PP에 의해 활성화되어 9-cis-retinoic acid receptor(RXR)와 heterodimer를 이룬 후 target gene들의 upstream에 있는 peroxisome proliferator response element (PPRE)에 결합하여 target gene들의 발현을 조절한다. 지금까지 연구된 PPAR$\alpha$의 target gene들은 모두 lipid와 lipoprotein 대사를 조절하는 것으로 알려져 있으며, 이러 한 결과들을 기초로 lipid 대사 및 energy balance와 관련된 질병들 - 동맥경화증, 관상동맥질환, 비만, 제 2형 당뇨병 등에서 PPAR$\alpha$의 역할이 집중적으로 연구되고 있다. PPAR$\alpha$가 활성화되면 lipoprotein lipase와 HDL이 증가되고 apo C-III가 감소됨으로써 동맥경화증에 대한 예방적 기능을 나타내고, 몸무게를 감소시킴으로써 비만을 방지할 수 있으며, 인슐린 감수성을 증가시켜 제 2형 당뇨병의 치료효과를 가지는 것으로 보인다. 그러나 PPAR$\alpha$-null mouse에서는 이러한 효과들이 나타나지 않는 것으로 보아 이들 질병에서 PPAR$\alpha$가 중요한 역할을 하는 것으로 생각된다.

• Asian Pacific Journal of Cancer Prevention
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• 제13권5호
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• pp.1809-1817
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• 2012

Background: Gastric cancer is frequently lethal despite aggressive multimodal therapies, and new treatment approaches are therefore needed. Retinoids are potential candidate drugs: they prevent cell differentiation, proliferation and malignant transformation in gastric cancer cell lines. They interact with nuclear retinoid receptors (the retinoic acid receptors [RARs] and retinoid X receptors [RXRs]), which function as transcription factors, each with three subclasses, ${\alpha}$, ${\beta}$ and ${\gamma}$. At present, little is known about retinoid expression and influence on prognosis in gastric cancers. Patients and Methods: We retrospectively analyzed the expression of the subtypes RARa, $RAR{\beta}$, $RAR{\gamma}$, RXRa, $RXR{\beta}$, $RXR{\gamma}$ by immunohistochemistry in 147 gastric cancers and 51 normal gastric epithelium tissues for whom clinical follow-up data were available and correlated the results with clinical characteristics. In addition, we quantified the expression of retinoid receptor mRNA using real-time PCR (RT-PCR) in another 6 gastric adenocarcinoma and 3 normal gastric tissues. From 2008 to 2010, 80 patients with gastric cancers were enrolled onto therapy with all-trans-retinoic acid (ATRA). Results: RARa, $RAR{\beta}$, $RAR{\gamma}$ and $RXR{\gamma}$ positively correlated with each other (p < 0.001) and demonstrated significantly lower levels in the carcinoma tissue sections (p < 0.01), with lower $RAR{\beta}$, $RAR{\gamma}$ and RXRa expression significantly related to advanced stages (p < =0.01). Tumors with poor histopathologic grade had lower levels of RARa and $RAR{\beta}$ in different histological types of gastric carcinoma (p < 0.01). Patients whose tumors exhibited low levels of RARa expression had significantly lower overall survival compared with patients who had higher expression levels of this receptor (p < 0.001, HR=0.42, 95.0% CI 0.24-0.73), and patients undergoing ATRA treatment had significantly longer median survival times (p = 0.007, HR=0.41, 95.0% CI 0.21-0.80). Conclusions: Retinoic acid receptors are frequently expressed in epithelial gastric cancer with a decreased tendency of expression and RARa may be an indicator of a positive prognosis. This study provides a molecular basis for the therapeutic use of retinoids against gastric cancer.

• Toxicological Research
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• 제30권1호
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• pp.19-25
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• 2014

Licochalcone (LC), a major phenolic retrochalcone from licorice, has anti-inflammatory activity. This study investigated the effects of licochalcone A (LCA) and licochalcone E (LCE) on Liver X receptor-${\alpha}$ ($LXR{\alpha}$)-mediated lipogenic gene expression and the molecular mechanisms underlying those effects. LCA and LCE antagonized the ability of $LXR{\alpha}$ agonists (T0901317 or GW3965) to increase sterol regulatory element binding protein-1c (SREBP-1c) expression and thereby inhibited target gene expression (e.g., FAS and ACC) in HepG2 cells. Moreover, treatment with LCA and LCE impaired $LXR{\alpha}/RXR{\alpha}$-induced CYP7A1-LXRE-luciferase (CYP7A1) transactivation. The AMPK-Sirt1 signaling pathway is an important regulator of energy metabolism and, therefore, a potential therapeutic target for metabolic diseases, including hepatic steatosis. We found here that LCE increased AMPK phosphorylation and Sirt1 expression. We conclude that LC inhibits SREBP-1c-mediated hepatic lipogenesis via activation of the AMPK/Sirt1 signaling pathway.

• Journal of Microbiology and Biotechnology
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• 제25권2호
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• pp.247-254
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• 2015

In this presentation, I describe the expression and purification of the recombinant liver X receptor β-ligand binding domain proteins in E. coli using a commercially available double cistronic vector, pACYCDuet-1, to express the receptor heterodimer in a single cell as the soluble form. I describe here the expression and characterization of a biologically active heterodimer composed of the liver X receptor β-ligand binding domain and retinoid X receptor α-ligand binding domain. Although many of these proteins were previously seen to be produced in E. coli as insoluble aggregates or "inclusion bodies", I show here that as a form of heterodimer they can be made in soluble forms that are biologically active. This suggests that co-expression of the liver X receptor β-ligand binding domain with its binding partner improves the solubility of the complex and probably assists in their correct folding, thereby functioning as a type of molecular chaperone.

• BMB Reports
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• 제46권6호
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• pp.322-327
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• 2013

The ATP-binding cassette transporters ABCG5 and ABCG8 form heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion. To identify cis-regulatory elements of the two genes, we have cloned and analyzed twenty-three evolutionary conserved region (ECR) fragments using the CMV-luciferase reporter system in HepG2 cells. Two ECRs were found to be responsive to the Liver-X-Receptor (LXR). Through elaborate deletion studies, regions containing putative LXREs were identified and the binding of $LXR{\alpha}$ was demonstrated by EMSA and ChIP assay. When the LXREs were inserted upstream of the intergenic promoter, synergistic activation by $LXR{\alpha}/RXR{\alpha}$ in combination with GATA4, $HNF4{\alpha}$, and LRH-1, which had been shown to bind to the intergenic region, was observed. In conclusion, we have identified two LXREs in ABCG5/ABCG8 genes for the first time and propose that these LXREs, especially in the ECR20, play major roles in regulating these genes.

• Molecules and Cells
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• 제44권1호
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• pp.1-12
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• 2021

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is the master transcriptional regulator in adipogenesis. PPARγ forms a heterodimer with another nuclear receptor, retinoid X receptor (RXR), to form an active transcriptional complex, and their transcriptional activity is tightly regulated by the association with either coactivators or corepressors. In this study, we identified T-cell death-associated gene 51 (TDAG51) as a novel corepressor of PPARγ-mediated transcriptional regulation. We showed that TDAG51 expression is abundantly maintained in the early stage of adipogenic differentiation. Forced expression of TDAG51 inhibited adipocyte differentiation in 3T3-L1 cells. We found that TDAG51 physically interacts with PPARγ in a ligand-independent manner. In deletion mutant analyses, large portions of the TDAG51 domains, including the pleckstrin homology-like, glutamine repeat and proline-glutamine repeat domains but not the proline-histidine repeat domain, are involved in the interaction with the region between residues 140 and 506, including the DNA binding domain, hinge, ligand binding domain and activation function-2 domain, in PPARγ. The heterodimer formation of PPARγ-RXRα was competitively inhibited in a ligand-independent manner by TDAG51 binding to PPARγ. Thus, our data suggest that TDAG51, which could determine adipogenic cell fate, acts as a novel negative regulator of PPARγ by blocking RXRα recruitment to the PPARγ-RXRα heterodimer complex in adipogenesis.