• Asian Pacific Journal of Cancer Prevention
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• 제14권11호
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• pp.6761-6767
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• 2013

The nuclear receptor, peroxisome proliferator-activated receptor gamma ($PPAR{\gamma}$), is expressed in various cancer cells including breast, prostate, colorectal and cervical examples. An endogenous ligand of $PPAR{\gamma}$, 15-deoxy-${\Delta}^{12,14}$ prostaglandin $J_2$ (PGJ2), is emerging as a potent anticancer agent but the exact mechanism has not been fully elucidated, especially in breast cancer. The present study compared the anticancer effects of PGJ2 on estrogen receptor alpha ($ER{\alpha}$)-positive (MCF-7) and $ER{\alpha}$-negative (MDA-MB-231) human breast cancer cells. Based on the reported signalling cross-talk between $ER{\alpha}$ and $ER{\alpha}$, the effect of the $ER{\alpha}$ ligand, $17{\beta}$-estradiol (E2) on the anticancer activities of PGJ2 in both types of cells was also explored. Here we report that PGJ2 inhibited proliferation of both MCF-7 and MDA-MB-231 cells by inducing apoptotic cell death with active involvement of mitochondria. The presence of E2 potentiated PGJ2-induced apoptosis in MCF-7, but not in MDA-MB-231 cells. The $ER{\alpha}$ antagonist, GW9662, failed to block PGJ2-induced activities but potentiated its effects in MCF-7 cells, instead. Interestingly, GW9662 also proved capable of inducing apoptotic cell death. It can be concluded that E2 enhances $ER{\alpha}$-independent anticancer effects of PGJ2 in the presence of its receptor.

• 생약학회지
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• 제45권3호
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• pp.194-199
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• 2014

The roots of Paeonia lactiflora (PL) has been traditionally used as analgesic, spasmolytic and tonic in Korea, China, and Japan. As part of a search for herbal medicine to treat diabetes and obesity, we confirmed hypoglycemic effect of PL through high fat diet-induced obese and diabetic mice experiments in vivo. Treatment of ethanolic extract from PL led to a significant decrease in glucose level, which is comparable to that of an antidiabetic drug metformin. In addition, PL selectively stimulates the transcriptional activities of both peroxisome proliferator-activated receptor $(PPAR){\alpha}$ and ${\gamma}$, and inhibits enzymatic activity of protein tyrosine phosphatase 1B (PTP1B), which are predicted to be therapeutic target in treatment of type2 diabetes and obesity. Especially, the n-hexane fraction (Hx) from PL ethanol extract showed more potent activities on $PPAR{\alpha}$ and than others and exihibited moderate inhibitory activity against PTP1B.

• 한국발생생물학회지:발생과생식
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• 제22권4호
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• pp.351-360
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• 2018

The adipogenesis is a maturation process of pre-adipocyte cell into mature lipid-filled adipocyte cell. The adipogenesis begins at the late prenatal stage and continues until the early postnatal age. Because the adipogenesis and formation of adipose tissue persist during postnatal period and are precisely regulated by the action of numerous gene products, the present research was attempted to determine the expressional patterns of adipose tissue-associated genes in the rat epididymal fat pad at different postnatal ages, from 7 days to 2 years of ages, using a quantitative real-time PCR analysis. The basal expression levels of CCAAT/enhancer binding protein gamma, sterol regulatory element binding transcription factor 1, fatty acid binding protein 4, adiponectin, leptin, and resistin at the early postnatal ages were significantly lower than those at the elderly ages, even though a fluctuation of expressional levels was observed at some ages. The lowest expressional level of delta like non-canonical Notch ligand 1 was detected at 44 days and 5 months of ages. The expression of peroxisome proliferator-activated receptor gamma ($PPAR{\gamma}$) was the highest at 44 days of age, followed by a diminished expression of $PPAR{\gamma}$ at the elderly ages. These results indicate the existence of a complex regulatory mechanism(s) for expression of adipose tissueassociated genes in the rat epididymal fat during postnatal period.

• Asian-Australasian Journal of Animal Sciences
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• 제22권10호
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• pp.1420-1428
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• 2009

In this study we cloned and characterized a novel lipid-accumulating gene, the oxidized low-density lipoprotein receptor 1 (OLR1), which is associated with lipogenesis. We analyzed the gene structure and detected the mRNA transcriptional expression levels in pig adipose tissues at different months of age (MA) and in different economic types (lean type and obese type) using real-time fluorescence quantitative PCR. OLR1 expression profile in different tissues of pig was analyzed. Finally, we studied the correlation between OLR1 and lipid metabolism related genes including peroxisome proliferator-activated $receptor{\gamma}2$ ($PPAR{\gamma}2$), fatty acid synthetase (FAS), triacylglycerol hydrolase (TGH), CAAT/enhancer binding protein $\alpha$ ($C/EBP{\alpha}$) and sterol regulatory element binding protein-1c (SREBP-1c). Results indicated that the OLR1 gene of the pig exhibited the highest homology with the cattle (84%), and the lowest with the mouse (27%). The signal peptide located from amino acid 38 to 60 and the domain from amino acid 144 to 256 were shared by the C-type lectin family. The expression level of OLR1 in pig lung was exceedingly higher than other tested tissues (p<0.01). In pig adipose tissue, the expression level of OLR1 mRNA increased significantly with growth (p<0.01). The expression level of OLR1 mRNA in obese-type pigs was significantly higher than that of lean-type pigs of the same monthly age (p<0.05). In adipose tissue, the expression of OLR1 correlated with $PPAR{\gamma}2$, FAS and SREBP-1c, but not TGH or C/EBP${\alpha}$. In conclusion, OLR1 was highly associated with fat deposition and its transcription, as suggested by high correlations, was possibly regulated by $PPAR{\gamma}2$ and SREBP-1c.

• 생명과학회지
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• 제24권5호
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• pp.476-484
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• 2014

비만은 감염원 없이 진행되는 낮은 수준의 만성적인 전신성 염증상태로 간주되며, 만성대사질환의 원인이 된다. 본 연구에서는 미나리를 발효하여 만든 식초가 3T3-L1 지방전구세포의 분화 및 RAW 264.7 세포에서의 항염증 효과에 미치는 영향을 확인하였다. MDI (IBMX, dexamethasone, insulin)에 의해 분화가 유발된 3T3-L1 지방전구세포에 대한 미나리 식초의 분화 억제능을 Oil-red-O staining을 통해 확인하였으며, western blot법을 통해 지방세포 형성 시 중요한 전사인자인 peroxisome proliferator-activated receptor-${\gamma}$ (PPAR-${\gamma}$)와 CCAAT-enhancer-binding protein ${\alpha}$ ($C/EBP{\alpha}$)의 발현을 감소시키는 것으로 나타났다. 또한, 미나리 식초가 lipopolysaccharide (LPS)에 의해 염증이 유발 된 RAW 264.7 세포의 nitric oxide (NO) 생성을 억제시켰으며, inducible NO synthase (iNOS)와 cyclooxygenase-2 (COX-2)의 단백질 발현을 감소시키는 것을 확인하였다. 이러한 결과들을 통해 미나리 발효 식초는 지방세포 분화와 염증 억제 효과를 가지고 있음을 확인하였다. 따라서 미나리 발효 식초는 대사성 질환을 예방할 수 있는 천연물 소재로 이용 가능할 것으로 생각된다.

• 생명과학회지
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• 제28권7호
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• pp.765-771
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• 2018

$PPAR{\gamma}$는 지방세포의 분화를 조절하는 핵심적인 전사 인자로서 이를 조절하는 후성유전학적 조절 기전이 비만억제 연구에서 중요하게 주목 받고 있다. 선행연구에서 CACUL1이 $PPAR{\gamma}$의 전사 활성 및 지방세포의 분화를 억제하는 corepressor로서 작용함을 밝힌 바 있으며 본 연구에서는 CACUL1의 새로운 결합 단백질로 발굴된 protein arginine methyltransferase 5 (PRMT5)의 $PPAR{\gamma}$ 조절 기능을 분석하였다. PRMT5가 CACUL1과 결합함을 immunoprecipitation assay in vivo와 GST-pull down assay in vitro를 통하여 확인하였다. Luciferase reporter assay 결과로 두 단백질이 상호 협력하여 $PPAR{\gamma}$의 전사 활성을 억제함을 확인하였다. PRMT5가 안정적으로 과발현 또는 knockdown되는 3T3-L1 세포주를 제작하여 지방세포 분화에 미치는 영향을 분석한 결과, PRMT5가 3T3-L1세포의 지방세포 분화를 억제함을 증명하였다. 같은 맥락으로 PRMT5는 $PPAR{\gamma}$의 타겟 유전자인 Lpl과 aP2의 발현을 억제하는 것을 RT-qPCR로 확인하였다. 이상의 연구 결과로 PRMT5이 CACUL1과 결합하여 $PPAR{\gamma}$의 전사 활성을 방해, 나아가 지방세포의 분화를 억제하는 기존에 알려지지 않은 분자적 기전을 처음으로 밝혔다. 따라서, PRMT5 효소 활성의 조절은 비만 억제를 위한 약물 개발에 단서를 제공할 것이다.

• 한국식품과학회지
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• 제49권2호
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• pp.192-202
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• 2017

황정 주정 추출물 ID1216의 고지방 식이 유도 비만 마우스에서의 체중 증가 억제 효과에 대한 분자생물학적 기전을 확인하고자 단백질과 mRNA 수준에서 지질 및 에너지 대사 관련 유전자들의 발현 변화를 관찰하였다. 본 연구에서 확인된 지표들 간의 상호 작용 및 ID1216의 조절 여부에 관해 Fig. 10에 나타내었다. 실험 결과 ID1216은 고지방 식이 유도 비만 마우스에서 체중 증가 억제를 나타내었으며, 비만 대사 관련 pathway의 상위 유전자로 사료되는 SIRT1과 AMPK의 발현을 조절하는 것으로 나타났다. 활성화된 SIRT1과 AMPK는 $PGC1{\alpha}$의 활성화에 관여하고, 이를 통해 열 발산 대사와 관련된 UCP 단백질과 핵 수용체 단백질인 $PPAR{\alpha}$의 발현이 백색지방, 갈색지방, 간 및 근육에서 증가되는 것이 확인되었다. 각 조직 별로 RT-PCR을 진행한 결과에서는 $PPAR{\alpha}$의 하위 유전자인 aP2, ACO, Acadl, Acadm, CPT1a, CPT1b의 mRNA 발현 수준을 향상시켜 주어 ID1216이 지방산 산화 대사인 ${\beta}$-oxidation의 활성화에 기여할 가능성을 보여주었다. 이와는 별개로 ID1216은 중성지질을 분해하는 것으로 알려진 ATGL의 mRNA 발현 또한 증가시키는 것으로 확인되었다. 본 연구를 통해 ID1216이 조직에 따라 지질 및 에너지 대사와 관련된 인자의 발현에 영향을 주는 체중 조절에 효과적인 소재임을 알 수 있었다. 또한 비만 치료제와의 기전적 차별성과 생약 특유의 섭취 안전성을 특징으로 하는 체중 또는 체지방 조절 기능성 소재로의 활용 가능성도 충분히 가지고 있음을 확인할 수 있었다.

• 한국식품과학회지
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• 제48권4호
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• pp.384-391
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• 2016

선행연구(12,13)에 따르면 10주간 ID1216을 투여한 비만 마우스에서 체중과 체지방이 감소하였고 이는 SIRT1-$PGC1{\alpha}$의 발현을 조절하여 나타나는 것으로 확인하였다. 본 연구는 $SIRT1-PGC1{\alpha}-PPAR{\alpha}$의 하위 기전인 UCPs, ACO, aP2의 발현 조절에 ID1216이 영향을 미쳐 그 효과를 나타내는 것을 추가로 확인한 것에 의미가 있다. 또한 10주간 ID1216을 투여한 비만 마우스의 혈액 분석 결과에서도 혈중 중성지방, LDL, HDL total cholesterol등의 혈중 지방질 수치가 개선됨과 동시에 free fatty acid의 농도는 감소하였는데 이는 ID1216이 HSL과 같은 지방질분해효소의 활성을 조절하여 중성지방의 분해과정에 관여하기는 하나 에너지 대사와 지방산 산화 과정에도 복합적으로 관여하여 최종적으로 나타내는 비만 대사 조절 효과에 의한 것으로 판단된다. 따라서 ID1216은 $SIRT1-PGC1{\alpha}-PPAR{\alpha}$ pathway를 촉진시켜 세포와 조직 수준에서 열발생(thermogenesis)에 관여하는 유전자인 UCP1, UCP2, UCP3의 발현을 증가시켰고 ${\beta}$-oxidation에 관여하는 유전자인 ACO와 aP2의 발현도 증가시켰으며 또한 지방분해(lypolysis)에 관여하는 유전자인 ATGL과 HSL의 발현을 증가시키는 분자생물학적 기전을 나타내어 체지방 감소 효과를 나타내는 것으로 확인되었다.

• Yonsei Medical Journal
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• 제59권9호
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• pp.1096-1106
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• 2018

Purpose: Alzheimer's disease (AD) is the sixth most common cause of death in the United States. MicroRNAs have been identified as vital players in neurodegenerative diseases, including AD. microRNA-128 (miR-128) has been shown to be dysregulated in AD. This study aimed to explore the roles and molecular mechanisms of miR-128 in AD progression. Materials and Methods: Expression patterns of miR-128 and peroxisome proliferator-activated receptor gamma ($PPAR-{\gamma}$) messenger RNA in clinical samples and cells were measured using RT-qPCR assay. $PPAR-{\gamma}$ protein levels were determined by Western blot assay. Cell viability was determined by MTT assay. Cell apoptotic rate was detected by flow cytometry via double-staining of Annexin V-FITC/PI. Caspase 3 and $NF-{\kappa}B$ activity was determined by a Caspase 3 Activity Assay Kit or $NF-{\kappa}B$ p65 Transcription Factor Assay Kit, respectively. Bioinformatics prediction and luciferase reporter assay were used to investigate interactions between miR-128 and $PPAR-{\gamma}$ 3'UTR. Results: MiR-128 expression was upregulated and $PPAR-{\gamma}$ expression was downregulated in plasma from AD patients and $amyloid-{\beta}$ $(A{\beta})-treated$ primary mouse cortical neurons (MCN) and Neuro2a (N2a) cells. Inhibition of miR-128 decreased $A{\beta}-mediated$ cytotoxicity through inactivation of $NF-{\kappa}B$ in MCN and N2a cells. Moreover, $PPAR-{\gamma}$ was a target of miR-128. $PPAR-{\gamma}$ upregulation attenuated $A{\beta}-mediated$ cytotoxicity by inactivating $NF-{\kappa}B$ in MCN and N2a cells. Furthermore, $PPAR-{\gamma}$ downregulation was able to abolish the effect of anti-miR-128 on cytotoxicity and $NF-{\kappa}B$ activity in MCN and N2a cells. Conclusion: MiR-128 inhibitor decreased $A{\beta}-mediated$ cytotoxicity by upregulating $PPAR-{\gamma}$ via inactivation of $NF-{\kappa}B$ in MCN and N2a cells, providing a new potential target in AD treatment.

• Journal of Nutrition and Health
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• 제57권2호
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• pp.171-184
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• 2024

Purpose: Although activating thermogenic adipocytes is a promising strategy to reduce the risk of obesity and related metabolic disorders, emerging evidence suggests that it is difficult to induce adipocyte thermogenesis in obesity. Therefore, this study aimed to investigate the regulation of adipocyte thermogenesis in diet-induced obesity. Methods: Adipose progenitor cells were isolated from the white and brown adipose tissues of control diet (CD) or high-fat diet (HFD) fed mice, and fully differentiated white and brown adipocytes were treated with β-agonists or 18-carbon fatty acids for β-adrenergic activation or peroxisome proliferator-activated receptor (PPAR) activation. Results: Compared to the CD-fed mice, the expression of uncoupling protein 1 (Ucp1) was lower in the white adipose tissue of the HFD-fed mice; however, this was not observed in the brown adipose tissue. The expression of peroxisome proliferator-activated receptor gamma (Pparg) was lower in the brown adipose progenitor cells isolated from HFD-fed mice than in those isolated from the CD-fed mice. Norepinephrine (NE) treatment exerted lesser effect on peroxisome proliferator-activated receptor-γ coactivator (Pgc1a) upregulation in white adipocytes derived from HFD-fed mice than those derived from CD-fed mice. Regardless which 18-carbon fatty acids were treated, the expression levels of thermogenic genes including Ucp1, Pgc1a, and positive regulatory domain zinc finger region protein 16 (Prdm16) were higher in the white adipocytes derived from HFD-fed mice. Oleic acid (OLA) and γ-linolenic acid (GLA) upregulated Pgc1a expression in white adipocytes derived from HFD-fed mice. Brown adipocytes derived from HFD-fed mice had higher expression levels of Pgc1a and Prdm16 compared to their counterparts. Conclusion: These results indicate that diet-induced obesity may downregulate brown adipogenesis and NE-induced thermogenesis in white adipocytes. Also, HFD feeding may induce thermogenic gene expression in white and brown primary adipocytes, and OLA and GLA could augment the expression levels.