• 대한의생명과학회지
• /
• 제12권2호
• /
• pp.65-72
• /
• 2006

Thiazolidinediones (TZDs) are widely used antidiabetic drugs that activate the nuclear peroxisome proliferator-activated receptor ${\gamma}(PPAR{\gamma})$, and thereby improve the metabolic abnormalities linking hypertriglyceridemia to diabetes, hyperglycemia, insulin resistance, and cardiovascular disease. To determine whether the $PPAR{\gamma}$ ligand troglitazone regulates lipid metabolism with sexual dimorphism, we examined the effects of troglitazone on circulating lipids, body weight and the expression of hepatic genes responsible for lipid metabolism in both sexes of C57BL/6J mice. Compared to mice fed a low fat control diet, both sexes of mice fed a troglitazone-treated low fat diet for 14 weeks did not exhibit changes in body weight gain, serum total cholesterol, HDL-cholesterol and LDL-cholesterol levels. However, serum triglycerides were significantly reduced in both sexes of mice, although these effects were more pronounced among males. Furthermore, troglitazone regulated the expression of hepatic genes critical for lipid and lipoprotein metabolism, the magnitudes of which were much higher in males compared to females, as evidenced by results for increased acyl-CoA oxidase and decreased apolipoprotein C-III mRMA levels. These results suggest that $PPAR{\gamma}$ activator troglitazone may exert sexually dimorphic control of serum triglycerides in part through the differential activation of $PPAR{\gamma}$ in liver between male and female mice.

• Biomolecules & Therapeutics
• /
• 제18권1호
• /
• pp.16-23
• /
• 2010

Adipocyte differentiation in human bone marrow mesenchymal stem cells (hBM-MSCs) is not as efficient as that in murine pre-adipocytes when induced by adipogenic agents including insulin, dexamethasone, and 3-isobutyl-1-methylxanthine (IDX condition). Therefore, the promotion of adipocyte differentiation in hBM-MSCs has been used as a cell culture model to evaluate insulin sensitivity for anti-diabetic drugs. In hBM-MSCs, $PPAR{\gamma}$ agonists or sulfonylurea anti-diabetic drugs have been added to IDX conditions to promote adipocyte differentiation. Here we show that troglitazone, a peroxisome proliferator-activated receptor-gamma ($PPAR{\gamma}$) agonist, significantly reduced the levels of anti-adipogenic $PGE_2$ in IDX-conditioned hBM-MSC culture supernatants when compared to $PGE_2$ levels in the absence of $PPAR{\gamma}$ agonist. However, there was no difference in the mRNA levels of cyclooxygenases (COXs) and the activities of COXs and prostaglandin synthases during adipocyte differentiation in hBM-MSCs with or without troglitazone. In hBM-MSCs, troglitazone significantly increased the mRNA level of 15-hydroxyprostaglandin dehydrogenase (HPGD) which can act to decrease $PGE_2$ levels in culture. These results suggest that the role of $PPAR{\gamma}$ activation in promoting adipocyte differentiation in hBM-MSCs is to reduce anti-adipogenic $PGE_2$ levels through the up-regulation of HPGD expression.

• 한방비만학회지
• /
• 제4권1호
• /
• pp.1-11
• /
• 2004

Objectives: The effects of peroxisome proliferator-activated receptor ${\gamma}2\;(PPAR{\gamma}2)$ Pro12Ala (P12A) polymorphism on body mass index (BMI) and type 2 diabetes are well documented; however, until now, only a few studies have evaluated the effects of this polymorphism on body fat distribution. This study was conducted to elucidate the effects of this polymorphism on computed tomography (CT)-measured body fat distribution and other obesity-related parameters in Korean female subjects. Methods & Results: The frequencies of $PPAR{\gamma}2$ genotypes were: PP type, 93.0%; PA type, 6.8%; and AA type, 0.2%. The frequency of the A allele was 0.035. Body weight (P .012), BMI (P .012), and waist-to-hip ratio (WHR) (P .001) were significantly higher in subjects with PA/AA compared with subjects with PP. When body composition was analyzed by bioimpedance analysis, lean body mass and body water content were similar between the 2 groups. However, body fat mass (P .003) and body fat percent (P .025) were significantly higher in subjects with PA/AA compared with subjects with PP. Among overweight subjects with BMI of greater than 25, PA/AA was associated with significantly higher abdominal subcutaneous fat (P .000), abdominal visceral fat (P .031), and subcutaneous upper and lower thigh adipose tissue (P .010 and .013). However, among lean subjects with BMI of less than 25, no significant differences associated with $PPAR{\gamma}2$ genotype were found, suggesting that the fat-accumulating effects of the PA/AA genotype were evident only among overweight subjects, but not among lean subjects. When serum lipid profiles, glucose, and liver function indicators were compared among overweight subjects, no significant difference associated with $PPAR{\gamma}2$ genotype was found. Changes in body weight, BMI, WHR, and body fat mass were measured among overweight subjects who finished a 1-month weight lose program of a hypocaloric diet and exercise; no significant differences associated with $PPAR{\gamma}2$ genotype were found. Conclusions: The results of this study suggest that the $PPAR{\gamma}2$ PA/AA genotype is associated with increased subcutaneous and visceral fat areas in overweight Korean female subjects, but does not significantly affect serum biochemical parameters and outcomes of weight loss programs.

• 동의생리병리학회지
• /
• 제20권1호
• /
• pp.93-97
• /
• 2006

To investigate whether GyeongshinhaeGihwan 1(GGT1), an anti-obesity herbal medicine widely used in oriental medicine, regulates the expression of obesity-related genes, we measured the changes in mRNA levels of these genes by GGT1 in human growth hormone transgenic (hGHTg) obese male rats, and these effects by GGT1 were compared with those of reductil (RD), an anti-obesity drug approved by FDA. Rats received once daily oral administrations of autoclaved water, RD, or GGT1 for 8 weeks. At the end of study, rats were sacrificed and tissues were harvested. Total RNA from adipose tissue, liver and kidney was prepared and the mRNA levels for LPL (lipoprotein lipase), PPAR $\gamma$ (peroxisome proliferator activated receptor-gamma), PPAR$\delta$ (peroxisome proliferator activated receptor-delta), leptin, TNF$\alpha$ (tumor necrosis factor-alpha), and internal standard G3PDH (glyceraldehyde-3- phosphate dehydrogenase) were analyzed by RT-PCR. PPAR$\gamma$ mRNA levels of liver and kidney were decreased in drug-treated groups compared with control group and the decrease of PPAR$\gamma$ expression was more prominent in GGT1 group than in RD group, suggesting that GGT1 is effective in the inhibition of adipogenesis and lipid storage by decreasing the PPAR$\gamma$ expression. In contrast, PPAR$\delta$ mRNA levels of adipose tissue and kidney were increased by RD and GGT1 , and the magnitudes of increase were higher in GGT1 group than in RD group, indicating that GGT1 stimulates fatty acid oxidation and energy metabolism by activating PPAR$\delta$ expression, Compared with control and RD groups, GGT1 group had higher concentrations of serum leptin, a well-known inhibitor of appetite. However, The mRNA levels of leptin, LPL, and TNF$\alpha$ were not changed by GGT1 and RD, compared with DW. These results demonstrate that GGT1 not only decreases PPAR$\gamma$ expression of liver and kidney, but also increases PPAR$\delta$ expression of adipose tissue and kidney, leading to the regulation of obesity and that these effects were more pronounced in GGT1 group compared with RD group. In addition, GGT1 seems to prevent obesity by increasing the serum leptin levels.

• 생명과학회지
• /
• 제28권7호
• /
• pp.857-863
• /
• 2018

본 연구는 함초의 보충식이가 고지방식이 흰쥐의 혈청 및 조직의 중성지방 농도와 골격근 내 $PGC-1{\alpha}$와 $PPAR-{\gamma}$ 단백질 발현에 미치는 영향에 대하여 연구하였다. SD계 수컷 흰쥐를 대조군(CD, n=8), 고지방식이군(HD, n=8), 고지방식이+ 5% 함초 보충식이군(SD, n=8)으로 분류하여 8주간 사육하였다. 그 결과 SD군의 지방조직 중량은 HD군에 비해 약 25%정도 유의하게 감소한 반면 골격근의 중량은 SD군이 HD군에 비해 약 5%정도 유의하게 증가하였다(p<0.01). SD군의 혈청과 간장 내 중성지방은 HD군에 비해 약 20% 유의하게 감소하였다(p<0.05). SD군의 골격근 내 $PGC-1{\alpha}$ 와 $PPAR-{\gamma}$ 단백질 발현은 HD군에 비해 1.5배 유의하게 높게 나타났다(p<0.01). 이상의 결과로 부터 함초 보충은 골격근 내 $PGC-1{\alpha}$와 $PPAR-{\gamma}$ 단백질 발현의 증가를 통하여 지방감소 및 근육량 증가에 효과적이었음이 시사되었다.

• BMB Reports
• /
• 제47권11호
• /
• pp.599-608
• /
• 2014

As the prevalence of obesity has increased explosively over the last several decades, associated metabolic disorders, including type 2 diabetes, dyslipidemia, hypertension, and cardiovascular diseases, have been also increased. Thus, new strategies for preventing and treating them are needed. The nuclear peroxisome proliferator-activated receptors (PPARs) are involved fundamentally in regulating energy homeostasis; thus, they have been considered attractive drug targets for addressing metabolic disorders. Among the PPARs, $PPAR{\gamma}$ is a master regulator of gene expression for metabolism, inflammation, and other pathways in many cell types, especially adipocytes. It is a physiological receptor of the potent anti-diabetic drugs of the thiazolidinediones (TZDs) class, including rosiglitazone (Avandia). However, TZDs have undesirable and severe side effects, such as weight gain, fluid retention, and cardiovascular dysfunction. Recently, many reports have suggested that $PPAR{\gamma}$ could be modulated by post-translational modifications (PTMs), and modulation of PTM has been considered as novel approaches for treating metabolic disorders with fewer side effects than the TZDs. In this review, we discuss how PTM of $PPAR{\gamma}$ may be regulated and issues to be considered in making novel anti-diabetic drugs that can modulate the PTM of $PPAR{\gamma}$.

• 생명과학회지
• /
• 제13권3호
• /
• pp.314-323
• /
• 2003

지금까지 estrogen 호르몬이 유방암의 발생과 진전에 관여한다는 사실을 뒷받침 할 수 있는 여러 가지 증거가 제시되어 왔지만, 암화에 관여하고 있는 estrogen의 분자생물학적 작용기전에 대해서는 아직 명확히 알려져 있지 않다. 유방암 세포의 발암현상은 다양한 핵 수용체들과 이들 각각의 신호전달경로들 사이의 기능적 상호교류 (Functional Cross-talk)에 의해 조절되는 것으로 추측되고 있다. 그러므로, 유방암세포의 성장과 증식에 관여하는 신호전달경로중에서 estrogen의 작용을 조절할 수 있는 핵 수용체를 밝혀내고, 이러한 수용체와 estrogen receptor사이에 어떠한 기능적 상호교류가 일어나는지를 규명하는 것은 암화와 관련된 estrogen의 분자생물학적 작용기전을 이해하는 데 중요한 진전을 가져올 수 있다. 따라서 본 연구의 목적은 유방암세포 내에서 estrogen의 작용이 xenobiotic nuclear receptor에 의해 조절되는지를 규명하기 위하여, 두 종류의 유방암세포인 estrogen receptor가 발현되는 MCF-7 세포와 ER의 발현이 일어나지 않는 MDA-MB-231세포를 배양하여, 에스트로겐에 의해 전사가 촉진되는 보고유전자의 발현이 CAR, SXR, 그리고 PPAR${\gamma}$에 의해서 어떻게 영향을 받는지를 조사하고 그 결과를 간암세포에서의 반응과 비교 분석하였다. 최근에 보고된 연구결과와 일치하게, xenobiotic nuclear receptor가 간세포에서 일어나는 에스트로겐 수용체의 신호전달경로에 영향을 줄 수 있음을 확인하였다. PPAR${\gamma}$를 제외한 핵 수용체 CAR와 SXR은 ER의 전사활성 효과를 현저하게 또는 어느 정도 각각 감소시켰다. Hep G2세포에서와는 달리 유방암세포에서는 조사된 세가지의 xenobiotic 핵 수용체가 ER의 전사활성에 그다지 영향을 미치지 않거나 유방암세포의 종류와 각각의 수용체에 따라서 다소 촉진하는 경향을 나타내었다. MCF-7 세포에서는 CAR와 PPAR${\gamma}$을 제외한 SXR이 ER의 transactivation 효과를 약간 촉진한 반면 MDA-MB-231세포는 SXR을 제외한 CAR와 PPAR${\gamma}$에 의해 ER의 transactivation 효과가 약간 증가되는 경향을 보였다. 이러한 결과는 유방암세포에서는 CAR, SXR, PPAR${\gamma}$과 같은 xenobiotic nuclear receptor에 의한 ER transactivation 효과가 간암세포와는 다르게 나타나며, 유방암의 종류에 따라서 endogenous CAR, SXR, PPAR${\gamma}$수용체가 다르게 발현됨으로써 이들에 대한 반응이 서로 상이한 특징을 나타낼 수 있을 것으로 사료된다. 따라서 estrogen receptor에 의해 매개되는 estrogn의 전사활성조절기전이 표적세포에 따라 다른 경로를 포함 할 수 있음을 시사한다.

• BMB Reports
• /
• 제36권2호
• /
• pp.207-213
• /
• 2003

Peroxisome proliferator-activated receptors (PPARs) are orphan nuclear hormone receptors that are known to control the expression of genes that are involved in lipid homeostasis and energy balance. PPARs activate gene transcription in response to a variety of compounds, including hypolipidemic drugs. Most of these compounds have high affinity to the ligand-binding domain (LBD) of PPARs and cause a conformational change within PPARs. As a result, the receptor is converted to an activated mode that promotes the recruitment fo co-activators such as the steroid receptor co-activator-1 (SRC-1). Based on the activation mechanism of PPARs (the ligand binding to $PPAR{\gamma}$ induces interactions of the receptor with transcriptional co-activators), we performed Western blot and ELISA. These showed that the indomethacin, a $PPAR{\gamma}$ ligand, increased the binding between $PPAR{\gamma}$ and SRC-1 in a ligand dose-dependent manner. These results suggested that the in vitro conformational change of $PPAR{\gamma}$ by ligands was also induced, and increased the levels of the ligand-dependent interaction with SRC-1. Collectively, we developed a novel and useful ELISA system for the mass screening of $PPAR{\gamma}$ ligands. This screening system (based on the interaction between $PPAR{\gamma}$ and SRC-1) may be a promising system in the development of drugs for metabolic disorders.

• The Korean Journal of Physiology and Pharmacology
• /
• 제15권2호
• /
• pp.83-88
• /
• 2011

A large body of evidence has indicated that induction of endogenous antioxidative proteins seems to be a reasonable strategy for delaying the progression of cell injury. In our previous study, cilostazol was found to increase the expression of the antioxidant enzyme heme oxygenase-1 (HO-1) in synovial cells. Thus, the present study was undertaken to examine whether cilostazol is able to counteract tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$)-induced cell death in endothelial cells via the induction of HO-1 expression. We exposed human umbilical vein endothelial cells (HUVECs) to TNF-${\alpha}$ (50 ng/ml), with or without cilostazol ($10{\mu}M$). Pretreatment with cilostazol markedly reduced TNF-${\alpha}$-induced viability loss in the HUVECs, which was reversed by zinc protoporphyrine IX (ZnPP), an inhibitor of HO-1. Moreover, cilostazol increased HO-1 protein and mRNA expression. Cilostazol-induced HO-1 induction was markedly attenuated not only by ZnPP but also by copper-protoporphyrin IX (CuPP). In an assay measuring peroxisome proliferator-activated receptor-${\gamma}$ (PPAR-${\gamma}$) transcription activity, cilostazol directly increased PPAR-${\gamma}$ transcriptional activity which was completely abolished by HO-1 inhibitor. Furthermore, increased PPAR-${\gamma}$ activity by cilostazol and rosiglitazone was completely abolished in cells transfected with HO-1 siRNA. Taken together, these results indicate that cilostazol up-regulates HO-1 and protects cells against TNF-${\alpha}$-induced endothelial cytotoxicity via a PPAR-${\gamma}$-dependent pathway.

• Bulletin of the Korean Chemical Society
• /
• 제33권7호
• /
• pp.2219-2223
• /
• 2012

Human peroxisome proliferator-activated receptor gamma ($hPPAR{\gamma}$) has been implicated in numerous pathologies, including obesity, diabetes, and cancer. Previously, we verified that amentoflavone is an activator of $hPPAR{\gamma}$ and probed the molecular basis of its action. In this study, we investigated the mechanism of action of amentoflavone in cancer cells and demonstrated that amentoflavone showed strong cytotoxicity against MCF-7 and HeLa cancer cell lines. We showed that $hPPAR{\gamma}$ expression in MCF-7 and HeLa cells is specifically stimulated by amentoflavone, and suggested that amentoflavone-induced cytotoxic activities are mediated by activation of $hPPAR{\gamma}$ in these two cancer cell lines. Moreover, amentoflavone increased PTEN levels in these two cancer cell lines, indicating that the cytotoxic activities of amentoflavone are mediated by increasing of PTEN expression levels due to $hPPAR{\gamma}$ activation.