• Environmental Mutagens and Carcinogens
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• v.17 no.2
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• pp.78-91
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• 1997

Peroxisome is a single membrane-bounded organelle found in hepatic parenchymal cells and kidney tubular epithelial cells. A number of enzymes exist in peroxisome contributing to anabolic and catabolic peroxisomal functions. Extramitochontriai $\beta$-oxidation of fatty acid is a major function of peroxisome. Peroxisomes can be proliferated by many structually unrelated compounds such as hypolipidemic drugs, plasticizers, pesticides, some pharmaceutical agents and high fat diet. These chemicals, called peroxisome proliferators, act via the peroxisome proliferator activated receptor, to induce peroxisome proliferation, hepatomegaly and hepatocellular carcinoma in rodent. The clear mechanisms of peroxisome proliferator-induced hepatocarcinogenesis have been not demonstrated. Since they are not genotoxic, biochemical changes or changes in gene expressions may be involved. A free radical theory has been suggested based on the finding of oxidative damages of macromolecules by hydrogen peroxide released in the peroxisomal $\beta$-oxidation of fatty acid. Increased cell proliferation by a peroxisome proliferator has been also thought to be an important factor in the hepatocarcinogenesis as suggested in other cases of nongenotoxic carcinogenesis. The alternation of eicosanoid concentrations by peroxisome proliferators may be important in the peroxisome proliferator-induced hepatocarcinogenesis since peroxisome proliferators decrease the concentration of eicosanoids, and the peroxisome proliferator ciprofibrate-eicosanoid combination is comitogenic and costimulates some mitogenic signals in hepatocytes. All of proposed mechanisms should be considered in the peroxisome prolifrator-induced hepatocarcinogenesis.

• Archives of Pharmacal Research
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• v.21 no.2
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• pp.120-127
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• 1998

Peroxisome proliferators induce hepatic peroxisome proliferation and hepatic tumors in rodents. These chemicals increase the expression of the peroxisomal $\beta$-oxidation pathway and the cytochrome P-450 4A family, which metabolizes lipids, including eicosanoids. Peroxisome proliferators transiently induce increased cell proliferation in vivo. However, peroxisome proliferators are weakly mitogenic and are not co-mitogenic with epidermal growth factor (EGF) in cultured hepatocytes. Earlier study found that the peroxisome proliferator ciprofibrate is cornitogenic with eicosanoids. In order to study possible mechanisms of the comitogenicity of peroxisome proliferator ciprofibrate and eicosanoids' we hypothesized that the co-mitogenicity may result from synergistic or additive increases of second messengers in mitogenic signal pathways. We therefore examined the effect of the peroxisome proliferator ciprofibrate, prostaglandin $F_2_{\alpha}$($PGF_2{\alpha}$) and the combination of ciprofibrate and $PGF_2{\alpha}$ with or without growth factors on the protein kinase C (PKC) activity, and inositol-1, 4, 5-triphosphate ($IP_{3-}$) and intracellular calcium ($[Ca^{2+}]_i$) concentrations in cultured rat hepatocytes. The combination of ciprofibrate and $PGF_2{\alpha}$ significantly increased particulate PKC activity. The combination of ciprofibrate and $PGF_2{\alpha}$ also significantly increased EGF, transforming growth factor-$\alpha$ ($TGF_2{\alpha}$) and hepatic growth factor (HGF)-induced particulate PKC activity. The combination of ciprofibrate and $PGF_2_\alpha$greatly increased $[Ca^{2+}]_i$. However, the increases of PKC activity and $[Ca^{2+}]_i$ by ciprofibrate and $PGF_2{\alpha}$ alone were much smaller. Neither ciprofibrate or $PGF_2{\alpha}$ alone nor the combination of ciprofibrate and $PGF_2{\alpha}$ significantly increased the formation of $IP_3$. The combination of ciprofibrate and $PGF_2{\alpha}$, however, blocked the inhibitory effect of $TGF-{\beta}$ on particulate PKC activity and formation of $IP_3$ induced by EGF. These results show that co-mitogenicity of the peroxisome proliferator ciprofibrate and eicosanoids may result from the increase in particulate PKC activity and intracellular calcium concentration but not from the formation of $IP_3$.

• The Zoological Society Korea : Newsletter
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• v.18 no.2
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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.

• The Journal of Internal Korean Medicine
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• v.28 no.4
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• pp.902-910
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• 2007

Objective : Peroxisome proliferator-activated receptor (PPAR)-gamma, a transcription factor in adipocyte differentiation, has important effects on insulin sensitivity, atherosclerosis, endothelial cell function and inflammation. Through these effects, PPAR-gamma2 might be involved with type 2 diabetes and vascular disease, including diabetic complications. Recently, it has been reported that the C161T polymorphism in the exon 6 of PPAR-gamma is associated with type 2 diabetes interacting with uncoupling protein 2 (UCP2) gene, and is associated with acute myocardial infarction. We studied the association of this polymorphism with type 2 diabetes and its complications, such as retinopathy, ischemic stroke, nephropathy and neuropathy in Korean non-diabetic and type 2 diabetic populations. Methods : Three hundred and thirty eight type 2 diabetic patients (retinopathy: 64, ischemic stroke: 67, nephropathy: 39 and neuropathy: 76) and 152 healthy matched control subjects were evaluated. The PPAR-gamma C161T polymorphism was analyzed by PCR-RFLP. Results : PPAR-gamma C161T genotype and allele frequency did not show significant differences between type 2 diabetic patients and healthy controls (T allele: 17.0 vs. 14.5, OR= 1.21, P=0.3188). In the analysis for diabetic complications, T allele in diabetic nephropathy was significantly higher than controls (P=0.0358). T allele in the ischemic stroke patients was also higher than healthy controls, although it had no significance (P=0.1375). Conclusions : These results suggest that the C161T polymorphism of the PPAR-gamma gene might be associated with diabetic nephropathy in type 2 diabetes.

• Biomedical Science Letters
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• v.14 no.3
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• pp.139-146
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• 2008

The peroxisome proliferator-activated receptor ${\gamma}$ $(PPAR{\gamma})$ plays a central role in adipogenesis and lipid storage. The $(PPAR{\gamma})$ ligands, thiazolidinediones (TZDs), enhance in vitro adipogenesis in several cell types, but the role of the TZDs on in vivo adipogenesis is still poorly understood. To investigate how $PPAR{\gamma}$ ligand troglitazone regulates adipogenesis in female mice, we examined the effects of the troglitazone on adipose tissue mass, morphological changes of adipocytes, and the expression of $PPAR{\gamma}$ target and adipocyte-specific genes in low fat diet-fed female C57BL/6 mice. Administration of troglitazone for 13 weeks did not change body and total white adipose tissue weights compared with control mice. Troglitazone treatment also did not cause a significant decrease in the average size of adipocytes in parametrial adipose tissue although it is reported to increase the number of small adipocytes in male animals. Troglitazone did not affect the mRNA expression of $PPAR{\gamma}$ and its target genes as well as adipocyte-specific genes in parametrial adipose tissue. These results suggest that $PPAR{\gamma}$ does not seem to be associated with adipogenesis in females with functioning ovaries and that its inability to induce adipogenesis may be due to sex-related factors.

• Proceedings of the Korean Society of Toxicology Conference
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• 2001.10a
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• pp.116-117
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• 2001

The phthalates have been shown to produce hepatic peroxisome proliferation and certain peroxisome proliferators (PPs) are also known to increase the incidence of liver tumors in rodents. In this study we investigated the correlation between oxidative injury, changes in peroxisomal and microsomal enzymes and tumor formation in PP-treated rats.(omitted)

• Journal of Life Science
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• v.33 no.8
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• pp.651-662
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• 2023

Peroxisomes, known as microbodies, are a class of morphologically similar subcellular organelles commonly found in most eukaryotic cells. They are 0.2~1.8 ㎛ in diameter and are bound by a single membrane. The matrix is usually finely granular, but occasionally crystalline or fibrillary inclusions are observed. They characteristically contain hydrogen peroxide (H₂O₂) generating oxidases and contain the enzyme catalase, thus confining the metabolism of the poisonous H₂O₂ within these organelles. Therefore, the eukaryotic organelles are greatly dynamic both in morphology and metabolism. Plant peroxisomes, in particular, are associated with numerous metabolic processes, including β-oxidation, the glyoxylate cycle and photorespiration. Furthermore, plant peroxisomes are involved in development, along with responses to stresses such as the synthesis of important phytohormones of auxins, salicylic acid and jasmonic acids. In the past few decades substantial progress has been made in the study of peroxisome biogenesis in eukaryotic organisms, mainly in animals and yeasts. Advancement of sophisticated techniques in molecular biology and widening of the range of genomic applications have led to the identification of most peroxisomal genes and proteins (peroxins, PEXs). Furthermore, recent applications of proteome study have produced fundamental information on biogenesis in plant peroxisomes, together with improving our understanding of peroxisomal protein targeting, regulation, and degradation. Nonetheless, despite this progress in peroxisome development, much remains to be explained about how peroxisomes originate from the endoplasmic reticulum (ER), then assemble and divide. Peroxisomes perform dynamic roles in many phases of plant development, and in this review, we focus on the latest progress in furthering our understanding of plant peroxisome functions, biogenesis, and dynamics.

• Proceedings of the Korean Society of Toxicology Conference
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• 1998.10a
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• pp.55-55
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• 1998

• Journal of The Korean Society of Inherited Metabolic disease
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• v.5 no.1
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• pp.57-64
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• 2005

• Biomolecules & Therapeutics
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• v.3 no.1
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• pp.12-20
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• 1995

Clofibrate, a peroxisome proliferator, is hepatocarcinogenic in rats in a dose-dependent manner. A total of 70 male and female F344 rats, 5-week-old, were divided into three groups. Rats were fed clofibrate at 0, 0.25, or 0.5% in diet for 30 days. All rats were anesthetized with $CO_2$, blood samples were taken by cardiac puncture for hematology and clinical chemistry, and the rats were killed by exsanguination. Livers, kidenys, pancreas, adrenal glands, spleen, heart, lungs, thyroid gland, reproductive organs, and digestive organs were removed, weighed, later processed, and embedded with paraplast for histological examination. The relative liver and kidney weights with respect to final body weight in the clofibrate-treated group were significantly increased compared with those of control group at all dose levels (p<0.01). It has been suggested that clofibrate may influence on hepatotoxicity by increases in peroxisomal proliferation.