Endocrinology and Metabolism

Kyu Lim (Lim K)

6 Articles

Endocrine Research
Omega-3 Polyunsaturated Fatty Acids May Attenuate Streptozotocin-Induced Pancreatic β-Cell Death via Autophagy Activation in Fat1 Transgenic Mice: Won-Min Hwang, Dong-Ho Bak, Dong Ho Kim, Ju Young Hong, Seung-Yun Han, Keun-Young Park, Kyu Lim, Dong-Mee Lim, Jae Gu Kang; Endocrinol Metab. 2015;30(4):569-575. Published online December 31, 2015; DOI: https://doi.org/10.3803/EnM.2015.30.4.569

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Background

Inflammatory factors and β-cell dysfunction due to high-fat diets aggravate chronic diseases and their complications. However, omega-3 dietary fats have anti-inflammatory effects, and the involvement of autophagy in the etiology of diabetes has been reported. Therefore, we examined the protective effects of autophagy on diabetes using fat-1 transgenic mice with omega-3 self-synthesis capability.

Methods

Streptozotocin (STZ) administration induced β-cell dysfunction in mice; blood glucose levels and water consumption were subsequently measured. Using hematoxylin and eosin (H&E) and Masson's trichrome staining, we quantitatively assessed STZ-induced changes in the number, mass, and fibrosis of pancreatic islets in fat-1 and control mice. We identified the microtubule-associated protein 1A/1B light chain 3-immunoreactive puncta in β-cells and quantified p62 levels in the pancreas of fat-1 and control mice.

Results

STZ-induced diabetic phenotypes, including hyperglycemia and polydipsia, were attenuated in fat-1 mice. Histological determination using H&E and Masson's trichrome staining revealed the protective effects of the fat-1 expression on cell death and the scarring of pancreatic islets after STZ injection. In the β-cells of control mice, autophagy was abruptly activated after STZ treatment. Basal autophagy levels were elevated in fat-1 mice β-cells, and this persisted after STZ treatment. Together with autophagosome detection, these results revealed that n-3 polyunsaturated fatty acid (PUFA) enrichment might partly prevent the STZ-related pancreatic islet damage by upregulating the basal activity of autophagy and improving autophagic flux disturbance.

Conclusion

Fat-1 transgenic mice with a n-3 PUFA self-synthesis capability exert protective effects against STZ-induced β-cell death by activating autophagy in β-cells.

Citations

Citations to this article as recorded by

Mitochondrial Dysfunction and Mitophagy in Type 2 Diabetes: Pathophysiology and Therapeutic Targets
Nadezda Apostolova, Teresa Vezza, Jordi Muntane, Milagros Rocha, Víctor M. Víctor
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β Cell and Autophagy: What Do We Know?
Hamid-Reza Mohammadi-Motlagh, Mona Sadeghalvad, Niloofar Yavari, Rosita Primavera, Setareh Soltani, Shashank Chetty, Abantika Ganguly, Shobha Regmi, Tina Fløyel, Simranjeet Kaur, Aashiq H. Mirza, Avnesh S. Thakor, Flemming Pociot, Reza Yarani
Biomolecules.2023; 13(4): 649. CrossRef
The ameliorating effects of mesenchymal stem cells compared to α‐tocopherol on apoptosis and autophagy in streptozotocin‐induced diabetic rats: Implication of PI3K/Akt signaling pathway and entero‐insular axis
Heba A. Mubarak, Manal M. Kamal, Yossra Mahmoud, Fatma S. Abd‐Elsamea, Eman Abdelbary, Marwa G. Gamea, Reham I. El‐Mahdy
Journal of Cellular Biochemistry.2023; 124(11): 1705. CrossRef
Nutraceuticals as Modulators of Autophagy: Relevance in Parkinson’s Disease
Michał Rakowski, Szymon Porębski, Agnieszka Grzelak
International Journal of Molecular Sciences.2022; 23(7): 3625. CrossRef
High n-3 fatty acids counteract hyperglycemia-induced insulin resistance in fat-1 mice via pre-adipocyte NLRP3 inflammasome inhibition
Qingyao Yu, Tiantian Wang, Feng Wang, Yong Yang, Canxia He, Wenge Yang, JinJie Zhang, Zuquan Zou
Food & Function.2021; 12(1): 230. CrossRef
Metabolic and Metabolomic Insights Regarding the Omega-3 PUFAs Intake in Type 1 Diabetes Mellitus
Carmen Purdel, Anca Ungurianu, Denisa Margina
Frontiers in Molecular Biosciences.2021;[Epub] CrossRef
Effects of the linoleic acid/docosahexaenoic acid ratio and concentration inducing autophagy in Raw264.7 cells against Staphylococcus aureus
Li-Ying Xu, Min Mu, Man-Li Wang, Jin-Cheng Liu, Yuan-Jie Zhou, Jing Wu, Bing-You Jiang, Ming-Gong Chen, Dong Hu, Xing-Rong Tao
Journal of Clinical Biochemistry and Nutrition.2020; 67(2): 146. CrossRef
Free fatty acid receptor 3 differentially contributes to β-cell compensation under high-fat diet and streptozotocin stress
Medha Priyadarshini, Connor Cole, Gautham Oroskar, Anton E. Ludvik, Barton Wicksteed, Congcong He, Brian T. Layden
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology.2020; 318(4): R691. CrossRef
Mitochondria and T2D: Role of Autophagy, ER Stress, and Inflammasome
Milagros Rocha, Nadezda Apostolova, Ruben Diaz-Rua, Jordi Muntane, Victor M. Victor
Trends in Endocrinology & Metabolism.2020; 31(10): 725. CrossRef
Omega-3 Polyunsaturated Fatty Acids Prevent Toxoplasma gondii Infection by Inducing Autophagy via AMPK Activation
Choi, Lee, Lee, Park, Lee, Shin, Cha, Lee, Lim, Yuk
Nutrients.2019; 11(9): 2137. CrossRef
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Yu-Xue Xu, Caoxin Huang, Minyi Liu, Ningning Chen, Wenting Chen, Chen Yang, Yan Zhao, Xuejun Li, Junguo Duan, Suhuan Liu, Shuyu Yang
Experimental Cell Research.2018; 364(2): 152. CrossRef
Autophagy in Metabolic Age-Related Human Diseases
Manon Moulis, Cecile Vindis
Cells.2018; 7(10): 149. CrossRef
A comparison of the anti-diabetic potential of d-ribose-l-cysteine with insulin, and oral hypoglycaemic agents on pregnant rats
Abraham A.A. Osinubi, Leke Jacob Medubi, Edidiong N. Akang, Lawal K. Sodiq, Titilola A. Samuel, Taiwo Kusemiju, James Osolu, Danladi Madu, Olufemi Fasanmade
Toxicology Reports.2018; 5: 832. CrossRef
β-Cell Autophagy in Diabetes Pathogenesis
Michelle R Marasco, Amelia K Linnemann
Endocrinology.2018; 159(5): 2127. CrossRef
Endogenous synthesis of n-3 polyunsaturated fatty acids in fat-1 transgenic mice ameliorates streptozocin-induced diabetic nephropathy
Yuan-Ming Zhang, Xiao-Hong Zhang, Pan Zhu, Rong-Hui Tan, Jin-Shun Zhao, Feng Wang, Jin-Jie Zhang, Wang Yan, Yang Xi, Jian-Bo Wan, Jing-Xuan Kang, Zu-Quan Zou, Shi-Zhong Bu
Journal of Functional Foods.2018; 45: 427. CrossRef
PHLPP: a putative cellular target during insulin resistance and type 2 diabetes
Alpana Mathur, Vivek Kumar Pandey, Poonam Kakkar
Journal of Endocrinology.2017; 233(3): R185. CrossRef
Coenzyme Q10 ameliorates cerebral ischemia reperfusion injury in hyperglycemic rats
Cui-Jie Lu, Yong-Zhen Guo, Yang Zhang, Lan Yang, Yue Chang, Jing-Wen Zhang, Li Jing, Jian-Zhong Zhang
Pathology - Research and Practice.2017; 213(9): 1191. CrossRef
Changes in pancreatic histology, insulin secretion and oxidative status in diabetic rats following treatment with Ficus deltoidea and vitexin
Samsulrizal Nurdiana, Yong Meng Goh, Hafandi Ahmad, Sulaiman Md Dom, Nur Syimal’ain Azmi, Noor Syaffinaz Noor Mohamad Zin, Mahdi Ebrahimi
BMC Complementary and Alternative Medicine.2017;[Epub] CrossRef
Comparative analysis of the efficacy of omega-3 fatty acids for hypertriglyceridaemia management in Korea
H.-S. Kim, H. Kim, Y. J. Jeong, S. J. Yang, S. J. Baik, H. Lee, S.-H. Lee, J. H. Cho, I.-Y. Choi, H. W. Yim, K.-H. Yoon
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Transcriptional Regulation of the Estrogen Receptor alpha Gene by Testosterone in Cultures of Primary Rat Sertoli Cells.: Sang Kuk Yang, Kyung Ah Yoon, Eun Jin Yun, Kyoung Sub Song, Jong Seok Kim, Young Rae Kim, Jong Il Park, Seung Kiel Park, Byung Doo Hwang, Kyu Lim; J Korean Endocr Soc. 2006;21(2):106-115. Published online April 1, 2006; DOI: https://doi.org/10.3803/jkes.2006.21.2.106

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Abstract PDF: BACKGROUND
We wanted to identify the presence of the estrogen receptor (ER) alpha in Sertoli cells and gain insight on the regulation of the ER alpha gene expression by testosterone in Sertoli cells. The transcriptional regulation of the ER alpha gene was investigated in primary Sertoli cell cultures by in situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR). METHODS: Primary Sertoli cell culture was performed. The expression levels of ER alpha and ER beta mRNA in Sertoli cells were detected by Northern blot, RT-PCR, immunocytochemistry and in situ hybridization. RESULTS: The ovary, testis and epididymis showed a moderate to high expression of ER alpha while the prostate, ovary and LNCap cells showed the ER beta expression. ER alpha mRNA and protein were detected in the germ cells and Sertoli cells by in situ hybridization and immunocytochemistry. The level of ER alpha mRNA was gradually decreased in a time-dependent manner after testosterone treatment, and the changes of ER alpha mRNA were dependent on the concentration of testosterone. Androgen binding protein and testosterone-repressive prostate message-2 (TRPM-2) mRNA were reduced at 24 hour by estradiol, while the transferrin mRNA was not affected. ER alpha mRNA was strongly detectable in the testes of 7 days-old-rats, but it was gradually decreased from 14 to 21 days of age. The primary Sertoli cells also showed the same pattern. The ER alpha gene expression was also regulated by testosterone in the Sertoli cells prepared from the 14- and 21-day old rats. CONCLUSIONS: These results suggest that ER alpha is transcriptionally regulated by testosterone and it may play some role in the Sertoli cells.

Mechanism of Castration-induced Apoptosis of Ventral Prostate in Rat.: Chung Park, Jong Il Park, Eun Jin Yun, Kyoung Sub Song, Jong Seok Kim, Young Rae Kim, Sang Do Lee, Seung Keil Park, Byung Doo Hwang, Kyu Lim; J Korean Endocr Soc. 2005;20(3):230-241. Published online June 1, 2005; DOI: https://doi.org/10.3803/jkes.2005.20.3.230

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Abstract PDF: BACKGROUND
S: Castration-induced androgen deprivation triggers a sequence of events, which activates apoptotic cell death of the androgen-dependent epithelial cells within the rat ventral prostate. To investigate the mechanism of castration-dependent apoptosis in the rat ventral prostate, the regulation of apoptosis-related genes was been investigated. METHODS: Azaline B was subcutaneously injected into Sprague-Dawley rat. The Fas receptor (Fas), Fas ligand (FasL) and bcl-2 mRNA, as well as the protein levels were detected by RT-PCR and Western blot analyses. Azaline B-dependent apoptosis was determined using TUNEL and a DNA fragmentation assay. The transacting factor of the FasL promoter was identified by DNA footprinting and a DNA mobility shift assay. RESULTS: The rat prostate was regressed after castration, with and the involuted ventral prostate regenerated by testosterone pretreatment, but not by that with FSH. Apoptosis of the ventral prostate was detected, after castration, using toluidine blue staining, a TUNEL assay and an apoptotic DNA fragmentation assay. The levels of Fas, FasL mRNA and protein were increased after castration. In the DNase I footprinting assay, using the FasL promoter and a nuclear extract prepared from a control prostate, at least two sites were protected: the SP-1 binding site at -283 bp and the prostate-unidentified factor(P-UF) binding site at -247 bp. The SP-1 binding activity vanished in the nuclear extract prepared from castrated rats. In the DNA mobility shift assay, the SP-1 binding activity was slightly decreased after castration. Both the Bcl-2 mRNA and Bcl-2 protein were downregulated after castration. CONCLUSION: These results suggest that the Fas/FasL system and Bcl-2 may be important to castrationdependent apoptosis in the rat ventral prostate, with SP-1 related to the castration-dependent regulation of the FasL gene

Specialized Functions and Hormonal Regulation of Sertoli Cell.: Kyu Lim, Chung Park, Kyung Ah Yun, Eun Jin Yun, Jong Il Park, Seung Kiel Park, Byung Doo Hwang; J Korean Endocr Soc. 2003;18(2):120-136. Published online April 1, 2003

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Abstract PDF: No abstract available.

Transcriptional REpression of Vimentin Gene During All-TTrans Retinoic Acid-Induced Differentiation of HL-60 Cells.: Kyu Lim, Do Won Kwon, Seung Min Kim, Kyung Ah Yoon, Mi Young Son, Myoung Sun Lee, Jong Il Park, Wan Hee Yoon, Byung Doo Hwang; J Korean Endocr Soc. 1998;13(4):601-611. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Vimentin is the major intermediate-size filament in the cytoplasm of cells from mesenchymal origin. The HL-60 cell is a unique human leukemic cell line capable of terminal differentiation with several chemical inducers, and then the cell line becomes a fre#quently described model system for cell differentiation in vitro. Vimentin mRNA is reduced during all-trans retinoic acid (retinoic acid) -dependent differentication but increased by 12-0-tetradecanoylphorbol-13-acetate (TPA). In this paper, we have investigated on the mechanism of transcriptional repression of vimentin gene during retinoic acid-dependent differentication of HL-60 cell. METHODS: HL-60 cells were grown in RPMI 1640 medium supplemented with 10% heat-inactivated fetal bovine serum and antibiotics in a humidified 5% CO at 37C. Total RNA was prepared by a modification of the method of Karlinsey et al. Northern blot hybridization was performed by the method of Virca et al. EcoRI fragment of pVIM-GEM was used as probe for vimentin mRNA. DNA mobility shift assay was performed by the method of Lim et al. End labeled DNA probe (Upper strand, 5-CGCITGATGAGTCAGCCG-3) for AP-1 binding activity was mixed with nuclear extracts in a 20 pL reaction volume containing 300 mM KCI, 60 mM HEPES, pH 7.9, 25mM MgC1, 1mM EDTA, 1mM DTT, 60% glycerol, and 2 pg of poly[dI-dC]. RESULTS: The level of vimentin mRNA was decreased at 12 hours after retinoic acid treatment, and not detected at 48 hours. The level of vimentin mRNA was reduced in proportion to concentration of retinoic acid, Retinoic acid-reduced vimentin mRNA was no change in cells treated with cycloheximide. Retinoic acid-dependent decrease of vimentin mRNA was partially recovered by staurosporin pretreatment. In DNA mobility shift assay, AP-1 binding activity was reduced at 48 hr during retinoic acid-induced differentiation. CONCLUSION: These results suggest that the transcriptional repression of vimentin gene during retinoic acid-induced differentiation in HL-60 cells is correlated with reduction of DNA binding activity of AP-1.

Thyrotropin Suppresses INF-r Mediated Gene Expression by Inhibiting Signal Transducer and Activation of Transcription 1(STAT1) Activity in FRTL-5 Cells.: Min Ho Song, Young Kun Kim, Heung Kyu Ro, Eun Shin Park, Soon Hee Yoo, Ho Kim, Kang Wook Lee, Hee Jung Han, Won Chan Joo, Jin Ho Won, Kyu Lim, Oh Yoo Kwon; J Korean Endocr Soc. 1998;13(4):536-553. Published online January 1, 2001

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Abstract PDF: BACKGROUND
The proinflammatory cytokine, IFN-y has been shown to exert pleiotropic effects in a variety of pathophysiologic conditions in autoimmune thyroid disease. The thyrocyte response to IFN-y is mediated two distinct classes of proteins, Janus kinases(Jakl and Jak2) and Signal Transducers and Activation of Transcription(STATl). The activation of STAT 1 is involved in the regulation of many interferon stimulated genes, such as MHC class II, intercellular adhesion molecules-1(ICAM-1) and MHC class II transactivator(CIITA) after the binding to the GASgFN- pactivated site) of the gene promoters. Recently we found TSH/forskolin inhibits IFN-y stimulated maximal expression of ICAM-1 in FRTL-5 cell. IFN-y action is localized between -175 bp and -97 bp from the start of translation of ICAM-1 gene which contains regulatory elements known to be involved in IFN-y action in other eukaryotic cells, palindromic IFN-y activated site(GAS)(5-TTTCCGGGAAA-3) which could bind STAT1, STAT3, STAT5, STAT6. Furthermore, the addition of TSH and forskolin causes a decrease in ICAM-1 promoter activity and its action was localized in GAS. These findings suggested TSH/cAMP signaling pathways downregulate IFN-y activated Janus kinase-STAT signaling path. We wanted to explore the possible involvement of elevated cAMP in the negative regulation of IFN-y induced STAT1 activation in thyroid cells. METHOD: We made several 5-deletion constructs of rat ICAM-1 promoter and analyzed the promoter activities by measuring the luciferase activity after tranfection into FRTL-5 cells. The protein/DNA complex was measured by electrophoretic mobility shift analysis using labeled oligonucleotide. We checked the level of total and phosphorylated STATl protein by immunoblot analysis using specific antibodies. RESULTS: Stimulation of IFN-y in FRTL-5 cells resulted in rapid activation of STATl/DNA binding activity, which was apparent after several minute of stimulation, maintains its activity until 48 h. Incubation of cells with TSH result in suppression of IFN-p mediated STAT1/DNA binding activity throughout the time course of activation by IFN-y. Addition of TSH into 5H maintained FRTL-5 cells did not change the total amount of latent STAT1 amount and also not affect IFN-y mediated production of total STAT1 until 4 h. IFN-y(100 U/mL) rapidly induced phosphorylation of STAT1 within 30 min. and maintained its level without significant change until 48 hours. Cells treated with TSH dramatically lowered the level of IFN-y induced production and phosphorylation of STAT1 after 12 h, 24 h, 36 h, and 48 h but TSH had no effect on the level of phosphorylated STATl within 4 h after IFN-y stimulation. The proteasome inhibitor, MG132 and phosphatase inhibitor, sodium orthovanadate did not block the TSH or forskolin mediated downregulation of phosphorylated STAT1. CONCLUSION: These results indicate a regulatory mechanism which TSH signaling can modulate the prolonged activation of Jak/Stat by IFN-y. We identified one of mechanisms related to TSH mediated negative suppression of the ICAM-1 gene; TSH/cAMP signaling pathways downregulate the cytokine activated Janus kinase-STAT signaling path.

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