Endocrinology and Metabolism

Original Articles

Miscellaneous
AM1638, a GPR40-Full Agonist, Inhibited Palmitate- Induced ROS Production and Endoplasmic Reticulum Stress, Enhancing HUVEC Viability in an NRF2-Dependent Manner: Hwan-Jin Hwang, Joo Won Kim, SukHwan Yun, Min Jeong Park, Eyun Song, Sooyeon Jang, Ahreum Jang, Kyung Mook Choi, Sei Hyun Baik, Hye Jin Yoo; Endocrinol Metab. 2023;38(6):760-769. Published online November 2, 2023; DOI: https://doi.org/10.3803/EnM.2023.1774

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Abstract PDF PubReader ePub: Background
G protein-coupled receptor 40 (GPR40) is a key molecule in diabetes and fatty liver, but its role in endothelial dysfunction remains unclear. Our objective in this study was to determine whether GPR40 agonists protect endothelial cells against palmitatemediated oxidative stress.
Methods
Human umbilical vein endothelial cells (HUVECs) were used to investigate effects of various GPR40 agonists on vascular endothelium.
Results
In HUVECs, AM1638, a GPR40-full agonist, enhanced nuclear factor erythroid 2–related factor 2 (NRF2) translocation to the nucleus and heme oxygenase-1 (HO-1) expression, which blocked palmitate-induced superoxide production. Those antioxidant effects were not detected after treatment with LY2922470 or TAK875, GPR40-partial agonists, suggesting that GPR40 regulates reactive oxygen species (ROS) removal in a ligand-dependent manner. We also found that palmitate-induced CCAAT/enhancer‐binding protein homologous protein expression; X-box binding protein-1 splicing, nuclear condensation, and fragmentation; and caspase-3 cleavage were all blocked in an NRF2-dependent manner after AM1638 treatment. Both LY2922470 and TAK875 also improved cell viability independent of the NRF2/ROS pathway by reducing palmitate-mediated endoplasmic reticulum stress and nuclear damage. GPR40 agonists thus have beneficial effects against palmitate in HUVECs. In particular, AM1638 reduced palmitate-induced superoxide production and cytotoxicity in an NRF2/HO-1 dependent manner.
Conclusion
GPR40 could be developed as a good therapeutic target to prevent or treat cardiovascular diseases such as atherosclerosis.

Diabetes
Pioglitazone Attenuates Palmitate-Induced Inflammation and Endoplasmic Reticulum Stress in Pancreatic β-Cells: Seok-Woo Hong, Jinmi Lee, Jung Hwan Cho, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Cheol-Young Park, Ki-Won Oh, Sung-Woo Park, Won-Young Lee; Endocrinol Metab. 2018;33(1):105-113. Published online March 21, 2018; DOI: https://doi.org/10.3803/EnM.2018.33.1.105

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19 Web of Science
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Abstract PDF PubReader ePub

Background

The nuclear receptor peroxisome proliferator-activator gamma (PPARγ) is a useful therapeutic target for obesity and diabetes, but its role in protecting β-cell function and viability is unclear.

Methods

To identify the potential functions of PPARγ in β-cells, we treated mouse insulinoma 6 (MIN6) cells with the PPARγ agonist pioglitazone in conditions of lipotoxicity, endoplasmic reticulum (ER) stress, and inflammation.

Results

Palmitate-treated cells incubated with pioglitazone exhibited significant improvements in glucose-stimulated insulin secretion and the repression of apoptosis, as shown by decreased caspase-3 cleavage and poly (adenosine diphosphate [ADP]-ribose) polymerase activity. Pioglitazone also reversed the palmitate-induced expression of inflammatory cytokines (tumor necrosis factor α, interleukin 6 [IL-6], and IL-1β) and ER stress markers (phosphor-eukaryotic translation initiation factor 2α, glucose-regulated protein 78 [GRP78], cleaved-activating transcription factor 6 [ATF6], and C/EBP homologous protein [CHOP]), and pioglitazone significantly attenuated inflammation and ER stress in lipopolysaccharide- or tunicamycin-treated MIN6 cells. The protective effect of pioglitazone was also tested in pancreatic islets from high-fat-fed KK-Ay mice administered 0.02% (wt/wt) pioglitazone or vehicle for 6 weeks. Pioglitazone remarkably reduced the expression of ATF6α, GRP78, and monocyte chemoattractant protein-1, prevented α-cell infiltration into the pancreatic islets, and upregulated glucose transporter 2 (Glut2) expression in β-cells. Moreover, the preservation of β-cells by pioglitazone was accompanied by a significant reduction of blood glucose levels.

Conclusion

Altogether, these results support the proposal that PPARγ agonists not only suppress insulin resistance, but also prevent β-cell impairment via protection against ER stress and inflammation. The activation of PPARγ might be a new therapeutic approach for improving β-cell survival and insulin secretion in patients with diabetes mellitus

Citations

Citations to this article as recorded by

Nr1h4 and Thrb ameliorate ER stress and provide protection in the MPTP mouse model of Parkinson’s
Nancy Ahuja, Shalini Gupta, Rashmi Arora, Ella Bhagyaraj, Drishti Tiwari, Sumit Kumar, Pawan Gupta
Life Science Alliance.2024; 7(7): e202302416. CrossRef
Prosthetic vascular grafts engineered to combat calcification: Progress and future directions
Taylor K. Brown, Sara Alharbi, Karen J. Ho, Bin Jiang
Biotechnology and Bioengineering.2023; 120(4): 953. CrossRef
Obesity, diabetes mellitus, and cardiometabolic risk: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2023
Harold Edward Bays, Shagun Bindlish, Tiffany Lowe Clayton
Obesity Pillars.2023; 5: 100056. CrossRef
Metformin promotes osteogenic differentiation and prevents hyperglycaemia-induced osteoporosis by suppressing PPARγ expression
Lifeng Zheng, Ximei Shen, Yun Xie, Hong Lian, Sunjie Yan, Shizhong Wang
Acta Biochimica et Biophysica Sinica.2023; 55(3): 394. CrossRef
Peroxisome proliferator-activated receptors as targets to treat metabolic diseases: Focus on the adipose tissue, liver, and pancreas
Henrique Souza-Tavares, Carolline Santos Miranda, Isabela Macedo Lopes Vasques-Monteiro, Cristian Sandoval, Daiana Araujo Santana-Oliveira, Flavia Maria Silva-Veiga, Aline Fernandes-da-Silva, Vanessa Souza-Mello
World Journal of Gastroenterology.2023; 29(26): 4136. CrossRef
Nicotinamide N-methyltransferase upregulation contributes to palmitate-elicited peroxisome proliferator-activated receptor transactivation in hepatocytes
Qing Song, Jun Wang, Alexandra Griffiths, Samuel Man Lee, Iredia D. Iyamu, Rong Huang, Jose Cordoba-Chacon, Zhenyuan Song
American Journal of Physiology-Cell Physiology.2023; 325(1): C29. CrossRef
The global perspective on peroxisome proliferator-activated receptor γ (PPARγ) in ectopic fat deposition: A review
Yanhao Qiu, Mailin Gan, Xingyu Wang, Tianci Liao, Qiuyang Chen, Yuhang Lei, Lei Chen, Jinyong Wang, Ye Zhao, Lili Niu, Yan Wang, Shunhua Zhang, Li Zhu, Linyuan Shen
International Journal of Biological Macromolecules.2023; 253: 127042. CrossRef
Chemical inducer of regucalcin attenuates lipopolysaccharide‐induced inflammatory responses in pancreatic MIN6 β‐cells and RAW264.7 macrophages
Tomiyasu Murata, Kazunori Hashimoto, Susumu Kohno, Chiaki Takahashi, Masayoshi Yamaguchi, Chihiro Ito, Itoigawa Masataka, Roji Kojima, Kiyomi Hikita, Norio Kaneda
FEBS Open Bio.2022; 12(1): 175. CrossRef
Targets for rescue from fatty acid-induced lipotoxicity in pancreatic beta cells
Seok-Woo Hong, Won-Young Lee
Cardiovascular Prevention and Pharmacotherapy.2022; 4(2): 57. CrossRef
Analysis of changes in the proteomic profile of porcine corpus luteum during different stages of the oestrous cycle: effects of PPAR gamma ligands
Zuzanna Kunicka, Karol Mierzejewski, Aleksandra Kurzyńska, Robert Stryiński, Jesús Mateos, Mónica Carrera, Monika Golubska, Iwona Bogacka, Xiaolong Wang
Reproduction, Fertility and Development.2022; 34(11): 776. CrossRef
Activation of PPARγ Protects Obese Mice from Acute Lung Injury by Inhibiting Endoplasmic Reticulum Stress and Promoting Mitochondrial Biogenesis
Yin Tang, Ke Wei, Ling Liu, Jingyue Ma, Siqi Wu, Wenjing Tang, Stéphane Mandard
PPAR Research.2022; 2022: 1. CrossRef
Effect of Pioglitazone on endoplasmic reticulum stress regarding in situ perfusion rat model
Vivien Telek, Luca Erlitz, Ibitamuno Caleb, Tibor Nagy, Mónika Vecsernyés, Bálint Balogh, György Sétáló, Péter Hardi, Gábor Jancsó, Ildikó Takács
Clinical Hemorheology and Microcirculation.2021; 79(2): 311. CrossRef
Inflammation in Metabolic Diseases and Insulin Resistance
Won-Young Lee
Cardiovascular Prevention and Pharmacotherapy.2021; 3(2): 31. CrossRef
Current Status of Endoplasmic Reticulum Stress in Type II Diabetes
Sagir Mustapha, Mustapha Mohammed, Ahmad Khusairi Azemi, Abubakar Ibrahim Jatau, Aishatu Shehu, Lukman Mustapha, Ibrahim Muazzamu Aliyu, Rabi’u Nuhu Danraka, Abdulbasit Amin, Auwal Adam Bala, Wan Amir Nizam Wan Ahmad, Aida Hanum Ghulam Rasool, Mohd Rais M
Molecules.2021; 26(14): 4362. CrossRef
JunD Regulates Pancreatic β-Cells Function by Altering Lipid Accumulation
Kexin Wang, Yixin Cui, Peng Lin, Zhina Yao, Yu Sun
Frontiers in Endocrinology.2021;[Epub] CrossRef
Pioglitazone even at low dosage improves NAFLD in type 2 diabetes: clinical and pathophysiological insights from a subgroup of the TOSCA.IT randomised trial
Giuseppe Della Pepa, Marco Russo, Marilena Vitale, Fabrizia Carli, Claudia Vetrani, Maria Masulli, Gabriele Riccardi, Olga Vaccaro, Amalia Gastaldelli, Angela A. Rivellese, Lutgarda Bozzetto
Diabetes Research and Clinical Practice.2021; 178: 108984. CrossRef
Radioprotective Effect of Pioglitazone Against Genotoxicity Induced by Ionizing Radiation in Healthy Human Lymphocytes
Roya Kazemi, Seyed J. Hosseinimehr
Cardiovascular & Hematological Agents in Medicinal Chemistry .2021; 19(1): 72. CrossRef
Recent Insights Into Mechanisms of β-Cell Lipo- and Glucolipotoxicity in Type 2 Diabetes
Maria Lytrivi, Anne-Laure Castell, Vincent Poitout, Miriam Cnop
Journal of Molecular Biology.2020; 432(5): 1514. CrossRef
Artemisinin and dihydroartemisinin promote β-cell apoptosis induced by palmitate via enhancing ER stress
Ke Chen, Hu Hua, Ziyang Zhu, Tong Wu, Zhanjun Jia, Qianqi Liu
Apoptosis.2020; 25(3-4): 192. CrossRef
Mechanisms of impaired pancreatic β‑cell function in high‑fat diet‑induced obese mice: The role of endoplasmic reticulum stress
Xiaoqing Yi, Xuan Cai, Sisi Wang, Yanfeng Xiao
Molecular Medicine Reports.2020;[Epub] CrossRef
Docosahexaenoic and Eicosapentaenoic Acids Prevent Altered-Muc2 Secretion Induced by Palmitic Acid by Alleviating Endoplasmic Reticulum Stress in LS174T Goblet Cells
Quentin Escoula, Sandrine Bellenger, Michel Narce, Jérôme Bellenger
Nutrients.2019; 11(9): 2179. CrossRef
PPAR-γ agonist, pioglitazone, reduced oxidative and endoplasmic reticulum stress associated with L-NAME-induced hypertension in rats
Eman Soliman, Shereen F. Behairy, Nabila N. El-maraghy, Shimaa M. Elshazly
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Changes of MODY signal pathway genes in the endoplasmic reticulum stress in INS-1-3 cells
Yanan Dong, Shirui Li, Wenhui Zhao, Yanlei Wang, Tingting Ge, Jianzhong Xiao, Yukun Li, Herve Le Stunff
PLOS ONE.2018; 13(6): e0198614. CrossRef

Obesity and Metabolism
Exendin-4 Inhibits the Expression of SEPP1 and Fetuin-A via Improvement of Palmitic Acid-Induced Endoplasmic Reticulum Stress by AMPK: Jinmi Lee, Seok-Woo Hong, Se Eun Park, Eun-Jung Rhee, Cheol-Young Park, Ki-Won Oh, Sung-Woo Park, Won-Young Lee; Endocrinol Metab. 2015;30(2):177-184. Published online June 30, 2015; DOI: https://doi.org/10.3803/EnM.2015.30.2.177

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Abstract PDF PubReader

Background

Selenoprotein P (SEPP1) and fetuin-A, both circulating liver-derived glycoproteins, are novel biomarkers for insulin resistance and nonalcoholic fatty liver disease. However, the effect of exendin-4 (Ex-4), a glucagon-like peptide-1 receptor agonist, on the expression of hepatokines, SEPP1, and fetuin-A, is unknown.

Methods

The human hepatoma cell line HepG2 was treated with palmitic acid (PA; 0.4 mM) and tunicamycin (tuni; 2ug/ml) with or without exendin-4 (100 nM) for 24 hours. The change in expression of PA-induced SEPP1, fetuin-A, and endoplasmic reticulum (ER) stress markers by exendin-4 treatment were evaluated using quantitative real-time reverse transcription polymerase chain reaction and Western blotting. Transfection of cells with AMP-activated protein kinase (AMPK) small interfering RNA (siRNA) was performed to establish the effect of exendin-4-mediated AMPK in the regulation of SEPP1 and fetuin-A expression.

Results

Exendin-4 reduced the expression of SEPP1, fetuin-A, and ER stress markers including PKR-like ER kinase, inositol-requiring kinase 1α, activating transcription factor 6, and C/EBP homologous protein in HepG2 cells. Exendin-4 also reduced the expression of SEPP1 and fetuin-A in cells treated with tunicamycin, an ER stress inducer. In cells treated with the AMPK activator 5-aminoidazole-4-carboxamide ribonucleotide (AICAR), the expression of hepatic SEPP1 and fetuin-A were negatively related by AMPK, which is the target of exendin-4. In addition, exendin-4 treatment did not decrease SEPP1 and fetuin-A expression in cells transfected with AMPK siRNA.

Conclusion

These data suggest that exendin-4 can attenuate the expression of hepatic SEPP1 and fetuin-A via improvement of PA-induced ER stress by AMPK.

Citations

Citations to this article as recorded by

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