請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72679
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳靜宜(Ching-Yi Chen) | |
dc.contributor.author | Sin-Jin Li | en |
dc.contributor.author | 李欣瑾 | zh_TW |
dc.date.accessioned | 2021-06-17T07:03:26Z | - |
dc.date.available | 2022-08-01 | |
dc.date.copyright | 2019-08-01 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-07-30 | |
dc.identifier.citation | [1] Chang HC, Yang HC, Chang HY, Yeh CJ, Chen HH, Huang KC, et al. Morbid obesity in Taiwan: Prevalence, trends, associated social demographics, and lifestyle factors. PloS one. 2017;12:e0169577.
[2] World Health Organization. World Health Organization obesity and overweight fact sheet. 2018. [3] Alpert MA. Obesity cardiomyopathy: pathophysiology and evolution of the clinical syndrome. The American journal of the medical sciences. 2001;321:225-36. [4] Khan MF, Movahed MR. Obesity cardiomyopathy and systolic function: obesity is not independently associated with dilated cardiomyopathy. Heart failure reviews. 2013;18:207-17. [5] Minamino T, Komuro I, Kitakaze M. Endoplasmic reticulum stress as a therapeutic target in cardiovascular disease. Circulation research. 2010;107:1071-82. [6] Özcan U, Cao Q, Yilmaz E, Lee A-H, Iwakoshi NN, Özdelen E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306:457-61. [7] Panzhinskiy E, Hua Y, Culver B, Ren J, Nair S. Endoplasmic reticulum stress upregulates protein tyrosine phosphatase 1B and impairs glucose uptake in cultured myotubes. Diabetologia. 2013;56:598-607. [8] Petrovski G, Gurusamy N, Das DK. Resveratrol in cardiovascular health and disease. Annals of the New York academy of sciences. 2011;1215:22-33. [9] Hsu HC, Liu CH, Tsai YC, Li SJ, Chen CY, Chu CH, et al. Time-dependent cellular response in the liver and heart in a dietary-induced obese mouse model: the potential role of ER stress and autophagy. European journal of nutrition. 2016;55:2031-43. [10] Li SJ, Liu CH, Chu HP, Mersmann HJ, Ding ST, Chu CH, et al. The high-fat diet induces myocardial fibrosis in the metabolically healthy obese minipigs—The role of ER stress and oxidative stress. Clinical nutrition. 2017;36:760-7. [11] Tanjore H, Lawson WE, Blackwell TS. Endoplasmic reticulum stress as a pro-fibrotic stimulus. Biochimica et Biophysica Acta (BBA)-molecular basis of disease. 2013;1832:940-7. [12] Ayala P, Montenegro J, Vivar R, Letelier A, Urroz PA, Copaja M, et al. Attenuation of endoplasmic reticulum stress using the chemical chaperone 4-phenylbutyric acid prevents cardiac fibrosis induced by isoproterenol. Experimental and molecular pathology. 2012;92:97-104. [13] Shen S, Kepp O, Kroemer G. The end of autophagic cell death? : Taylor & Francis; 2012. [14] Lavandero S, Chiong M, Rothermel BA, Hill JA. Autophagy in cardiovascular biology. The journal of clinical investigation. 2015;125:55-64. [15] Ceylan-Isik AF, Kandadi MR, Xu X, Hua Y, Chicco AJ, Ren J, et al. Apelin administration ameliorates high fat diet-induced cardiac hypertrophy and contractile dysfunction. Journal molecular cell cardiology. 2013;63:4-13. [16] Chen CY, Hsu HC, Lee BC, Lin HJ, Chen YH, Huang HC, et al. Exercise training improves cardiac function in infarcted rabbits: involvement of autophagic function and fatty acid utilization. European journal of heart failure. 2010;12:323-30. [17] Gao H, Yang Q, Dong R, Hou F, Wu Y. Sequential changes in autophagy in diabetic cardiac fibrosis. Molecular medicine reports. 2016;13:327-32. [18] Hsu H-C, Chen C-Y, Lee B-C, Chen M-F. High-fat diet induces cardiomyocyte apoptosis via the inhibition of autophagy. European journal of nutrition. 2016;55:2245-54. [19] Wiersma M, Meijering RA, Qi XY, Zhang D, Liu T, Hoogstra‐Berends F, et al. Endoplasmic reticulum stress is associated with autophagy and cardiomyocyte remodeling in experimental and human atrial fibrillation. Journal of the American heart association. 2017;6:e006458. [20] Taegtmeyer H. Energy metabolism of the heart: from basic concepts to clinical applications applications. Current problems in cardiology. 1994;19:61-113. [21] Neely JR, Morgan HE. Relationship between carbohydrate and lipid metabolism and the energy balance of heart muscle. Annual review of physiology. 1974;36:413-59. [22] Hall A, Burke N, Dongworth R, Hausenloy D. Mitochondrial fusion and fission proteins: novel therapeutic targets for combating cardiovascular disease. British journal of pharmacology. 2014;171:1890-906. [23] Marzetti E, Csiszar A, Dutta D, Balagopal G, Calvani R, Leeuwenburgh C. Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics. American journal of physiology-heart and circulatory physiology. 2013;305:H459-76. [24] Sverdlov AL, Elezaby A, Qin F, Behring JB, Luptak I, Calamaras TD, et al. Mitochondrial reactive oxygen species mediate cardiac structural, functional, and mitochondrial consequences of diet‐induced metabolic heart disease. Journal of the American heart association. 2016;5:e002555. [25] Sverdlov AL, Elezaby A, Behring JB, Bachschmid MM, Luptak I, Tu VH, et al. High fat, high sucrose diet causes cardiac mitochondrial dysfunction due in part to oxidative post-translational modification of mitochondrial complex II. Journal of molecular and cellular cardiology. 2015;78:165-73. [26] Wai T, García-Prieto J, Baker MJ, Merkwirth C, Benit P, Rustin P, et al. Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science. 2015;350:aad0116. [27] Pisano A, Cerbelli B, Perli E, Pelullo M, Bargelli V, Preziuso C, et al. Impaired mitochondrial biogenesis is a common feature to myocardial hypertrophy and end-stage ischemic heart failure. Cardiovascular pathology. 2016;25:103-12. [28] Kolwicz Jr SC, Purohit S, Tian R. Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes. Circulation research. 2013;113:603-16. [29] Pohjoismäki JL, Goffart S. The role of mitochondria in cardiac development and protection. Free radical biology and medicine. 2017;106:345-54. [30] Liu J, Wang P, Zou L, Qu J, Litovsky S, Umeda P, et al. High-fat, low-carbohydrate diet promotes arrhythmic death and increases myocardial ischemia-reperfusion injury in rats. American journal of physiology-heart and circulatory physiology. 2014;307:H598-608. [31] Patel VB, Shah S, Verma S, Oudit GY. Epicardial adipose tissue as a metabolic transducer: role in heart failure and coronary artery disease. Heart failure reviews. 2017;22:889-902. [32] Sinha SK, Thakur R, Jha MJ, Goel A, Kumar V, Kumar A, et al. Epicardial adipose tissue thickness and its association with the presence and severity of coronary artery disease in clinical setting: a cross-sectional observational study. Journal of clinical medicine research. 2016;8:410-9. [33] Börekçi A, Gür M, Özaltun B, Baykan AO, Harbalioglu H, Seker T, et al. Epicardial fat thickness in stable coronary artery disease: its relationship with high-sensitive cardiac troponin T and N-terminal pro-brain natriuretic peptide. Coronary artery disease. 2014;25:685-90. [34] Shah RV, Anderson A, Ding J, Budoff M, Rider O, Petersen SE, et al. Pericardial, but not hepatic, fat by CT is associated with CV outcomes and structure: the multi-ethnic study of atherosclerosis. JACC: Cardiovascular imaging. 2017;10:1016-27. [35] Gaborit B, Sengenes C, Ancel P, Jacquier A, Dutour A. Role of epicardial adipose tissue in health and disease: a matter of fat? Comprehensive physiology. 2011;7:1051-82. [36] Karastergiou K, Evans I, Ogston N, Miheisi N, Nair D, Kaski J-C, et al. Epicardial adipokines in obesity and coronary artery disease induce atherogenic changes in monocytes and endothelial cells. Arteriosclerosis, thrombosis, and vascular biology. 2010;30:1340-6. [37] Greulich S, de Wiza DH, Preilowski S, Ding Z, Mueller H, Langin D, et al. Secretory products of guinea pig epicardial fat induce insulin resistance and impair primary adult rat cardiomyocyte function. Journal of cellular and molecular medicine. 2011;15:2399-410. [38] Bernasochi GB, Boon WC, Curl CL, Varma U, Pepe S, Tare M, et al. Pericardial adipose and aromatase: a new translational target for aging, obesity and arrhythmogenesis? Journal of molecular and cellular cardiology. 2017;111:96-101. [39] He Y, Ma N, Tang M, Jiang Z, Liu H, Mei J. The differentiation of beige adipocyte in pericardial and epicardial adipose tissues induces atrial fibrillation development. European review medicine pharmacological science. 2017;21:4398-405. [40] Li SJ, Liu CH, Chang CW, Chu HP, Chen KJ, Mersmann HJ, et al. Development of a dietary‐induced metabolic syndrome model using miniature pigs involvement of AMPK and SIRT 1. European journal of clinical investigation. 2015;45:70-80. [41] Li SJ, Ding ST, Mersmann HJ, Chu CH, Hsu CD, Chen CY. A nutritional nonalcoholic steatohepatitis minipig model. The journal of nutritional biochemistry. 2016;28:51-60. [42] Lossi L, D’Angelo L, De Girolamo P, Merighi A. Anatomical features for an adequate choice of experimental animal model in biomedicine: II. Small laboratory rodents, rabbit, and pig. Annals of Anatomy-Anatomischer Anzeiger. 2016;204:11-28. [43] Milani-Nejad N, Janssen PM. Small and large animal models in cardiac contraction research: advantages and disadvantages. Pharmacology & therapeutics. 2014;141:235-49. [44] Hsieh YH, Wang HT, Hsu JT, Chen CY. Albusin B, mass‐produced by the Saccharomyces cerevisiae suppression system, enhances lipid utilisation and antioxidant capacity in mice. Journal of the science of food and agriculture. 2013;93:2758-64. [45] Ayalon N, Gopal DM, Mooney DM, Simonetti JS, Grossman JR, Dwivedi A, et al. Preclinical left ventricular diastolic dysfunction in metabolic syndrome. The American journal of cardiology. 2014;114:838-42. [46] Dorn II GW. Mitochondrial dynamics in heart disease. Biochimica Et Biophysica Acta (BBA)-molecular cell research. 2013;1833:233-41. [47] Zorzano A. Regulation of mitofusin-2 expression in skeletal muscle. Applied physiology, nutrition, and metabolism. 2009;34:433-9. [48] Ryan JJ, Marsboom G, Fang Y-H, Toth PT, Morrow E, Luo N, et al. PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension. American journal of respiratory and critical care medicine. 2013;187:865-78. [49] Karamanlidis G, Garcia-Menendez L, Kolwicz Jr SC, Lee CF, Tian R. Promoting PGC-1α-driven mitochondrial biogenesis is detrimental in pressure-overloaded mouse hearts. American journal of physiology-heart and circulatory physiology. 2014;307:H1307-H16. [50] Wang K, Long B, Jiao JQ, Wang JX, Liu JP, Li Q, et al. miR-484 regulates mitochondrial network through targeting Fis1. Nature communications. 2012;3:781. [51] Vásquez‐Trincado C, García‐Carvajal I, Pennanen C, Parra V, Hill JA, Rothermel BA, et al. Mitochondrial dynamics, mitophagy and cardiovascular disease. The journal of physiology. 2016;594:509-25. [52] Kubli DA, Gustafsson ÅB. Mitochondria and mitophagy: the yin and yang of cell death control. Circulation research. 2012;111:1208-21. [53] Blumensatt M, Fahlbusch P, Hilgers R, Bekaert M, De Wiza DH, Akhyari P, et al. Secretory products from epicardial adipose tissue from patients with type 2 diabetes impair mitochondrial β-oxidation in cardiomyocytes via activation of the cardiac renin–angiotensin system and induction of miR-208a. Basic research in cardiology. 2017;112:2. [54] Wang CY, Li SJ, Wu TW, Lin HJ, Chen JW, Mersmann HJ, et al. The role of pericardial adipose tissue in the heart of obese minipigs. European journal of clinical investigation. 2018;48:e12942. [55] Song M, Gong G, Burelle Y, Gustafsson ÅB, Kitsis RN, Matkovich SJ, et al. Interdependence of Parkin-mediated mitophagy and mitochondrial fission in adult mouse hearts. Circulation research. 2015;117:346-51. [56] Bustillo-Zabalbeitia I, Montessuit S, Raemy E, Basañez G, Terrones O, Martinou J-C. Specific interaction with cardiolipin triggers functional activation of dynamin-related protein 1. PloS one. 2014;9:e102738. [57] Chang CR, Blackstone C. Dynamic regulation of mitochondrial fission through modification of the dynamin‐related protein Drp1. Annals of the New York academy of sciences. 2010;1201:34-9. [58] Chen Y, Liu Y, Dorn GW. Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circulation research. 2011;109:1327-31. [59] Dorn II GW. Parkin-dependent mitophagy in the heart. Journal of molecular and cellular cardiology. 2016;95:42-9. [60] Kubli DA, Zhang X, Lee Y, Hanna RA, Quinsay MN, Nguyen CK, et al. Parkin protein deficiency exacerbates cardiac injury and reduces survival following myocardial infarction. Journal of biological chemistry. 2013;288:915-26. [61] Yu W, Gao B, Li N, Wang J, Qiu C, Zhang G, et al. Sirt3 deficiency exacerbates diabetic cardiac dysfunction: role of Foxo3A-Parkin-mediated mitophagy. Biochimica et Biophysica Acta (BBA)-molecular basis of disease. 2017;1863:1973-83. [62] Kobayashi S, Liang Q. Autophagy and mitophagy in diabetic cardiomyopathy. Biochimica et Biophysica Acta (BBA)-molecular basis of disease. 2015;1852:252-61. [63] Hsu HC, Li SJ, Chen CY, Chen MF. Eicosapentaenoic acid protects cardiomyoblasts from lipotoxicity in an autophagy-dependent manner. Cell biology and toxicology. 2018;34:177-89. [64] Hsu HC, Chen CY, Chiang CH, Chen MF. Eicosapentaenoic acid attenuated oxidative stress-induced cardiomyoblast apoptosis by activating adaptive autophagy. European journal of nutrition. 2014;53:541-7. [65] Li SJ, Wu TW, Chien MJ, Mersmann HJ, Chen -Y. Involvement of pericardial adipose tissue in cardiac fibrosis of dietary-induced obese minipigs—Role of mitochondrial function. Biochimica et Biophysica Acta (BBA)-molecular and cell biology of lipids. 2019;1864:957-65. [66] van de Weijer T, Schrauwen-Hinderling VB, Schrauwen P. Lipotoxicity in type 2 diabetic cardiomyopathy. Cardiovascular research. 2011;92:10-8. [67] Watanabe T, Saotome M, Nobuhara M, Sakamoto A, Urushida T, Katoh H, et al. Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance. Experimental cell research. 2014;323:314-25. [68] Ong S-B, Subrayan S, Lim SY, Yellon DM, Davidson SM, Hausenloy DJ. Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation. 2010;121:2012-22. [69] Disatnik MH, Ferreira JC, Campos JC, Gomes KS, Dourado PM, Qi X, et al. Acute inhibition of excessive mitochondrial fission after myocardial infarction prevents long‐term cardiac dysfunction. Journal of the American heart association.. 2013;2:e000461. [70] Ong SB, Hall AR, Hausenloy DJ. Mitochondrial dynamics in cardiovascular health and disease. Antioxidants & redox signaling. 2013;19:400-14. [71] Kornfeld OS, Qvit N, Haileselassie B, Shamloo M, Bernardi P, Mochly-Rosen D. Interaction of mitochondrial fission factor with dynamin related protein 1 governs physiological mitochondrial function in vivo. Scientific reports. 2018;8:14034. [72] Shirihai OS, Song M, Dorn GW. How mitochondrial dynamism orchestrates mitophagy. Circulation research. 2015;116:1835-49. [73] Qi X, Qvit N, Su Y-C, Mochly-Rosen D. A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. Journal of Cell Science. 2013;126:789-802. [74] Priault M, Salin B, Schaeffer J, Vallette Fd, Di Rago J, Martinou J. Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast. Cell death and differentiation. 2005;12:1613-21. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72679 | - |
dc.description.abstract | 根據世界衛生組織調查,心臟疾病盤踞著全球十大死因第一位長達十五年之久。因心臟為一高度氧化代謝之器官,故粒線體對於維持心臟正常功能扮演著重要的角色。近來粒線體動態平衡 (mitochondrial dynamics)常與心血管疾病共同探討。然而,粒線體動態平衡於肥胖心肌病變 (obesity cardiomyopathy)致病機轉中所扮演之角色尚未釐清。於本試驗中,我們建立藉由高脂飼糧之餵飼誘導李宋小型豬產生肥胖誘發之心肌病變。這些肥胖心肌病變豬隻,具有較重之體重、異位脂肪堆積且具代謝症候群之情況。內質網壓力 (endoplasmic reticulum stress)、細胞自嗜 (autophagy)及脂毒性 (lipotoxicity)參與了豬隻肥胖心肌病變之進程。此外,更發現心肌病變豬隻其心臟中之腺苷三磷酸 (ATP)較低。因此,本篇研究進一步藉由體外及體內試驗,以釐清粒線體動態平衡於肥胖心肌病變中之角色。
我們發現肥胖心肌病變豬隻,具心臟氧化壓力、損傷粒線體生合成、動態平衡失衡及誘導粒線體自嗜。為了進一步釐清粒線體動態平衡於高脂飼糧誘發心肌病變中之機制,棕櫚酸處理予H9C2細胞以誘發脂毒性。在體外模式中,棕櫚酸破壞粒線體動態平衡並造成細胞死亡,而抑制粒線體分裂 (fission,抑制DRP1表現)之情況下,於最初可維持粒線體功能並增加細胞存活率。然而,當延長棕櫚酸處理後,不論siDRP1功能存在與否,基礎粒線體氧化功能皆下降。同時,我們也發現,心臟周邊具有較多之心包脂肪堆積 (pericardial adipose tissue)。肥胖豬隻之心包脂肪具有較高量之IL-6及丙二醛 (malondialdehyde)。 為了進一步了解,是否心包脂肪分泌物質對於肥胖心肌病變中粒線體具有局部調節作用,H9C2細胞將給予心包脂肪之條件培養基 (conditioned medium)進行處理。結果顯示,處理心包脂肪條件培養基之組別,其粒線體呼吸作用及ATP產量被抑制,因此造成H9C2之細胞凋亡反應。而粒線體動態平衡或粒線體自嗜作用之相關蛋白質表現皆下降。 綜上所述,此結果指出粒線體動態平衡參與高脂飼糧誘導心肌纖維化之進程。體外模式證實,循環性影響 (棕櫚酸)及局部調節 (心包脂肪分泌物質)皆參與高脂飼糧造成之心肌病變。棕櫚酸及心包脂肪分泌物質兩者皆造成粒線體功能損傷及誘導細胞死亡,而抑制過多粒線體分裂作用於脂毒性初期時,可給予細胞延長壽命之優勢,但當延長棕櫚酸處理時,並無法恢復粒線體功能。儘管有其侷限性,但我們奠定了具潛力的新治療策略的關鍵階段,藉由siDRP1而降低肥胖心肌病變之風險。 | zh_TW |
dc.description.abstract | According to the World Health Organization, heart diseases remained in the top rank of ten leading causes of death globally in the last 15 years. The heart is a highly oxidative tissue and mitochondria play a critical role in maintaining optimal cardiac function. Recently, mitochondrial dynamics have been connected with cardiovascular diseases (CVD). However, the exact role of mitochondrial dynamics in the pathogenesis of obesity cardiomyopathy (OCM) remains unclear. In present study, we established an OCM minipig model by high-fat diet (HFD) feeding for 6 months. These OCM pigs had a heavier body mass, accumulated more ectopic fat, and exhibited metabolic syndrome. The endoplasmic reticulum stress, autophagy, and lipotoxicity were participated in the cardiac pathological mechanism of OCM pigs. Moreover, a decreasing cardiac ATP production was observed in these OCM pigs. Therefore, the aim of this study was to elucidate the role of mitochondrial dynamics in OCM, in vitro and in vivo.
We found that enhanced cardiac oxidative stress, impairment of mitochondrial biogenesis and dynamics, and induced mitophagy were involved in the OCM pigs. To further elucidate the mechanisms of mitochondrial dynamics involved in HFD-induced cardiomyopathy, palmitate was used to induce lipotoxicity in H9C2 cells. In the cell model, palmitate disrupted mitochondrial dynamics and induced cell death, whereas inhibition of mitochondrial fission (DRP1) at the onset of lipotoxicity maintained the mitochondrial function and cell survival. However, there was lower basal mitochondrial oxidative function after prolonged palmitate treatment regardless of the functionality of siDRP1 was present or not. Meanwhile, there was more pericardial adipose tissue (PAT) accumulation around the heart. An elevated content of IL-6 and malondialdehyde was found in the PAT of obese pigs. To examine whether local effect of PAT secretomes regulated the mitochondrial function in OCM, H9C2 cells were treated with PAT-conditioned medium (CM). PAT-CM inhibited basal mitochondrial respiration and ATP production, thus leading to apoptosis of H9C2 cells. The protein expressions of mitochondrial dynamics- and a mitophagy-related protein were suppressed by PAT-CM. In conclusion, the results indicated that mitochondrial dynamics was involved in the progression of HFD-induced cardiac pathogenesis. The model in vitro demonstrated that HFD caused cardiomyopathy via systemic effect (palmitate) and local regulation (PAT secretomes). Both palmitate and PAT secretomes disrupted mitochondrial functions and induced cell death, whereas inhibiting excessive mitochondrial fission at the onset of lipotoxicity provided a prolonged survival advantage, but did not restore mitochondrial function after prolonged lipotoxicity by palmitate. Despite the limitation, we showed a critical stage for potential new therapeutic strategies to reduce the risk of OCM via siDRP1. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T07:03:26Z (GMT). No. of bitstreams: 1 ntu-108-D04626001-1.pdf: 7298630 bytes, checksum: b2d2d9b3419e8d86a9108ddbcf3f0535 (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | 謝誌 iii
中文摘要 iv Abstract vi List of figures xi List of tables xiii Chapter 1: Background and aims 1 1.1 Obesity cardiomyopathy (OCM) 1 1.1.1 The role of endoplasmic reticulum in the heart 2 1.1.2 The role of autophagy in the heart 2 1.1.3 The role of mitochondrial dynamic in the heart 3 1.2 Cardiac fat on obesity cardiomyopathy 4 1.3 Our specific aims for this project are 6 Chapter 2: Materials and methods 7 2.1 Animals and experiment diets 7 2.2 Body composition analysis 7 2.3 Blood analysis 8 2.4 Intravenous glucose tolerance test (IVGTT) 8 2.5 Triglyceride content in left ventricular 9 2.6 RNA extraction and determination by Real-Time PCR 9 2.7 Masson’s trichrome staining and measurement of total collagen content 9 2.8 Oxygen radical absorbance capacity (ORAC) 10 2.9 Thiobarbituric acid reactive substances (TBARS) 10 2.10 Western blotting 11 2.11 ATP production 12 2.12 Preparation of conditioned medium (CM) 12 2.13 Cell culture and treatment 13 2.14 Cell viability 14 2.15 Early apoptosis and cell death detection 14 2.16 Knockdown of DRP1 14 2.17 Mitochondria respiration 15 2.18 Statistics methods 16 Chapter 3: Results 19 3.1 Study the ER function, autophagy, and mitochondrial dynamics in the heart of OCM minipigs. 19 3.1.1 Set up the animal model for obesity cardiomyopathy 19 3.1.2 The ER stress and autophagy are involved in cardiomyopathy pigs 25 3.1.3 Mitochondrial dynamics are involved in cardiomyopathy in pigs 28 3.2 Involvement of pericardial adipose tissue in cardiac fibrosis of dietary-induced obese minipigs 34 3.3 Investigate the mechanism of mitochondrial dynamics on cardiomyopathy in the H9C2 cell model. 37 3.3.1 Palmitate impaired mitochondrial function and triggered apoptosis in H9C2 cells 37 3.3.2 Inhibiting mitochondrial fission restored ATP production and improved cell viability after palmitate stimulation 37 3.3.3 Inhibiting mitochondrial fission increased mitochondrial respiration in palmitate-treated H9C2 cells 38 3.3.4 High-fat diet changed the characters of PAT, but not EAT 44 3.3.5 PAT-CM caused apoptosis of H9C2 cells 45 3.3.6 PAT-CM caused mitochondrial dysfunction of H9C2 cells 45 Chapter 4: Discussions 52 4.1 Mitochondrial dynamics are involved in cardiomyopathy in Lee-Sung minipigs 52 4.2 High-fat diet changed the secretomes of PAT 53 4.3 PAT secretomes modulated mitochondrial function in the heart 54 4.4 Lee-Sung minipigs as an obesity cardiomyopathy model 56 4.5 Inhibition of excessive mitochondrial fission protects the cardiomyocyte against palmitate-induced lipotoxicity 59 4.6 DRP1 has a key mediator role in mitochondrial quality control 60 Chapter 5: Conclusions 62 References 63 Supplementary data 68 Appendix 71 Curriculum vitae of author 72 | |
dc.language.iso | en | |
dc.title | 藉由李宋小型豬探討粒線體於肥胖心肌病變中之影響 | zh_TW |
dc.title | The role of mitochondria involved in obesity
cardiomyopathy in the Lee-Sung minipig model | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-2 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 丁詩同(Shih-Torng Ding) | |
dc.contributor.oralexamcommittee | 許秀卿(Hsiu-Ching Hsu),張育嘉(Yu-Jia Chang),陳洵一(Shuen-Ei Chen),林原佑(Yuan-Yu Lin) | |
dc.subject.keyword | 李宋豬,肥胖心肌病變,粒線體動態平衡,DRP1,心包脂肪,內質網壓力,細胞自嗜, | zh_TW |
dc.subject.keyword | Lee-Sung miniature pigs,obesity cardiomyopathy,mitochondrial dynamics,DRP1,pericardial fat,ER stress,autophagy, | en |
dc.relation.page | 78 | |
dc.identifier.doi | 10.6342/NTU201902107 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2019-07-30 | |
dc.contributor.author-college | 生物資源暨農學院 | zh_TW |
dc.contributor.author-dept | 動物科學技術學研究所 | zh_TW |
顯示於系所單位: | 動物科學技術學系 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-108-1.pdf 目前未授權公開取用 | 7.13 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。