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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 丁詩同(Shih-Torng Ding) | |
dc.contributor.author | Chiao-Wei Lin | en |
dc.contributor.author | 林巧威 | zh_TW |
dc.date.accessioned | 2021-06-16T10:17:22Z | - |
dc.date.available | 2026-02-04 | |
dc.date.copyright | 2021-02-23 | |
dc.date.issued | 2021 | |
dc.date.submitted | 2021-02-06 | |
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Exp Biol Med (Maywood) 240, 809-820. Ogawa, Y., Imajo, K., Honda, Y., Kessoku, T., Tomeno, W., Kato, S., Fujita, K., Yoneda, M., Saito, S., Saigusa, Y., et al. (2018). Palmitate-induced lipotoxicity is crucial for the pathogenesis of nonalcoholic fatty liver disease in cooperation with gut-derived endotoxin. Sci Rep 8, 11365. Pais, R., Charlotte, F., Fedchuk, L., Bedossa, P., Lebray, P., Poynard, T., Ratziu, V., and Group, L.S. (2013). A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol 59, 550-556. Paisan-Ruiz, C., Jain, S., Evans, E.W., Gilks, W.P., Simon, J., van der Brug, M., Lopez de Munain, A., Aparicio, S., Gil, A.M., Khan, N., et al. (2004). Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44, 595-600. Palomer, X., Pizarro-Delgado, J., Barroso, E., and Vazquez-Carrera, M. (2018). 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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60405 | - |
dc.description.abstract | 目前的研究指出,肝臟發炎為非酒精性脂肪肝病程推展至肝纖維化或肝癌中扮演重要的角色。然而,於非酒精性脂肪肝中,肝臟如何進展至發炎之機制,尚未被完全了解。近來研究指出Leucine-rich repeat kinase 2 (LRRK2) 蛋白參與脂肪代謝,但其所扮演的功能,以及是否參與非酒精性脂肪肝的疾病發展,目前尚不清楚。利用高脂飼料誘導的非酒精性脂肪肝小鼠模式中發現,LRRK2基因在肝臟中的表現量,相較於健康小鼠明顯降低。在人類肝臟細胞株(HepG2) 中,處理棕櫚酸後,LRRK2蛋白的表現也被抑制。為了進一步探討LRRK2於脂肪代謝中所伴演的角色,在HepG2細胞中過表現 (overexpression) 及基因靜默 (knockdown) LRRK2基因。結果顯示過表現LRRK2蛋白可促進脂肪β氧化,反之,抑制LRRK2基因的表現則抑制脂肪β氧化。進一步探究LRRK2如何調控脂肪的β氧化後發現,操控LRRK2蛋白表現對調控脂肪β氧化反應的重要酵素CPT1A的表現量。且可能是透過活化AMPK或PPARα蛋白,而調控CPT1A的表現有一致性結果。此外,過表現LRRK2抑制由棕櫚酸所誘導的促發炎細胞素TNFα表現。前人的研究顯示,促進細胞的脂肪β氧化可抑制由棕櫚酸所誘導的細胞發炎。本研究指出,LRRK2促進脂肪β氧化並抑制肝細胞的發炎反應。因此,非酒精性脂肪肝中被下調的LRRK2基因,可能為肝臟發炎的原因之一。目前的研究支持藉由抑制肝臟發炎可抑制非酒精性脂肪肝發展成肝纖維化或肝癌的機會。靈芝 (Ganoderma lucidum) 為一傳統中草藥,具有免疫調節、抗發炎、抗氧化、抗菌以及改善腸道菌相的功效。細胞及動物實驗顯示靈芝萃取物及從靈芝分離之活化化合物具有改善非酒精性脂肪肝的效果;然而,其分子機制尚未清楚。從雞初代肝臟細胞及人類肝臟細胞株HepG2的實驗結果顯示,靈芝水萃物可抑制由棕櫚酸誘導的促發炎因子TNFα的表現,可增加抗氧化酵素catalase於經棕櫚酸處理HepG2細胞中的表現量。並且也可有效抑制因H2O2處理所產生的活性氧化物(ROS)。此外,於經棕櫚酸處理HepG2細胞中,靈芝水萃物增加FOXO1的表現量以及促進AMPK的活化。因此,AMPK及FOXO1分子路徑可能參與了靈芝水萃物的抗氧化效果。靈芝未來或許可應用於治療或預防與氧化壓力所導致的相關疾病,例如非酒精性脂肪肝。 | zh_TW |
dc.description.abstract | Hepatic inflammation in non-alcoholic fatty liver disease (NAFLD), a metabolic hepatic disease, contributes to progress to cirrhosis or hepatocellular carcinoma. However, etiology of the hepatic inflammation has not been fully understood. In the current study, we identified that leucine-rich repeat kinase 2 (LRRK2) was significantly down-regulated in the liver of NAFLD mouse model induced by a high-fat diet. In HepG2 cells, exposure to palmitic acid (PA) also down-regulated LRRK2. Overexpression and genetic knockdown of LRRK2 were performed to further investigate the role of LRRK2 in lipid metabolism. Results of HepG2 cells showed that β-oxidation was promoted by LRRK2 overexpression and consistently inhibited by LRRK2 knockdown. The expression of critical enzyme in β-oxidation, carnitine palmitoyltransferase 1A (CPT1A), was positively regulated by LRRK2 expression. The results suggested that the regulation of CPT1A by LRRK2 is likely to involve the activation of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα). Overexpression of LRRK2 reduced the production of a pro-inflammatory cytokine, tumor necrosis factor α (TNFα), induced by PA, suggesting that increase in β-oxidation may promote lipid catabolism to suppress inflammation induced by PA. These results indicated that LRRK2 participated in the regulation of β-oxidation and to suppress inflammation in the liver. Inhibiting hepatic inflammation may suppress the development of cirrhosis or hepatocellular carcinoma in NAFLD has been proposed. Ganoderma lucidum is a traditional herb having the activities of immunomodulation, anti-inflammation, anti-oxidation, antibacterial property, and improvement of microbiota. Moreover, supplementations of extracts or compounds isolated from G. lucidum have been shown to ameliorate NAFLD have been shown in cellular and animal models; however, despite that the molecular mechanisms have not been fully understood. In the current study, the water extracts of G. lucidum suppressed the increase of LITAF by PA in chicken primary hepatocytes and HepG2 cells. Treatment of G. lucidum water extract also increased the levels of catalase, an anti-oxidative enzyme, in PA-treated HepG2 cells. The treatment of G. lucidum water extract also increased total FOXO1 protein expression, the transcription factor that directly turns on catalase gene expression. Besides, activation of AMPK by the treatment of G. lucidum water extracts suggested the increase of catalase may be mediated through AMPK/FOXO1 pathway. Moreover, the treatment of G. lucidum water extracts suppressed the generation of reactive oxygen species (ROS) induced by H2O2. In conclusion, activation of AMPK/FOXO1 pathway may contribute to the anti-oxidant activity of G. lucidum water extracts. G. lucidum has the potential to treat the diseases which can be attributed to oxidative stress, such as NAFLD. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T10:17:22Z (GMT). No. of bitstreams: 1 U0001-0302202120244600.pdf: 5559653 bytes, checksum: f218a71413f59c379396a29cd073ece5 (MD5) Previous issue date: 2021 | en |
dc.description.tableofcontents | 口試委員會審定書 ⅰ 誌謝 ⅱ 中文摘要 ⅲ Abstract ⅴ Chapter 1: Literature review and specific aims 1 1.1 Nonalcoholic fatty liver disease (NAFLD) 1 1.2 The roles of palmitic acid (PA) in the development of NAFLD 2 1.3 The effects of oleic acids on hepatocytes 3 1.4 Lipid metabolism 4 1.5 The roles of AMPK in lipid metabolism 7 1.6 The roles of PPARα and PPARγ in lipid metabolism 7 1.7 Inflammation in NAFLD 8 1.8 The association between leucine-rich repeat kinase 2 (LRRK2) and lipid metabolism 10 1.9 Reactive oxygen species (ROS) 11 1.10 The roles of FOXO1 in lipid metabolism and redox regulation 12 1.11 Effects of Ganoderma lucidum on NAFLD 13 1.12 The effects of diets on NAFLD 15 1.13 Specific aims 17 Chapter 2: Materials and methods 18 2.1 Animals 18 2.2 Intraperitoneal glucose tolerance test (IPGTT) 18 2.3 Histological analyses 19 2.4 RNA extraction and real-time PCR analyses 19 2.5 Protein extraction and western blot 20 2.6 Cell cultures 21 2.7 Free fatty acid treatment 22 2.8 Knockdown of LRRK2 in HepG2 cells 22 2.9 Overexpression of LRRK2 in HepG2 cells 23 2.10 Measurement of TG and free fatty acids 23 2.11 Measurement the activity of fatty acid oxidation 24 2.12 Extraction of cytoplasmic and nuclear proteins 25 2.13 ELISA analyes of TNFα and Interleukin 8 concentrations 25 2.14 Isolation and culture of primary chicken hepatocytes 25 2.15 Preparation of water extract from fruit body of Ganoderma lucidum 26 2.16 Oil red O staining for cell lines 27 2.17 Alamar BlueTM cell viability assay 28 2.18 Dichlorodihydrofluorescin diacetate (DCFDA) assay 28 2.19 Statistical analysis 29 Chapter 3: Results 30 3.1 The obesity mouse model induced by high-fat diet 30 3.2 The obesity mouse model induced by high-fat diet showed the symptoms of diabetes 30 3.3 The obesity mice induced by the high-fat diet displayed nonalcoholic fatty liver disease 31 3.4 LRRK2 was down-regulated in the liver of high-fat diet induced NAFLD mice 31 3.5 Palmitic acid reduced the expression of LRRK2 in HepG2 cells 32 3.6 Overexpression of LRRK2 promoted catabolism of free fatty acid in PA-treated HepG2 cells 33 3.7 Overexpression of LRRK2 enhanced the activity of β-oxidation in HepG2 cells 34 3.8 LRRK2 positively regulated CPT1A in HepG2 cells 34 3.9 LRRK2 promoted the up-regulation of CPT1A induced by free fatty acids in HepG2 cells 35 3.10 LRRK2 activated AMPK and PPARα in HepG2 cells 35 3.11 LRRK2 suppressed the levels of TNFα in HepG2 cells after PA treatment 37 3.12 Water extracts of Ganoderma lucidum had no beneficial effects on the steatotic hepatic cells 38 3.13 Water extracts of Ganoderma lucidum fruit bodies suppressed the expression of TNFA induced by LPS 39 3.14 Water extracts of Ganoderma lucidum suppressed the expression of genes related to inflammation induced by PA 39 3.15 Water extracts of Ganoderma lucidum suppressed the levels of phosphorylated-p65 (S311) in HepG2 cells 40 3.16 Water extracts of Ganoderma lucidum increased the levels of catalase by the mediation of AMPK/FOXO1 pathway in palmitic acid- treated HepG2 cells 40 3.17 Water extracts of Ganoderma lucidum suppressed the intracellular ROS levels induced by H2O2 in SK-HEP1 cells 42 Chapter 4: Discussion 43 Chapter 5: References 87 Appendix 126 Figure 1. The obesity mouse model induced by high-fat diet 49 Figure 2. The obesity mouse model induced by high-fat diet showed the symptoms of diabetis 50 Figure 3. The obesity mice induced by the high-fat diet for nonalcoholic fatty liver disease 51 Figure 4. LRRK2 was down-regulated in the liver of high-fat diet induced NAFLD mice 53 Figure 5. Palmitic acid reduced the expression of LRRK2 in HepG2 cells 55 Figure 6. Overexpression of LRRK2 promoted catabolism of free fatty acid in PA-treated HepG2 cells 56 Figure 7. Manipulation of LRRK2 expression differentially affected the activity of β-oxidation in HepG2 cells 58 Figure 8. LRRK2 positively regulated CPT1A in HepG2 cells 60 Figure 9. LRRK2 promoted the up-regulation of CPT1A induced by free fatty acids in HepG2 cells 62 Figure 10. Overexpression of LRRK2 activated AMPK and PPARα in HepG2 cells 64 Figure 11. Overexpression of LRRK2 suppressed the levels of TNFα in HepG2 cells after PA treatment 66 Figure 12. Water extracts of Ganoderma lucidum had no beneficial effects on the steatotic hepatic cells 68 Figure 13. Water extracts of Ganoderma lucidum fruit bodies suppressed the expression of TNFA induced by LPS 70 Figure 14. Water extracts of Ganoderma lucidum suppressed the expression of the genes related to inflammation induced by PA 72 Figure 15. Water extract of Ganoderma lucidum suppressed the levels of phosphorylated-p65 (S311) in HepG2 cells 73 Figure 16. Water extract of Ganoderma lucidum increased the levels of catalase may be mediated via AMPK/FOXO1 pathway in palmitic acid- treated HepG2 cells 75 Figure 17. Water extracts of Ganoderma lucidum suppressed the intracellular ROS levels induced by H2O2 in SK-HEP1 cells 77 Figure 18. The proposed molecular model of LRRK2 in the regulation of lipid metabolism 80 Figure 19. The proposed molecular model of the anti-oxidation activity of Ganoderma lucidum water extract 81 Table 1. List of primer sets for real-time PCR 82 Table 2. List of antibodies for western blots 85 | |
dc.language.iso | en | |
dc.title | LRRK2蛋白表現之調降參與非酒精性脂肪肝與靈芝水萃物抑制肝臟細胞發炎之機制研究 | zh_TW |
dc.title | Down-regulation of LRRK2 contributes to the nonalcoholic fatty liver disease (NAFLD) and the mechanism by which Ganoderma lucidum water extract suppresses the inflammation in hepatocyte | en |
dc.type | Thesis | |
dc.date.schoolyear | 109-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 葉秀慧(Shiou-Hwei Yeh),林原佑(Yuan-Yu Lin),歐柏榮(Bor-Rung Ou),游玉祥(Yu-Hsiang Yu),陳洵一(Shuen-Ei Chen) | |
dc.subject.keyword | 非酒精性脂肪肝,LRRK2,脂肪β氧化,脂肪代謝,靈芝, | zh_TW |
dc.subject.keyword | nonalcoholic fatty liver disease,LRRK2,β-oxidation,lipid metabolism,Ganoderma lucidum, | en |
dc.relation.page | 126 | |
dc.identifier.doi | 10.6342/NTU202100471 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2021-02-07 | |
dc.contributor.author-college | 生物資源暨農學院 | zh_TW |
dc.contributor.author-dept | 生物科技研究所 | zh_TW |
顯示於系所單位: | 生物科技研究所 |
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