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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林璧鳳 | zh_TW |
| dc.contributor.advisor | Bi-Fong Lin | en |
| dc.contributor.author | 邱德益 | zh_TW |
| dc.contributor.author | Te-I Chiu | en |
| dc.date.accessioned | 2025-08-21T16:26:35Z | - |
| dc.date.available | 2025-08-22 | - |
| dc.date.copyright | 2025-08-21 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-08-04 | - |
| dc.identifier.citation | 黃薰儀 (2019)。探討gamma-胺基丁酸對Vhlh基因剔除小鼠腎臟病與免疫調節的影響。國立臺灣大學生化科技學系暨研究所博士論文。
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99114 | - |
| dc.description.abstract | 台灣末期腎臟病盛行率、洗腎人口高居世界之冠，其增幅亦名列前茅；又，國人葉酸邊緣缺乏盛行率漸增。本研究室已發表葉酸缺乏加劇高果糖高油誘發之小鼠腎損傷，以及補充 γ-aminobutyric acid (GABA) 延緩自發性腎炎小鼠之腎損傷之研究，故本研究欲探討葉酸、果糖和 GABA 飲食因子對腎小管細胞激素分泌及代謝之影響。研究方法為以人類腎小管上皮細胞株 HK-2 細胞在各濃度的葉酸、果糖和 GABA 以及有無 LPS 刺激、有無 LDH 抑制劑 oxamate 等不同條件下，分別測定促發炎細胞激素 IL-6、MCP-1、抗發炎/纖維化細胞激素 TGF-β1 分泌量、腎損傷相關基因 Vegf, Kim-1, Caspase-3 mRNA 表現量、乳酸生成和其生成酵素 lactate dehydrogenase (LDH) 活性，以及脂肪酸氧化酵素 carnitine-palmitoyltransferase 1 (CPT1A)、參與能量代謝與粒線體生合成之轉錄活化因子 PPARγ coactivator (PGC)-1α、纖維化指標 α-smooth muscle actin (α-SMA) 之表現量，並以海馬生物能量儀測定HK-2細胞在葉酸充足或缺乏時之耗氧率代表其粒線體功能。結果顯示，2 mM 果糖增加 HK-2 細胞 Vegf, Kim-1, Caspase-3 mRNA 表現量，5 mM 果糖促進其 IL-6、MCP-1 分泌；添加 GABA 則可減緩果糖處理或葉酸缺乏下之促發炎細胞激素分泌。葉酸缺乏的 HK-2 細胞內 ROS 累積、LDH 活性上升，造成胞內外乳酸含量上升。雖然 CPT1A 表現量上升，但粒線體基礎耗氧率下降，電子傳遞鏈去耦合且ATP產量下降。若以 oxamate 抑制葉酸缺乏 HK-2 細胞的乳酸生成，則使其 IL-6 分泌下降，而 MCP-1 分泌上升；反之，添加乳酸使 IL-6、TGF-β1 分泌量上升，但 MCP-1 分泌下降。由以上結果可知，葉酸缺乏的 HK-2 細胞粒線體 ATP 生成功能受損、乳酸生成增加，進而影響促發炎激素分泌；同時，葉酸缺乏亦加劇 LPS 刺激下的乳酸生成，顯示葉酸缺乏可能影響腎小管細胞的能量代謝傾向、促進乳酸生成，並增加促發炎細胞激素的分泌。 | zh_TW |
| dc.description.abstract | Taiwan has the highest prevalence of end-stage renal disease and hemodialysis globally, with a growing population suffered from folate insufficiency. Our previous studies have shown that folate deficiency worsened renal damage in mice fed with high-fructose, high-fat diet and that γ-aminobutyric acid (GABA) mitigated kidney injury in mice with spontaneous nephritis. Building on this, the present study aims to investigate how folate, fructose, and GABA might influence cytokine secretion and metabolism in renal tubular cells. HK-2 cells (human kidney proximal tubular epithelial cell line) were cultured with varying concentrations of folate, fructose, and GABA, with or without LPS stimulation, with or without oxamate (LDH inhibitor) for determination of IL-6, MCP-1 (pro-inflammatory cytokines), TGF-β1 (anti-inflammatory/profibrotic cytokine) secretion, Vegf, Kim-1, Caspase-3 (renal injury-related genes) expression, lactate production, and CPT1A (a key enzyme in fatty acid oxidation), PGC-1α (a key transcription factor in regulating mitochondrial biogenesis), α-SMA (a pro-fibrotic marker) expression, alongside oxygen consumption rate (mitochondrial function marker) using Seahorse Analyzer. Results showed that 2 mM fructose increased mRNA expression of Vegf, Kim-1, Caspase-3; 5 mM fructose increased IL-6, MCP-1 secretion, while GABA alleviated pro-inflammatory cytokine secretion induced by fructose or folate deficiency. Notably, folate deficiency led to ROS accumulation, elevated LDH activity, and lactate buildup. Folate deficient HK-2 cells showed decreased mitochondrial basal respiration, decoupling in ATP production, despite a rise in CPT1A expression. Inhibiting lactate production in folate-deficient HK-2 cells increased MCP-1 secretion, with suppressed IL-6 secretion; lactate addition increased IL-6 and TGF-β1 secretion, with reduced MCP-1 secretion. These findings suggest that folate deficiency impairs mitochondrial ATP synthesis, elevates lactate production, and exacerbates pro-inflammatory cytokine secretion and LPS-induced lactate production in HK-2 cells, highlighting its critical role in metabolic preference, lactate production, and proinflammatory cytokine secretion. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-08-21T16:26:35Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-08-21T16:26:35Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 摘要 i
Abstract iii 目次 v 圖次 ix 表次 x 第一章 文獻回顧 1 第一節 腎臟 1 一、腎臟結構與生理 1 二、腎臟病變 2 （一）腎臟疾病概述 2 （二）腎小管與急性腎損傷 2 （三）從急性腎損傷到慢性腎病變 3 （四）腎臟發炎、纖維化相關細胞激素 4 三、腎小管病變與代謝模式轉換 6 （一）腎小管的代謝偏好 6 （二）腎病變與代謝轉換 7 第二節 腎保健相關飲食因子 8 一、葉酸 8 （一）葉酸結構與化學特性 8 （二）葉酸來源與國人葉酸營養狀況 9 （三）葉酸的吸收與代謝 9 （四）葉酸之代謝角色 10 （五）葉酸缺乏與健康風險 11 二、果糖 13 （一）果糖的吸收與代謝 13 （二）果糖與腎臟 14 三、γ-胺基丁酸 15 （一）GABA簡介 15 （二）GABA與腎臟 15 第三節 研究動機與目的 16 第二章 實驗設計與材料方法 17 第一節、實驗設計 17 第二節、材料與方法 17 一、HK-2細胞株培養 17 （一）細胞培養 17 （二）細胞存活率標準曲線測定 19 （三）胞內葉酸含量測定 19 （四）藥品添加 21 （五）LPS刺激 21 二、細胞代謝指標測定 22 （一）上清液pH值測定 22 （二）胞內活性氧化物 (reactive oxygen species, ROS) 測定 22 （三）乳酸含量測定 23 （四）乳酸脫氫酶 (LDH) 活性測定 24 三、氧氣消耗率測定 25 四、細胞激素測定 27 （一）上清液IL-6、MCP-1測定 27 （二）上清液TGF-β1測定 28 五、基因mRNA表現量測定 30 六、Western blot 32 七、統計方法 36 第三章 實驗結果 37 第一節 飲食因子對HK-2細胞株腎損傷相關指標的影響 37 一、果糖對HK-2細胞株腎損傷相關指標mRNA表現之影響 37 二、果糖對HK-2細胞株促發炎激素分泌量之影響 38 三、GABA對HK-2細胞株促發炎激素分泌量之影響 40 四、葉酸缺乏對HK-2細胞株細胞激素分泌量之影響 43 第二節 葉酸對HK-2細胞株代謝影響促發炎的的可能性 45 一、葉酸缺乏對HK-2細胞株乳酸生成之影響 45 二、葉酸對HK-2細胞株粒線體脂肪酸氧化路徑之影響 47 三、葉酸缺乏致HK-2細胞株粒線體功能低下 49 四、葉酸缺乏下HK-2細胞株有氧糖解和發炎的關聯 51 第四章 討論與結論 53 第一節 討論 53 一、果糖對腎小管細胞的影響 53 二、GABA對腎小管細胞的影響 54 三、HK-2細胞株葉酸缺乏培養模式 54 四、葉酸缺乏或過量對發炎反應之影響 55 五、葉酸缺乏對CPT1A表達量的可能影響機轉 56 六、乳酸與促發炎激素IL-6、MCP-1分泌量之關係 56 七、乳酸與促纖維化激素TGF-β1分泌量之關係 57 八、有氧糖解與粒線體功能的交互作用 58 九、研究限制 58 第二節、結論 59 附錄 61 參考文獻 62 | - |
| dc.language.iso | zh_TW | - |
| dc.subject | HK-2細胞株 | zh_TW |
| dc.subject | 葉酸缺乏 | zh_TW |
| dc.subject | 乳酸 | zh_TW |
| dc.subject | 乳酸脫氫酶 | zh_TW |
| dc.subject | 粒線體 | zh_TW |
| dc.subject | 發炎 | zh_TW |
| dc.subject | folate deficiency | en |
| dc.subject | HK-2 | en |
| dc.subject | inflammation | en |
| dc.subject | mitochondria | en |
| dc.subject | LDH | en |
| dc.subject | lactate | en |
| dc.title | 葉酸缺乏促進HK-2腎小管細胞株發炎介質分泌與代謝重整 | zh_TW |
| dc.title | Folate deficiency boosted pro-inflammatory cytokine secretion and metabolic reprogramming in HK-2 renal tubular cells | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 江伯倫;謝佳倩;江孟燦;洪永瀚 | zh_TW |
| dc.contributor.oralexamcommittee | Bor-Luen Chiang;Chia-Chien Hsieh;Meng-Tsan Chiang;Yong-Han Hong | en |
| dc.subject.keyword | HK-2細胞株,葉酸缺乏,乳酸,乳酸脫氫酶,粒線體,發炎, | zh_TW |
| dc.subject.keyword | HK-2,folate deficiency,lactate,LDH,mitochondria,inflammation, | en |
| dc.relation.page | 72 | - |
| dc.identifier.doi | 10.6342/NTU202503757 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2025-08-08 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 生化科技學系 | - |
| dc.date.embargo-lift | N/A | - |
| 顯示於系所單位： | 生化科技學系 | |
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