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研究生:賴裕興
研究生(外文):Yu-Hsing Lai
論文名稱:TNF-α在高脂飼料誘發之脂肪肝老鼠造成的腎臟損傷所扮演之角色
論文名稱(外文):Role of TNF-α in renal damage in mice with hepatic steatosis induced by high fat diet
指導教授:鄭瑞棠鄭瑞棠引用關係
指導教授(外文):Juei-Tang Cheng
學位類別:碩士
校院名稱:長榮大學
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:40
中文關鍵詞:腫瘤壞死因子α脂肪肝
外文關鍵詞:TNF-αhepatic steatosis
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中文摘要
【目的】
脂肪肝(hepatic steatosis)是全球流行最廣的慢性肝病。近年來,國人在末期腎病之發生率和盛行率皆名列前茅,盛行率仍高居世界第一。本次實驗旨在研究脂肪肝動物模式對腎臟損傷之影響,並觀察TNF-α在其中所扮演的病生理角色。
【方法】
本實驗先用高脂飼料(high fat diet)來誘發C57BL/6J 公鼠(male mice) 產生脂肪肝。然後,分組用etanercept (TNF-α blockade) 或vehicle注射一個月。注射完,測量TNF-α,total cholesterol (TC), triglyceride (TG),LDL-cholesterol (LDL-C) 及HDL-cholesterol (HDL-C)。腎臟損傷由組織切片及測量血清 BUN and creatinine來觀察。並且,使用Western blot來測量C57BL/6J 公鼠的腎臟組織及培養的腎隔細胞(renal mesangial cell)中Peroxisome proliferator-activated receptors-delta (PPAR-delta)的表現。
【結果】
血清TNF-α濃度在產生脂肪肝的C57BL/6J 公鼠有顯著的升高,而etanercept改善了脂肪肝,但並未影響TC,TG, HDL-C, LDL-C 及 TNF-α濃度。etanercept顯示其腎臟保護功能因觀察到腎功能改善(recovery of serum BUN and creatinine levels)及腎組織損傷減少。腎組織PPAR-delta的表現也藉由etanercept之注射得著改善,TNF-α 對PPAR-delta 表現之影響亦在培養的腎隔細胞直接觀察到。
【結論】
本次實驗先用餵食高脂飼料誘發C57BL/6J 公鼠產生脂肪肝,發現所引起的腎臟損傷是由TNF-α上升並引發腎臟PPAR-delta 下降而產生,etanercept可以抑制TNF-α的作用,進而改善上述實驗中C57BL/6J 公鼠的腎功能及PPAR-delta之表現。


Abstract
Aim: The present study is designed to investigate the role of TNF-α in renal damage observed in mice with hepatic steatosis.
Materials and Methods: We induced hepatic steatosis in mice using high fat diet and treated mice with etanercept at the dose sufficient to block TNF-α receptors or vehicle for 1 month. Plasma TNF-α, total cholesterol (TC), triglyceride (TG), LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) were determined at the end of this treatment. Renal damage was identified by histologic observation and the higher of serum BUN and creatinine. Also, changes of PPAR-delta in kidney and renal mesangial cell (RMC) were analyzed using Western blot.
Results: Serum TNF-α was markedly raised in mice showing hepatic steatosis. However, the levels of blood lipids (TC, TG, HDL-C and LDL-C) and TNF-α were not modified by the treatment of etanercept although the hepatic steatosis has been improved. Etanercept shows renal protection from histological identification and recovery of serum BUN and creatinine levels. Moreover, restoration of PPAR-delta expression by etanercept was observed in mice kidney. Direct effect of TNF-α on PPAR-delta expression was also characterized in RMC cell.
Conclusion: The present study suggested that renal damage in mice with hepatic steatosis is mainly induced by increase of TNF-α through the decrease of renal PPAR-delta. Etanercept could block TNF-α to restore PPAR-delta and improve renal function in mice with hepatic steatosis.


目錄 Ⅰ
英文縮寫 Ⅲ
中文摘要 Ⅳ
英文摘要 Ⅵ
壹、導論 1
一、慢性腎衰竭 1
二、脂肪肝 2
三、慢性腎衰竭和肥胖及脂肪肝的關係 3
1. 慢性腎衰竭和肥胖的關係 3
2. 慢性腎衰竭和脂肪肝的關係 3

四、Peroxisome proliferator-activated receptors (PPARs). 5
1. Peroxisome. 5
2. Peroxisome proliferator-activated receptors 5

五、TNF-α 7
1. TNF-α. 7
2. TNF-α blocker: etanercept 8

貳、研究構想 9
參、研究材料與方法 10
一、實驗藥品 10
二、實驗動物 10
三、實驗步驟 10
1. 動物實驗 10
2. 測量TNF-α level. 11
3. 組織切片. 11
4. 測量活性氧自由基(reactive oxygen species) 12
5. 西方墨點法分析(Western blotting analysis). 12
6. 細胞培養(Cell cultures) 13
7. 統計分析 14

肆、結果 14
ㄧ、TNF-α blockade (etanercept )對血脂及肝臟的影響 14
二、TNF-α blockade (etanercept )對腎臟功能及腎組織切片的影響 15
三、TNF-α 的表現 15
四、PPAR-? 在高脂飼料公鼠腎臟的表現 15
五、活性氧自由基(reactive oxygen species; ROS)的變化 16
伍、討論 17
陸、結論 20
柒、參考文獻 21
捌、圖表 32



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