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研究生:林志儒
研究生(外文):Chih-Ju Lin
論文名稱:以活體多光子影像並量化病變老鼠對肝膽代謝之影響
論文名稱(外文):Multiphoton Imaging and Quantification of the Effects of Hepatobiliary Metabolism in Normal and Diseased Mouse Liver In Vivo
指導教授:董成淵
指導教授(外文):Chen-Yuan Dong
口試委員:張顏暉陳定信陳永芳駱遠李宣書胡博琛
口試委員(外文):Yuan-Huei ChangDing-Shinn ChenYang-Fang ChenYuan LuoHsuan-Shu LeePo-Sheng Hu
口試日期:2015-07-09
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:物理研究所
學門:自然科學學門
學類:物理學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:119
中文關鍵詞:肝竇系統急性肝破壞脂肪肝肝硬化肝細胞癌雙光子螢光顯微鏡肝膽系統代謝
外文關鍵詞:hepatic acinusacute hepatic damagefatty liverliver fibrosishepatocellular carcinomatwo-photon fluorescence microscopyhepatobiliary metabolism
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肝臟是人體儲存血量最大的一個器官,亦為維持日常生活機能的一個重要器官。肝臟如此的重要,然而肝病卻是造成全球人類死亡率很高的原因之一。全球每年約有數百萬的人口肝臟相關疾病死亡,而肝病分別來自於急性與慢性的肝細胞破壞,然而肝細胞的破壞往往造成肝細胞功能的損傷。因此,肝膽系統方面的研究一直是個熱門的研究領域,其中肝功能亦是一個非常重要的研究。然而,活體肝膽系統代謝研究,卻是較少被涉獵的部分。本論文中,我們以小鼠動物模型以6-羥基熒光素二醋酸鹽(6-carboxyfluorescein diacetate, 6-CFDA)化學分子來研究探討肝膽系統之代謝情形並予以量化。
肝臟腺胞(Hepatic acinus)為肝臟以功能性區分的最小單元,於此論文中,我們依據肝細胞代謝的能力來劃分肝臟腺胞的三個區帶,分別為Zone 1、2和3,並且建立一階代謝數學函數來量化肝細胞代謝之係數。於肝細胞的代謝過程中,物質(代謝物)經由竇氏膜(Sinusoid membrane)進入到肝細胞,並穿透頂膜(apical membrane)將代謝物代謝到膽小管中排出,此兩個主要的過程,我們分別利用一階代謝函數予以量化彼此之速率係數k1與k2。於正常肝臟中,我們得到k1係數在三個區帶分別為0.2392、0.2945、0.3379(1/min),k2的係數分佈在Zone 1、2和3的值分別為0.0117、0.0175與0.0332(1/min),Zone 3對6-CFDA為主要的代謝區域,與先前的研究定義的肝臟腺胞的定義較為接近,因此,我們以k2的分佈現象來劃分肝臟腺胞的三個區帶。
本論文中,我們分別研究急性肝臟損傷以及慢性肝臟疾病中,不同區帶之代謝速率係數與正常肝臟之差異以及變化。然而於急性肝損傷的老鼠,代謝速率較差為引發肝損傷後第4天,而約莫於第14天,代謝速率的分佈型態與正常的老鼠較為接近,依評估結果推定肝代謝功能恢復需要約莫14天。慢性肝臟疾病又針對非酒精性脂肪肝、肝硬化與肝細胞癌做觀察與探討。以6-CFDA的代謝結果,k1於脂肪肝的三個區帶為0.1792、0.2012與0.2822(1/min),肝纖維化的肝臟為0.2196、0.2293與0.2139(1/min),而肝癌為0.3718、0.3137與0.2680(1/min),此外,k2於脂肪肝的三個區帶值分別為0.0216、0.0263與0.0308(1/min),肝纖維化為0.0275、0.0282與0.0340(1/min),此外肝癌為0.0231、0.0237,及0.0283 (1/min)。k2值於有疾病之各區帶中幾乎都是增加的,而降低的反而是k1的值。此一結果,相信是肝臟學中一個新的研究成果。


Liver is the largest organ that contains blood, and it is the main organ responsible for maintaining daily function. Since liver is an important organ, therefore, hepatic diseases contributes to a high percentage of mortality rate in whole world. There are millions of people die due to hepatic diseases each year, and the basic causes are injury by acute or chronic hepatic factors. Thus, investigating hepatic diseases is an important subject, with the study of hepatic functions as an important direction to understand the liver. However, in vivo hepatobiliary metabolism remain to be further studied. In this thesis, we used the mouse model and molecular probe 6-carboxyfluorescein diacetate (6-CFDA) to investigate and quantify the hepatobiliary metabolism in normal and diseases livers.
Hepatic acinus is the unit that defined with hepatic functional distribution, there are three defined zones in the hepatic acinus. The three zones are Zone 1, Zone 2, and Zone 3. In this thesis, we setup a first-order mathematic hepatocellular metabolic function to quantify the ratio coefficients of hepatocellular metabolism. In hepatobiliary metabolism, xenobiotic was uptaken from sinusoid into hepatocytes via sinusoidal membrane, and the metabolite was excreted from hepatocytes into bile canaliculi via apical membrane. In these two main processes, the quantification of this two ratio coefficients was defined as k1 and k2 by first-order kinetic function. In normal liver, k1 of Zone 1, 2, and 3 are 0.239, 0.295, and 0.338 (1/min), k2 are 0.0117, 0.0175, and 0.0332 (1/min).
In this thesis, we investigate and quantify the differences and variances in zones of acute hepatic injury and chronic hepatic diseases. In acute liver injury and recovery, the metabolic ratio of Day 4 is the worst and hepatic metabolic function is needed 14 days to be repaired. For chronic hepatic diseases, we focus onto the nonalcoholic fatty liver, hepatic cirrhosis and hepatocellular carcinoma (HCC). For 6-CFDA metabolism, zonal k1 values of fatty liver are 0.179, 0.201, and 0.282 (1/min). The k1 value of three zones are 0.220, 0.229 and 0.2140 (1/min) in liver fibrosis, and 0.372, 0.314 and 0.268 (1/min) in hepatocellular carcinoma. Thus, k2 of fatty liver are 0.0216, 0.0263, and 0.0308 (1/min), k2 of liver fibrosis are 0.0275, 0.0282, and 0.0340 (1/min). Finally, k2 of Zone 1, 2, and 3 are 0.0231, 0.0237, and 0.0283 (1/min) in HCC.


致謝…………………………………………………………………………………….i
Abstract…………………………………………………………………...……...…...iii
摘要…………………………………………………………………………………...v
Publication List……………………………………………………………………….vii
Contents……………………………………………………………………….………ix
Figures Catalog…………………………………………………………………….....xii
Tables Catalog………………………………………………………………………xvii

Chapter 1. Introduction……………………………….……………….…….………1
1-1 Motivation ……………………………………………………………....…….1
1-2 Historical Review……………………………………………………………...4
Chapter 2. Principle of Microscopy and Hepatic Imaging Setup…………...……...7
2-1 Basic Concepts of Microscopy………………………..…...……………………7
2-1-1 Mode Locking…………………..……………………………….……….7
2-1-2 Point Spread Function……………..……………………………………..9
2-1-3 Resolution…………………..…………………………………………..12
2-2 Nonlinear Optics………………………………..…………………………...15
2-2-1 Historical perspectives………..…………………………...……………15
2-2-2 Two-photon Fluorescence Microscopy………..………………………..16
2-2-3 Second Harmonic Generation………………..…………………………20
2-3 Setup of Fluorescence Microscopy….…………………..…………………...25
2-4 Setup of Intravital Hepatic Imaging Window…………………...…………...28
Chapter 3. Hepatobiliary Metabolism in Hepatic Acinus…………..…………….31
3-1 Hepatic Histology and Hepatic Acinus…………………….…..…………….31
3-2 Hepatobiliary Metabolism………………………..………………………….35
3-3 Molecular Probe of 6-carboxyfluorescein Diacetate (6-CFDA) Metabolism in Hepatobiliary System……………………..………………………………….36
Chapter 4. Distributions of Hepatocellular Metabolic Coefficients in Hepatic Acinus…………………………………………………………………….….39
4-1 First-order Mathematic Metabolic Functions…………………………....…..39
4-2 Kinetic Constant Distributions and Analysis of Hepatic Acinus……..………49
4-3 Discussion…………………………..……………………………………….54
Chapter 5. Acute Hepatitis Caused Hepatocellular Metabolic Function Damage.55
5-1 Mechanism of Carbon Tetrachloride (CCl4) Metabolism and Damage in Hepatic Acinus……………………………………………………………….55
5-2 Hepatic Membrane Rupture in Dynamic Image………………..……………59
5-3 Metabolic Variance of Injury Hepatobiliary System……………..…………..61
5-4 Discussion…………………………………………………………………...68
Chapter 6. Chronic Hepatic Diseases Affect Hepatobiliary Metabolism…..…..…69
6-1 Mechanism of Methionine Choline Deficient (MCD) Induced Nonalcoholic Fatty Liver……………………………………………………………………69
6-2 Mechanism of Long-term Carbon Tetrachloride (CCl4) Cause Liver Fibrosis (Cirrhosis)…………………………………………………………………….74
6-3 Collagen of Liver Fibrosis……………..…………………………………….76
6-4 Hepatobiliary Metabolic Variance for Chronic Hepatic Diseases (Fatty Liver and Liver Fibrosis)……………………………………………………………78
6-5 Discussion…………………………………………………………………...86
Chapter 7. Effect of Hepatocellular Carcinoma (BNL eGFP Cell Lines) on Hepatobiliary Metabolism …………...…….……………………………87
7-1 BNL Tumor Cell Line………………………………………………………..87
7-2 eGFP for Multiphoton Fluorescence Microscopy……………………………88
7-3 Hepatobiliary Metabolism in Tumorous Liver………………………………89
7-4 Discussion…………………………………………………………………...95
Chapter 8. Conclusion………………………………………….…………………...97
Additional Experimental Results……………………………………………………103
References…………………………………………………………………………..107


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