2016-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/644845摘要：非酒精性脂肪肝(簡稱脂肪肝)會導致肝臟功能失常，進而影響肝損傷或肝切除後之再生能力。如何改善脂肪肝的肝臟再生，是臨床與基礎研究的重要議題。我們先前的研究証實，脂肪肝大鼠肝臟部份切除後，肝臟再生能力確實明顯降低，而肝組織中粒線體基質的抗凋亡蛋白Mcl-1，在脂肪肝也顯著下降，顯示肝臟細胞的抗凋亡機制與肝臟再生能力相當有關聯。此外，我們也發現脂肪肝粒線體之ATP 產率會降低，粒線體之mtROS (mitochondrial reactiveoxygen species)會大量增加、初步試驗結果也顯示抗氧化劑具有促進脂肪肝肝臟部份切除後之肝臟再生能力。由於粒線體的能量代謝機能與細胞凋亡關係密切，粒線體的代謝機能異常可能是導致脂肪肝影響肝再生重要的關鍵因素，目前並無這方面之研究報告。本計畫將以MCD(methionine choline-deficient)誘發脂肪肝小鼠，利用肝臟部份切除引發肝臟再生模式，探討脂肪肝粒線體之活性及能量代謝反應在肝臟再生過程中的角色，並研究粒線體治療之應用價值。分年目標與研究策略:第一年：以動物模式比較脂肪肝與正常肝接受部分肝臟切除後，肝臟再生過程中，肝臟組織粒線體之(a)數量;(b)活性;(c)細胞凋亡狀態之變化;並(d)找尋粒線體上細胞凋亡基因調節機制(如Mcl-1, Bcl-2 等)與肝臟再生能力的相關性。第二年：運用海馬生物能量測定儀(Seahorse XFe extracellular analyzer)以細胞模式比較不同脂肪肝程度與正常肝接受部分肝臟切除後，肝細胞與肝竇狀內皮細胞之粒線體代謝變化情形，包含(a)ATP;(b)ROS 產生;(c)耗氧率等之變化，並研究(d)粒線體代謝途徑之改變情形。第三年：以動物模式評估脂肪肝與正常肝接受部分肝臟切除後，以粒線體治療方式，調節粒線體能量代謝途徑:(a)增加粒線體數量;(b)增加ATP;(c)增加抗ROS 能力，測定(d)粒線體治療之分子機制對改善脂肪肝之肝臟再生潛力。本計畫可能產生對社會、經濟、學術發展等面向的預期影響性：脂肪肝是日趨嚴重的問題，期望本研究能釐清粒線體之能量代謝反應在脂肪肝情況下，影響肝臟再生的病理角色，並由粒線體治療方式，發展出可能的預防與治療策略。<br> Abstract: Patients with non-alkaholic fatty liver disease (NAFLD), or so called as fatty liver (FL), maylead to the liver dysfunction and impair the degree of liver regeneration (LR) after hepatic injury,such as partial hepatectomy (PH). How to improve the capability of LR are important both inclinical or basic issues. Our previous study has demonstrated the positive correlation between themitochondrial anti-apoptotic ability and the capability of LR after PH. In rat FL model, the lowexpression of anti-apoptosis protein Mcl-1 which is expressed in the matrix of mitochondrial iscorrelated with the poor LR process. We also found that in the methionine choline-deficient (MCDdiet) induced FL model, the ATP production is attenuated, and the mitochondrial reactive oxygenspecies (mtROS) production is increased in the remnant liver. Additionally, our preliminary datarevealed that anti-oxidant reagent could increase the capability of LR in FL after PH. However,whether the abnormal mitochondrial metabolism is the critical factor for the poorer LR of FL is notwell defined. Because the mitochondrial metabolism is highly related to the regulation of cellapoptosis and LR, in this project, we will use the MCD diet inducing FL mice, and perform PHinduced LR model to evaluate the role of mitochondrial variation, its energy metabolic response,and the effect of mitochondrial on therapy LR after PH in FL situation.The specific aim, strategy of each year:The first year, by using animal model, we will investigate the remnant liver tissue variation of: (a)mitochondrial number; (b) mitochondrial activity; (c) mitochondrial apoptotic genetic status; and (d)mitochondrial apoptosis regulatory mechanism; the relationship between mitochondrial changes andthe capability of LR in FL after PH.The second year, by using cell models, we will investigate the remnant liver cells (hepatocyte, andliver sinusoidal endothelial cells) metabolism of mitochondrial, including (a) ATP variations; (b)ROS changes; (c) Oxygen consumption status; and (d) mitochondrial energy production changingpathway in different degrees of FL during LR after PH.The third year, by using animal model, we will investigate the therapeutic effect of mitochondrialtherapy including: (a) increasing mitochondrial number; (b) increasing mitochondrial ATP; (c)enhance mitochondrial anti-ROS ability, and (d) try to find out the molecular effect ofmitochondrial therapy on FL during LR after PH.The population of FL is increasing nowadays; we expect to realize the pathological roles ofmitochondrial metabolism in poor LR after PH, and develop mitochondrial therapy for possibleprevention and therapeutic approach to improve LR and liver function in FL after PH.脂肪肝肝臟再生粒線體粒線體治療抗氧化Fatty liverLiver regenerationmitochondriamitochondrial therapyanti-oxidant