2013-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/659950摘要：非酒精性脂肪肝為最常見的慢性脂肪肝疾病之一，其肝臟中三酸甘油脂含量大於肝臟重量的 5%以上。主要成因為肝臟中脂肪以及其他生理代謝異常所造成，相關疾病，包括:肥胖、糖尿病、心血管疾病以及肝解毒功能下降甚至肝癌，皆對國人健康造成莫大影響。建立疾病動物模型可以有效了解機制外，亦可提供病因學上的研究；更重要的是，可進一步作為藥物篩選的工具，找出具有肝臟保護以及提高肝臟代謝能力與解毒功能的潛力藥物或化合物。為達此目的，本三年計畫欲建立熱休克蛋白 HLJ1基因剔除小鼠，藉由其所表現的脂肪肝病徵，探討肝臟內質網壓力失衡造成脂肪代謝異常機制。主要策略與目標有:建立與量產 HLJ1 基因剔除小鼠提供疾病研究模型、探討 HLJ1 蛋白在肝臟內質網壓力失衡下導致脂肪代謝異常的分子機制、利用基因體學策略(包含基因表現微陣列、新一代定序儀全轉錄體掃描)分析 HLJ1 所調控之重要訊息和路徑、利用代謝體學分析 HLJ1 影響之肝臟小分子代謝、利用飲食壓力或肝臟損傷或致癌物暴露等活體實驗探討 HLJ1 於肝臟保護作用能力、利用初代肝細胞培養與高涵量篩選系統找出潛力肝臟保護藥物或化合物。藉由三年計畫執行，除可了解脂肪肝相關疾病致病機制，亦可找出潛力保肝藥物或化合物提升肝臟健康。<br> Abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver steatosis disease with contenting of triglyceride exceeding 5% of liver weight. The major cause is the abnormality of lipid metabolism in liver. Related diseases including obesity, diabetes, cardiovascular diseases as well as hepatoma had a great impact to the health of citizens. To establish disease animal model can not only realize the mechanism but also investigate its etiology. The most important is this model can provide a powerful tool for potential drugs or compounds screening in liver protection and detoxification. To achieve this goal, this three year proposal aims to dissect the mechanism of liver steatosis due to unbalanced ER stress mediated metabolic abnormality by generation of heat shock protein, HLJ1, deficient mice exhibited fatty liver phenomena. The major strategies and specific aims are: a. Establishment and generation of HLJ1 deficient mice by gene targeting strategy for human disease modeling. b. To identify the HLJ1 involved molecular mechanism in liver unbalanced ER stress mediated lipid metabolic abnormality. c. To analyze HLJ1 regulated significant signaling and pathway by genomic strategy including gene expression microarray analysis and whole genome transcriptome scanning by next generation sequencer. d. To identify HLJ1 related small metabolites in liver by metabolomics strategy. e. To specify the liver protective effects of HLJ1 in vivo by utilizing experimental animal model of food feeding stress, liver injury and carcinogen exposure. f. To combine mouse primary hepatocyte isolation and high content screening system for identifying potential drug or compound in liver protection and detoxification. With the progress of this proposal, we can not only clarify the molecular mechanism and etiology of liver steatosis as well as related diseases but also identify potential liver protective drug or compound for health improvement.