臺灣博碩士論文加值系統

背景： 代謝相關性脂肪肝(Metabolic associated fatty liver disease, MAFLD)是最常見的慢性肝病，與肥胖、胰島素阻抗和糖尿病相關。先前研究已顯示出間歇性斷食(Time-restricted feeding, TRF)對代謝症候群的功效。但TRF 在 MAFLD及高脂飲食心臟損傷中的作用和詳細機制尚不清楚。
目的： 探討餵食高脂飲食(HFD)的小鼠進行間歇性斷食(TRF)的分子機制。
方法： 24隻C57BL/6 (5週大)小鼠隨機分配到Control 6隻(正常飲食)、HFD 6隻、HFD+TRF 5週6隻以及HFD+TRF 2週6隻(10：00-16：00，斷食18小時)實驗進行10週。評估體重、食物攝取量、血清生化分析。透過H&E和Oil Red O檢查心臟和肝臟的病理切片，接著透過轉錄體學的分析和西方墨點法，評估餵食高脂飲食的小鼠進行TRF的分子機制。
結果： TRF 5週組和TRF 2週組的體重在進行TRF一週後都有明顯降低，而且TRF兩組的總熱量攝取低於HFD組。在肝臟的H&E以及Oil Red O中在TRF組有減少脂肪的情形。而心臟的H&E也顯示改善了心肌纖維斷裂。相較之下TRF 5 週比TRF 2週組對於 HFD 引起的肥胖、心臟損傷和 MAFLD 症狀有更顯著效果。從心臟RNA-seq的差異基因帶入基因功能分類(GO)資料庫和京都基因與基因組百科全書(KEGG)資料庫中分析發現TRF 5週組心臟的差異基因參與了適應性產熱、體溫調節、晝夜節律路徑、 Rap1信號路徑，另外發現TRF 2週組心臟的差異基因參與脂質代謝的調節、冷影響產熱調節、晝夜節律、膽固醇代謝、PPAR信號路徑這些路徑。而TRF 5週組對於肝臟的差異基因則參與了脂肪酸代謝、磷酸核苷代謝的過程、PPAR信號通路、產熱作用，另外發現TRF 2週組肝臟的差異基因參與了Wnt信號路徑、血管平滑肌收縮路徑、PPAR信號路徑。我們進一步利用西方墨點法驗證，發現HFD組顯著增加脂肪酸合成與代謝，並顯著降低AMPK信號路徑，而TRF 5週組和TRF 2週組則顯著降低脂肪酸合成與代謝及顯著增加AMPK 信號路徑；胰島素阻抗、內質網壓力、MAPK信號路徑在HFD組中影響顯著增加，而在TRF 5週組和TRF 2週組則顯著降低。最後細胞自噬路徑在2個TRF組中均顯著增加。因此我們使用西方墨點法驗證TRF能夠藉由調控脂肪酸合成與代謝、胰島素阻抗、AMPK、內質網壓力、MAPK和細胞自噬相關路徑改善代謝相關性脂肪肝的情況。
結論： 我們對TRF改善代謝症候群的分子機制提供了更好的見解，這是對高脂飲食所導致的心臟代謝異常及MAFLD 的潛在策略。

Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease, which is related to obesity, insulin resistance, and diabetes. Time-restricted feeding (TRF) has shown the efficacy against metabolic symptoms. However, the detailed mechanisms remain unclear. This study aimed to explore the molecular mechanisms of TRF in high fat diet (HFD) induced MAFLD and heart injury. Twenty-four of C57BL/6 (5-week-old) mice. Six of mice were divided into control (normal chow diet), six of mice were divided into HFD, six of mice were divided into HFD+TRF 5 weeks and six of mice were divided into HFD+TRF 2 weeks (10-16 feeding, 18 hours fasting) for 10 weeks. In this study, we compared how different between HFD+TRF 2 weeks and HFD+TRF 5 weeks. Body weight, food intake, serum biochemical analysis, and lipid profiles were assessed, and both TRF groups had lower caloric intake than the HFD group. Pathology of heart and liver were examined by H&E and oil Red O. The mechanistic insights of TRF in HFD induced MAFLD and cardio-metabolic effects were analyzed by RNA sequencing and western blotting. Both of TRF 5 week and TRF 2 week significantly attenuated HFD-induced obesity, cardiac injury, and MAFLD symptoms. Analysis of RNA sequencing by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed significant enrichment of adaptive thermogenesis, temperature homeostasis, circadian rhythm and Rap1 signaling pathways in TRF 5 weeks heart tissue; significant enrichment of regulation of lipid metabolic process, regulation of cold-induced thermogenesis, circadian rhythm, cholesterol metabolism, PPAR signaling pathway in TRF 2 weeks heart tissue. In addition, fatty acid metabolism, nucleoside phosphate metabolism, PPAR signaling pathway and thermogenesis were significantly enriched in liver tissue after TRF 5 weeks; Wnt signaling pathway, vascular smooth muscle contraction, PPAR signaling pathway, and were significantly enriched in liver tissue after TRF 2 weeks. We further verified by western blotting method and found that the HFD group significantly increased fatty acid synthesis and metabolism and significantly decreased the AMPK signaling pathway, while TRF 5 weeks group and TRF 2 weeks group significantly decreased fatty acid synthesis and metabolism and significantly increased AMPK signaling pathway；Insulin resistance pathway, ER stress and MAPK pathways were significantly increased in the HFD group, while the TRF 5 weeks group and TRF 2 weeks group were significantly decreased. The autophagy pathway was significantly increased in both TRF groups. Therefore, we further used the western blotting method to verify that TRF can improve metabolic-related fatty liver by regulating fatty acid synthesis and metabolism, insulin resistance, AMPK, endoplasmic reticulum stress (ER stress), MAPK and autophagy. We thus provide a better understanding regarding molecular mechanisms of TRF against metabolic syndrome and it will be a potential strategy against HFD induced cardio-metabolic abnormalities and MAFLD.

目錄 頁
目錄........................................................................................................................I
圖目錄.................................................................................................................IV
表目錄.................................................................................................................. V
縮寫表.................................................................................................................VI
中文摘要.............................................................................................................IX
ABSTRACT .......................................................................................................XI
第一章、緒論....................................................................................................... 1
第一節、高脂飲食............................................................................................... 1
壹、 高脂飲食對身體影響............................................................................. 1
貳、 高脂飲食對肝臟的影響......................................................................... 1
一、 內質網壓力(ER stress)對非酒精性脂肪肝的影響 ........................ 2
二、 細胞自噬 (Autophagy)對非酒精性脂肪肝的影響........................ 3
三、 腸道菌群對非酒精性脂肪肝的影響.............................................. 3
參、 高脂飲食對心臟的影響......................................................................... 4
一、 高脂飲食的心臟對脂肪生成與代謝途徑...................................... 7
第二節、間歇性斷食........................................................................................... 8
壹、 間歇性斷食............................................................................................. 8
一、 168 斷食 ........................................................................................... 9
貳、 間歇性斷食對肝臟的影響................................................................... 10
參、 間歇性斷食對心臟的影響................................................................... 13
第三節、研究動機............................................................................................. 15
II
第二章、研究材料與方法................................................................................. 16
第一節、主要儀器及藥品試劑......................................................................... 16
壹、 儀器及器材........................................................................................... 16
貳、 藥品試劑............................................................................................... 17
參、 抗體....................................................................................................... 17
第二節、方法…................................................................................................. 18
壹、 動物飼養............................................................................................... 18
貳、 檢體組織冷凍包埋與油紅 O (Oil Red O)染色.................................. 20
參、 蛋白質濃度測定（Protein assay）..................................................... 21
肆、 西方墨點法（Western blotting）........................................................ 21
伍、 RNA Sequencing................................................................................... 28
第三章、結果..................................................................................................... 32
第一節、間歇性斷食對於 HFD 誘導的肥胖小鼠模型中體重變化及熱量攝取
與肝臟、腎臟損傷 ALT、AST 和血脂指標的影響....................... 32
第二節、間歇性斷食對於 HFD 誘導的肥胖小鼠模型中肝臟和心臟組織蘇木
素-伊紅染色(H＆E Stain)與油紅 O 染色(Oil Red O Stain)病理切
片分析................................................................................................. 34
第三節、間歇性斷食對於 HFD 誘導的肥胖小鼠模型中心臟基因表現差異分
析......................................................................................................... 35
第四節、間歇性斷食對於 HFD 誘導的肥胖小鼠模型中肝臟基因表現差異分
析......................................................................................................... 38
第五節、間歇性斷食對於 HFD 誘導的肥胖小鼠模型中肝臟組織的脂肪生合
成與代謝相關的蛋白表現................................................................. 41
第六節、間歇性斷食對於 HFD 誘導的肥胖小鼠模型中肝臟組織胰島素阻抗
III
相關的蛋白表現................................................................................. 42
第七節、間歇性斷食對於 HFD 誘導的肥胖小鼠模型中肝臟組織 AMPK 路
徑相關的蛋白表現............................................................................. 43
第八節、 間歇性斷食對於 HFD 誘導的肥胖小鼠模型中肝臟組織的內質網
壓力相關蛋白表現............................................................................. 44
第九節、 間歇性斷食對於 HFD 誘導的肥胖小鼠模型中肝臟組織的 MAPK
路徑相關蛋白表現............................................................................. 45
第十節、 間歇性斷食對於 HFD 誘導的肥胖小鼠模型中肝臟組織的細胞自
噬相關蛋白表現................................................................................. 46
第四章、討論..................................................................................................... 47
第一節、TRF 與不同斷食方法的差異............................................................ 47
壹、 TRF 與生酮飲食(Ketogenic diet ,KD)的比較.................................... 49
貳、 TRF 與戰士飲食 (Warrior Diet)的比較 ............................................. 52
第二節、透過轉錄體學分析 TRF 對心臟代謝的影響 ................................. 52
第三節、透過轉錄體學分析 TRF 對代謝相關性脂肪肝的影響 .................. 58
第四節、脂肪合成與代謝對代謝相關性脂肪肝的影響................................. 62
第五節、內質網壓力對代謝相關性脂肪肝的影響......................................... 63
第六節、MAPK 路徑對代謝相關性脂肪肝的影響 ....................................... 64
第七節、 細胞自噬作用代謝相關性脂肪肝的影響 ....................................... 65
第八節、 TRF (5 weeks)與 TRF (2 weeks)的比較......................................... 66
第五章、結論..................................................................................................... 68
第六章、參考文獻........................................................................................... 120
IV
圖目錄
Figure 1. TRF ameliorates HFD-induced body weight, ALT, AST and lipid
profile ...........................................................................................70-73
Figure 2. TRF ameliorates HFD-induced hepatic steatosis and histopathological
alterations in heart tissue of C57BL/6 model ................................74-76
Figure 3. Transcriptomic profiles of TRF heart using RNA sequencing .......77-84
Figure 4. Transcriptomic profiles of TRF liver using RNA sequencing........85-92
Figure 5. TRF reduced Fatty acid synthesis and metabolic pathways
in HFD-fed C57BL/6 mice ...........................................................93-94
Figure 6. TRF reduced Insulin resistance pathway in HFD-fed C57BL/6 mice
.........................................................................................................95-96
Figure 7. TRF reduced AMPK pathway in HFD-fed C57BL/6 mice ............97-98
Figure 8. TRF reduced ER stress in HFD-fed C57BL/6 mice .....................99-100
Figure 9. Time –restricted feeding reduced MAPK signaling in HFD-fed C57BL/6
mice ..............................................................................................101-102
Figure 10. TRF increases Autophagy signaling pathway in liver tissues..103-104
V
表目錄
Table 1. Top 20 differentially expressed genes in mice heart comparing the
Control with HFD after RNA-seq..............................................105-106
Table 2. Top 20 differentially expressed genes in mice heart comparing the
HFD with TRF (5 weeks) after RNA-seq..................................107-108
Table 3. Top 20 differentially expressed genes in mice heart comparing the
HFD with TRF (2 weeks) after RNA-seq ................................109-110
Table 4. Top 20 differentially expressed genes in mice heart comparing the
TRF (5 weeks) with TRF (2 weeks) after RNA-seq ........................ 111
Table 5. Top 20 differentially expressed genes in mice liver comparing the
Control with HFD after RNA-seq ............................................. 112-113
Table 6. Top 20 differentially expressed genes in mice liver comparing the
HFD with TRF (5 weeks) after RNA-seq.................................. 114-115
Table 7. Top 20 differentially expressed genes in mice liver comparing the
HFD with TRF (2 weeks) after RNA-seq.................................. 116-117
Table 8. Top 20 differentially expressed genes in mice liver comparing the
TRF (5 weeks) with TRF (2 weeks) after RNA-seq ................. 118-119

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