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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 蔡丰喬 | zh_TW |
| dc.contributor.advisor | Feng-Chiao Tsai | en |
| dc.contributor.author | 鄭耀斌 | zh_TW |
| dc.contributor.author | YAO-BIN ZHENG | en |
| dc.date.accessioned | 2024-08-27T16:08:10Z | - |
| dc.date.available | 2024-08-28 | - |
| dc.date.copyright | 2024-08-27 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-07-31 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/95055 | - |
| dc.description.abstract | NAFLD（非酒精性脂肪肝病）由於肥胖、糖尿病、胰島素抵抗、基因遺傳及肝臟脂肪代謝紊亂等因素發展而來，導致肝臟脂肪積累。這種脂肪積累會引起肝損傷、炎症和纖維化，進而可能發展成NASH（非酒精性脂肪性肝炎）、肝硬化甚至肝癌。在一項回顧性研究中，我們測試了hydroxychloroquine (HCQ)對脂肪性肝炎患者的治療潛力。結果顯示，接受HCQ治療的患者在一個月內serum alanine transaminase（ALT）水平顯著降低（治療前94.1 ± 44.9 U/L vs. 治療後一個月46.7 ± 24.0 U/L，N=26，p < 0.001）。因此，HCQ在緩解脂肪性肝炎方面非常有效。
為了理解HCQ如何緩解脂肪性肝炎的機制，我們將HCQ應用於包括hepatocytes、stellate cells（fibroblast）和Kupffer cells （monocytes/macrophages）在內的肝臟常駐活細胞。結果顯示，治療濃度下（1.45-2.90 μM）的HCQ不影響HepG2細胞的活力。此外，當使用palmitic acid（PA）刺激肝臟free fatty acid（FFA）積累時，HCQ對肝臟內的脂肪積累沒有顯著影響。有趣的是，我們發現HCQ可以抑制飢餓誘導下的肝細胞油滴生成，HCQ不僅減少了細胞內的油滴數量，還抑制了新油滴的形成。 然而，在細胞活力和活性方面，我們觀察到肝臟星狀細胞（HSCs）對HCQ比HepG2細胞更為敏感。HCQ通過自噬抑制減少了活化HSC中的F-actin信號，但對α-SMA和Collagen I的mRNA和蛋白表達水平沒有影響。 在免疫微環境方面，我們利用ELISA測量了涉及肝臟發炎的關鍵inflammatory cytokines，包括IL-1β、IL-6和TNF-α。結果顯示，治療濃度下的HCQ並不抑制THP-1免疫細胞和HSCs的cytokine secretion。 總結來說，我們發現HCQ不會改變營養過剩誘導的油滴形成，但會抑制飢餓誘導的油滴生成。然而，它可能通過靶向肝臟星狀細胞的活力來減少纖維化。通過建立這些平台，我們對HCQ緩解NAFLD的機制有了更好的理解。因此，HCQ未來可能成為治療NAFLD的新型潛力藥物。 | zh_TW |
| dc.description.abstract | NAFLD (Non-Alcoholic Fatty Liver Disease) arises from factors such as obesity, diabetes, insulin resistance, genetics, and disruptions in liver fat metabolism, which result in the accumulation of fat in the liver. This accumulation can cause liver damage, inflammation, and fibrosis, potentially progressing to NASH (Non-Alcoholic Steatohepatitis), cirrhosis, or even liver cancer. In a previous retrospective study, we tested the therapeutic potential of hydroxychloroquine (HCQ) in patients with steatohepatitis. The results showed that the patients receiving HCQ had significantly reduced serum alanine transaminase (ALT) levels within one month (94.1 ± 44.9 U/L before HCQ vs. 46.7 ± 24.0 U/L one month after HCQ, N=26, p < 0.001). Therefore, HCQ is very effective in alleviating steatohepatitis.
To understand the mechanism of how HCQ alleviated steatohepatitis, we applied HCQ to resident live cells including hepatocytes, stellate cells (fibroblast), and Kupffer cells (monocytes/macrophages). HCQ at therapeutic concentrations (1.45-2.90 μM) did not impact the viability of HepG2 cells. Additionally, when free fatty acid (FFA) accumulation in the liver was stimulated using palmitic acid (PA), HCQ did not significantly influence lipid accumulation within the liver. Interestingly, we discovered that HCQ can inhibit starvation-induced lipid droplet biogenesis in hepatocytes. HCQ not only decreased the number of lipid droplets within the cells but also prevented the formation of new lipid droplets. However, regarding cell viability and activity, we observed that hepatic stellate cells (HSCs) were more sensitive to HCQ than HepG2 cells. HCQ reduced F-actin signals in activated HSCs by inhibiting autophagy, but it did not impact the mRNA and protein expression levels of α-SMA and Collagen I. In terms of the immune microenvironment, we utilized ELISA to measure key inflammatory cytokines involved in liver inflammation, including IL-1β, IL-6, and TNF-α. Our results indicated that HCQ, at therapeutic concentrations, did not inhibit cytokine secretion from THP-1 immune cells and HSCs. In conclusion, we found that HCQ did not alter nutrient surplus-induced lipid droplet formation but inhibited starvation-induced lipid droplet formation. However, it may target the viability of hepatic stellate cells to reduce fibrosis. Through the establishment of these platforms, we have gained a better understanding of how HCQ alleviates NAFLD. Therefore, HCQ has the potential to become a novel therapeutic drug for NAFLD in the future. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-08-27T16:08:09Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-08-27T16:08:10Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員審定書 i
誌謝 ii 中文摘要 iii Abstract v Table of content vii Figures and Legends xii Tables xiv Chapter 1 Introduction 1 1-1 Overview of nonalcoholic fatty acid liver disease (NAFLD) 1 1-2 Drug therapy in NAFLD 2 1-3 The background of using Hydroxychloroquine (HCQ) in treating steatohepatitis 3 1-4 The pathogenesis of NAFLD 9 1-5 Molecular mechanisms of HCQ 11 1-6 The possible mechanism of how HCQ relieve NAFLD 12 1-6-1 Regulation of lipid metabolism in hepatocytes 12 1-6-2 Regulating immune response to inhibit inflammation 13 1-7 Aim of the study 13 Chapter 2 Material and Methods 15 2-1 Cell culture 15 2-2 Palmitic acid assay 16 2-3 Lipogenesis assay 16 2-4 Oil red O staining 17 2-5 Myofibroblast differentiation assay 17 2-6 Immunofluorescence staining of stress fiber 18 2-7 Immunofluorescence staining of actin cytoskeleton and Collagen I 19 2-8 Cell Counting Kit-8 (CCK-8) assay 20 2-9 Protein extraction and western blotting 21 2-9-1 protein extraction 21 2-9-2 SDS-PAGE and protein transfer 22 2-9-3 Primary and secondary antibody incubation 22 2-9-4 Chemiluminescent detection and quantification 23 2-10 RNA isolation and quantitative real-time PCR (qPCR) 23 2-11 Enzyme-linked immunosorbent assay (ELISA) assay 25 2-12 Monocyte adhesion assay 26 Chapter 3 Result 28 3-1 HCQ may not affect lipid accumulation in the liver during PA addition 28 3-1-1 Platform and quantification method establishment 28 3-1-2 HCQ at therapeutic concentrations (1.45 - 2.90 μM) did not alter lipid accumulation induced by palmitic acid 28 3-1-3 HCQ did not affect PLIN2 protein levels under high PA treatment 34 3-2 HCQ may inhibit starvation-induced lipid droplet biogenesis, particularly affecting the formation of small lipid droplets in HepG2 cells 36 3-2-1 Platform and quantification method establishment 36 3-2-2 HCQ reduced the formation of small lipid droplets without impacting the formation of large lipid droplets during nutrient deprivation 40 3-2-3 HCQ did not affect PLIN2 protein levels under 72 hours of serum starvation 45 3-3 HCQ targeted the viability and activity of stellate cells via autophagy inhibition 47 3-3-1 Platform and quantification method establishment 47 3-3-2 TGF-β combined with FGFRi enhanced α-SMA and COL1A1 expression 51 3-3-3 HCQ may target the viability and activity of HSCs via autophagy inhibition 54 3-3-4 HCQ may not affect the mRNA and protein expression levels of α-SMA and COL1A1 60 3-3-5 HCQ may not decrease inflammatory cytokine secretion in HSCs 62 3-4 HCQ may not decrease inflammatory cytokine secretion in THP-1 monocytes and macrophages within the therapeutic range 65 3-4-1 The inflammatory cytokine secretion in immune cells was not affected by HCQ 65 3-4-2 HCQ may not inhibit THP-1 adhesion in activated endothelial cells 69 Chapter 4 Conclusion 72 Chapter 5 Discussion 73 5-1 High HCQ concentration increased lipid accumulation 73 5-2 Starvation-induced LD biogenesis was activated by autophagy 75 5-3 HCQ might indirectly affect ER budding through its impact on the autophagy process 78 5-4 Thapsigargin-induced ER stress did not induce hepatic cell lipogenesis 83 5-5 Induce lipid droplet biogenesis using serum starvation stress conditions 85 5-6 The different quantification methods for lipid droplet signals between the PA assay and the starvation-induced LD biogenesis assay 86 5-7 α-SMA was not significantly expressed in TGF-β combined with FGFRi activated HSCs 87 5-8 Autophagy activation may be important for HSC activation 89 5-9 HCQ weakened the actin stress fiber signal, which might not be attributed to changes in actin stress fiber biogenesis 89 5-10 HCQ can inhibit LPS-induced immune responses 92 5-11 HCQ may inhibit the differentiation process of PMA-induced THP-1 macrophages 93 5-12 Limitations of this study 95 5-12-1 We did not measure TG levels in HepG2 cells following the addition of PA 95 5-12-2 The choice of cell line in hepatocyte studies 95 5-12-3 We focused solely on an in vitro platform to observe the effects of HCQ in steatohepatitis 96 Chapter 6 Future works 97 Chapter 7 References 98 Chapter 8 Supplementary information 105 8-1 Fluorescence correction in Oil Red O signal 105 8-2 Quantification of Oil Red O signal 108 8-3 Background subtraction for lipid droplets 117 8-4 Quantification of lipid droplets diameter and signal 119 8-5 Fluorescence correction in F actin and COL1A1 signal 133 8-6 Quantification of F actin and COL1A1 signal 135 8-7 Quantification of THP-1 and HUVEC cell number 144 | - |
| dc.language.iso | en | - |
| dc.subject | 免疫微環境 | zh_TW |
| dc.subject | 脂質生成 | zh_TW |
| dc.subject | 脂肪性肝炎 | zh_TW |
| dc.subject | 自噬抑制 | zh_TW |
| dc.subject | steatohepatitis | en |
| dc.subject | lipogenesis | en |
| dc.subject | autophagy inhibition | en |
| dc.subject | immune microenvironment | en |
| dc.title | 探討hydroxychloroquine如何緩解脂肪性肝炎 | zh_TW |
| dc.title | Investigating how hydroxychloroquine relieves steatohepatitis | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 林琬琬;楊宏志;王錦堂 | zh_TW |
| dc.contributor.oralexamcommittee | Wan-Wan Lin;Hung-Chih Yang;Jin-Town Wang | en |
| dc.subject.keyword | 脂肪性肝炎,脂質生成,自噬抑制,免疫微環境, | zh_TW |
| dc.subject.keyword | steatohepatitis,lipogenesis,autophagy inhibition,immune microenvironment, | en |
| dc.relation.page | 152 | - |
| dc.identifier.doi | 10.6342/NTU202402635 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2024-07-31 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 藥理學研究所 | - |
| dc.date.embargo-lift | 2029-07-30 | - |
| 顯示於系所單位： | 藥理學科所 | |
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