臺灣博碩士論文加值系統

本研究建立吳郭魚作為非酒精性脂肪肝 (nonalcoholic fatty liver disease, NAFLD) 之動物模式，以此模式及細胞模式評估台灣蜆 (Corbicula fluminea) 熱水萃後之殘肉 (residual meat of freshwater clam, FCR) 及其乙醇萃取物 (ethanol extract of FCR, FCRE) 減緩 NAFLD 之作用，鑑定 FCR 及 FCRE 之脂溶性機能性成分，並探討提升蜆機能性成分之育肥策略。
吳郭魚攝食高脂飼料 (high-fat diet, HFD) 2 週後，其血漿丙胺酸轉胺酶 (alanine aminotransferase, ALT)、天門冬胺酸基轉移酶 (aspartate transaminase, AST)分別較控制組高 3.7 及 3.3 倍、肝體比增 1.6 倍，肝臟三酸甘油酯和總膽固醇分別增加 2.2、2.3 倍，肝臟脂肪酸含量為控制組的 1.9 倍，單元不飽和脂肪酸 (monounsaturated fatty acids, MUFAs) 最高，佔 53%，其次為飽和脂肪酸 (saturated fatty acids, SFAs) 佔 37%；將 SFAs 去飽和為 MUFAs 的 stearoyl-CoA desaturase (SCD, C18:1n9/ C18:0) 由 2.72 升至 5.26；多元不飽和脂肪酸 (polyunsaturated fatty acids, PUFAs) 的 n3/n6 比值由控制組的 2.4 降至 0.5。肝細胞直徑增為控制組的 1.7 倍，為氣球樣變性 (ballooning degeneration)，肝臟並有發炎細胞浸潤，即為非酒精性肝炎 (nonalcoholic steatohepatitis, NASH)。
以攝食 HFD 之吳郭魚作為 in vivo 模式，評估 FCR 或 FCRE 護肝功效，攝食二者 2 週後均顯著 (p<0.05) 降低血漿 AST、ALT、肝體比及肝臟之總膽固醇、三酸甘油酯。FCRE 使肝臟之 SFAs、MUFAs 分別減少 50%、66%，SCD (C18:1n9/ C18:0) 下降 38%，PUFAs n3/n6 比值增加 2.1 倍；FCRE 並減緩肝細胞氣球樣變性、肝臟發炎指標 PGE2 和發炎細胞浸潤。血漿中三酸甘油酯、總膽固醇之濃度也顯著 (p<0.05) 低於 HFD 組，分別減少 50% 和 20% 以上。
吳郭魚作為模式以印證蜆之功效與小鼠之結果相同，均可以 HFD 誘發 NAFLD，並為可逆反應，與餵食小鼠 HFD 10 週後，血漿 ALT、肝臟三酸甘油酯和總膽固醇分別增加 1.9、4.1 和 2.0 倍，症狀相似，但吳郭魚誘導時間為小鼠的 1/5，可做為快篩護肝食品之模式動物。
HepG2 細胞之 in vitro 試驗中，FCRE 提升細胞存活率，減緩游離脂肪酸誘發之脂質堆積，顯著 (p<0.05) 降低脂肪酸合成酶活性、使脂肪酸 β-氧化酵素粒線體之 carnitine palmitoyltransferase-1 (CPT-1)、CPT-2，和過氧化體 (peroxisome) acyl-CoA oxidase (ACO) 之活性顯著 (p<0.05) 增加，並有濃度依存性。
在 FCR 和 FCRE 之脂溶性成分中，鑑定出其機能性含植物固醇，有 campesterol、brassicasterol、β-sitosterol、stigmasterol 及 PUFAs，其 n3/n6 比值均 > 2。FCRE 之總植物固醇 (3.18 mg/g) 和 n3 PUFAs (65.1 mg/g) 含量分別高於 FCR 達 7 倍和 4 倍。
蜆之植物固醇來自所濾食之微藻，以蛋白核小球藻、橢圓小球藻、四尾柵藻及二角盤星藻為主，以微藻或輪蟲育肥，蜆之植物固醇含量分別較控制組增加 13% 和 11%，以蜆殘肉水解物育肥增 5%，大豆蛋白水解物育肥植物固醇含量減少 8%。育肥之蜆。四種餌料均未能增加蜆之 n3 PUFAs，但蜆之肥滿度皆較控制組高，以輪蟲、蜆殘肉水解物育肥蜆之肥滿度均 >15%。
本研究確認吳郭魚可作為非酒精性脂肪肝疾病的模式動物，以製蜆精後之殘肉確認其降低肝臟脂肪酸生合成、提高脂肪酸 β-oxidation、調節肝臟脂肪酸去飽和之作用、減少肝臟脂質堆積、延緩發炎的功效，並發展出提升其機能性成分之育肥策略，自蜆肉護肝素材製成膠囊可於常溫貯藏 3.5 個月。

The purpose of this study was to develop an alternative animal model for assessing nonalcoholic fatty liver disease (NAFLD), applicable to evaluate the hepatoprotective effect of functional foods and ingredients. Tilapia was used as a test animal model and the residual meat of freshwater clam (FCR) and its ethanol extract (FCRE) were determined. The functional compounds of the FCR and FCRE were identified and strategy to increase functional compounds.
Tilapia were fed high-fat diet (HFD) for 2 weeks induced their alanine aminotransferase (ALT) and aspartate transaminase (AST) up to 3.7 times and 3.3 times, respectively, and hepatosomatic index (HSI) became 1.6 times greater. The triacylglycerol and total cholesterol content in liver increased up to 2.2 times and 2.3 times, respectively, being higher than those of the control group. The fatty acid content in the liver of HFD-fed tilapia increased to 1.9 times of the control group, of which monounsaturated fatty acids (MUFAs) was the highest (53%), followed by saturated fatty acids (SFAs, 37%). The stearoyl-CoA desaturase (SCD, C18:1n9/ C18:0), which modulates SFAs to MUFAs increased from 2.72 to 5.26. The ratio of polyunsaturated fatty acids (PUFAs) n3/n6 in liver decreased from 2.4 to 0.5. The histological examination of liver revealed that tilapia fed HFD induced nonalcoholic steatohepatitis (NASH), of which the hepatocyte was 1.7 times of the control group, and showed ballooning degeneration and inflammatory infiltrates.
Using the HFD-fed tilapia as an in vivo model. Intake of FCR or FCRE caused significant amelioration of AST and ALT in plasma, HSI, and total cholesterol and triacylglycerol content in liver. The concentrations of triacylglycerol (TG) and total cholesterol (TC) in tilapia plasma fed HFD supplemented with FCR or FCRE were significantly (p<0.05) lower than those fed only HFD, TG and TC decreased by 50% and 20% respectively. Feeding FCRE to tilapia decreased SFAs and MUFAs in liver by 50% and 60% respectively, SCD (C18:1n9/ C18:0) decreased by 38%, and the n3/n6 PUFAs ratio increased 2.1 times of those fed HFD alone. The ballooning degeneration, inflammatory infiltrates, and prostaglandin E2 (PGE2) in liver were also improved by feeding FCRE.
HFD elicited progression of NAFLD in tilapia similar to what drew forth in mice, expect mice took 10 weeks to induce their ALT in plasma became 1.9 times greater, TG and TC content in liver up to 4.1 times and 2.0 times, respectively, of the control group.
In HepG2 cells treated with free fatty acid increased lipid accumulation, while addition of FCRE significantly reduced lipid accumulation and cell death via decreased fatty acid synthase (FAS) activity and increased activities of carnitine palmitoyltransferase-1 (CPT-1), CPT-2 in mitochondria, and acyl-CoA oxidase (ACO) in peroxisome in a dose-dependent manner.
The lipid-soluble compounds in FCR and FCRE were identified as the functional compounds. They comprised phytosterols including campesterol, brassicasterol, β-sitosterol and stigmasterol, and PUFAs of which the ratio of n3/n6 >2. The total phytosterols (3.18 mg/g) and n3 PUFAs content (65.1 mg/g) in FCRE was 7 and 4 times of those in FCR, respectively.
The strategy to increase the phytosterols content in clam was to fertilize the cultured pond with the microalgae or the rotifer. Both techniques caused the phytosterol to increase by 13% and 11%, respectively, significantly higher than those from the control pond. The n3/n6 ratio of PUFAs in clam were not increased after fertilizing the culture pond. However, rotifer or FCR improved the fatness of clam by >15% increase.
For the first time, tilapia was established as an animal model for screening fatty-liver preventive effects in functional foods. In the in vivo and in vitro models of NAFLD, the residual clam meat generated as a by-product of clam essence production significantly decreased de novo lipogenesis, increased fatty acid β-oxidation and modulated fatty acid desaturation, thus suppressed lipid accumulation and inflammation. Strategy on enrichment of the functional compounds in the cultured pond was also first reported in this study. The residual clam meat can be utilize as a hepatoprotective ingredient was developed into the soft-gel capsule, which shelf life was 4.5 months stored at room temperature.

圖解摘要 I
Abstract IV
英文縮寫對照 XIII
壹、 前言 1
貳、 文獻整理 2
一、 非酒精性脂肪肝 2
1.1 發生率及特徵 2
1.2 病理進展 2
1.2.1 脂肪代謝、脂質毒性及胰島素抗性 3
1.2.2 脂肪組織功能失調 4
1.2.3 腸道菌叢失衡 4
1.3 治療 4
1.3.1 生活型態改變 4
1.3.2 藥物控制 5
二、 非酒精性脂肪肝之試驗模式 7
2.1 細胞模式 7
2.2 動物模式 7
2.2.1 高脂飼料 7
2.2.2 高膽固醇飼料 7
2.2.3 缺乏甲硫胺酸與膽鹼飼料 8
三、 魚類作為人類疾病之動物模式 8
四、 淡水蜆 11
4.1 蜆之生態及養殖 11
4.2 蜆濾食之特性 11
4.3 微藻成分對貝類生成與組成分之影響 12
4.4 蜆之生理活性 13
4.4.1 水萃取物 13
4.4.2 胜肽水解物 15
4.4.3 有機溶劑萃取物 15
參、 實驗架構 16
一、建立非酒精性脂肪肝動物模式 16
二、評估養殖蜆肉 (FCR) 及其萃取物 (FCRE) 護肝之功效-以吳郭魚為模式 16
三、探討蜆肉萃取物調節脂質代謝之作用-以 HepG2 細胞為模式 17
四、確立蜆濾食之特性及增加養殖蜆之機能性成分 17
肆、 材料方法 18
一、 材料 18
1. 台灣蜆 (Corbicula fluminea) 及其萃取物 18
1.1 蜆肉 18
1.2蜆肉乙醇萃取物 18
2. HepG2 細胞 18
3. 藥品 18
二、 方法 19
1. 高脂飼料誘導脂肪肝動物試驗之條件 19
1.1 小鼠 19
1.2 吳郭魚 19
2. 高脂飼料添加蜆殘肉之試驗 22
3. 高脂飼料添加蜆萃取物之試驗 22
4. 一般生理指標 22
5. 採血及血漿之製備 22
6. 血漿生化指標 22
6.1 酵素 ALT、AST 活性測定 22
6.2 三酸甘油酯 (triacylglycerol, TG) 23
6.3 總膽固醇 (Total cholesterol) 23
6.4 血漿中 HDL 與 LDL 23
6.5總抗氧化力 ( total antioxidant capacity, TAC ) 24
7. 肝臟組織 24
7.1 石蠟切片 24
7.2 Hematoxylin and eosin染色 24
8. 肝臟膽固醇及三酸甘油酯定量 25
9. 肝臟脂肪酸分析 25
10. 肝臟脂肪酸去飽和酶活性之計算 25
11. Hep G2細胞培養 25
11.1 細胞培養液 25
11.2 細胞繼代 25
11.3 細胞計數 26
11.4 游離脂肪酸 (free fatty acid, FFA) 誘導脂質堆積 26
11.5 蜆萃物減緩游離脂肪酸誘導細胞脂質堆積之試驗 26
11.6 細胞內中性脂質含量測定 26
11.7 細胞內三酸甘油酯含量測定 27
11.8 細胞內脂肪酸測定 27
11.9 脂質代謝酵素液製備 27
11.10 Fatty acid synthase (FAS) 活性 27
11.11 Acyl-CoA oxidase (ACO) 活性 28
11.12 Carnitine palmitoyltransferase (CPT) 活性 28
12. 蜆殘肉固醇萃取與分析 29
13. 脂肪酸分析 30
14. 葉綠素與總類胡蘿蔔素 30
15. 蜆萃物儲藏試驗 30
16. 蜆消化道及蜆池中藻種之鏡檢 30
17. 蜆組織之判定 31
18. 蜆組織之吸收光譜 31
19. 養殖蜆育肥試驗 31
20. 統計分析 32
伍、 結果與討論 33
一、 吳郭魚作為非酒精性脂肪肝動物模式之建立 33
1.1 攝食行為、肝指數及肝體比 33
1.2 肝臟三酸甘油酯及總膽固醇堆積 33
1.3 肝臟組織病變及脂肪肝 35
1.4 肝臟脂肪酸組成改變 36
1.4.1 飽和脂肪酸轉換成肝臟單元不飽和脂肪酸 36
1.4.2 多元不飽和脂肪酸 n3 及 n6 比例下降與發炎反應 37
二、吳郭魚與小鼠作為動物模式與人類之比較 45
2.1 吳郭魚與小鼠肝病變之異同 46
2.1.1肝指數及肝體比之差異 46
2.1.2 血漿、肝臟中脂質 46
2.1.3肝臟脂肪酸去飽和作用與組織病變程度 46
2.2 吳郭魚與人類肝病變之異同 47
2.2.1血漿中脂質與肝指數之差異 47
2.2.2 肝臟脂肪含量相近 47
2.2.3 肝組織氣球樣變性及發炎 47
2.3 吳郭魚、小鼠、人類共同之病程 48
2.3.1 肝指數 ALT、血漿三酸甘油酯 48
2.3.2. 肝臟飽和脂肪酸去飽和為單元不飽和脂肪酸 48
2.3.3多元不飽和脂肪酸 n3 及 n6 之生合成 48
三、以吳郭魚為模式評估養殖蜆肉護肝功能 52
3.1 肝體比下降 52
3.2 血脂下降及血漿抗氧化力上升 52
3.3 肝指數及肝臟脂質含量下降 53
四、蜆殘肉乙醇萃取物之護肝作用 54
4.1 減緩吳郭魚形成高血脂及脂肪肝 54
4.1.1 血脂濃度下降 54
4.1.2 肝指數及肝臟脂質含量下降 55
4.1.3 肝組織發炎情形及 PGE2 下降 55
4.2 肝臟脂肪酸去飽和作用 57
4.2.1 飽和脂肪酸、及單元不飽和脂肪酸下降 57
4.2.2 多元不飽和脂肪酸 n3 / n6 比例上升 59
4.3 抑制 HepG2 細胞脂質堆積 60
4.3.1 游離脂肪酸誘發肝細胞脂肪肝 60
4.3.2 對 HepG2 細胞脂肪肝之保護作用 61
五、蜆之脂溶性機能性成分及其安定性 67
5.1 固醇 67
5.2脂肪酸 69
5.3類胡蘿蔔素 70
5.4 蜆乙醇萃取物膠囊之儲藏期限 70
六、養殖蜆提升機能性成分之育肥策略 72
6.1 蜆池藻相與蜆濾食之關係 72
6.1.1 蜆池之藻相 72
6.1.2 蜆腸道內與微藻之色素 79
6.1.3 蜆池、蜆內臟及腸道微藻之大小 81
6.1.4 蜆消化微藻之選擇性 83
6.2 人工育肥對蜆之影響 85
6.2.2 育肥後蜆的生長及一般成分 85
6.2.3 葉綠素及類胡蘿蔔素 87
6.2.4 固醇 90
6.2.5 脂肪酸 90
陸、 結論 96
一、吳郭魚、小鼠、人類非酒精性脂肪肝之症狀相似 96
二、蜆逆轉吳郭魚和 HepG2 細胞非酒精性脂肪肝之機制 96
三、蜆機能性成分增加之育肥技術 96
四、總結 96
柒、參考文獻 97
捌、附錄 108

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