非酒精性脂肪肝病變是目前最常見的肝臟病變，這類病變根據嚴重度從單純脂肪肝，到非酒精性脂肪肝炎，以及最終導致肝纖維化。目前的治療包括飲食習慣的改變，運動與減重為主。固然有許多新興的治療藥物在臨床試驗中，美國食品藥物管理局到目前為止仍沒有正式通過任何一個可以治療脂肪肝的藥物。本論文於是要研究實際可供臨床治療的藥物選擇與一個新的手術方式來治療。第一個部分，我們使用昇糖素類似胜肽-1 (Glucagon-like peptide-1, GLP-1)並探討它成功治療脂肪肝的機轉是否和促進肝細胞自噬作用有關，第二個部分，我們施以十二指腸空腸繞道手術成為一個新型手術方式用以減少胰島素抗性來治療非酒精性脂肪肝炎。
人體及動物實驗有指出GLP-1對非酒精性脂肪肝病變具有有意義的治療效果，目前也知道肝細胞的自噬作用在氧化壓力(oxidative stress)與脂肪代謝扮演一個重要的角色。然而，是否GLP-1改善脂肪肝是經由調控細胞的自噬作用還並不清楚。我們先研究GLP-1對於肝細胞中脂肪堆積與細胞自噬作用的影響，使用Sprague-Dawley公鼠餵食12周高脂飲食誘發一個非酒精性脂肪肝病變的動物模式，接受GLP-1治療後觀察對肝臟脂肪堆積與自噬體(autophagosome)的影響如何。之後使用人類肝細胞癌細胞株HepG2與小鼠肝細胞株AML12並給予油酸(oleic acid)與棕櫚酸(palmitic acid)以建立一個脂肪肝細胞實驗模式，然後細胞給予GLP-1治療觀察對於肝細胞中脂肪堆積與細胞自噬作用的影響。最後將AML12細胞株轉染短髮夾核糖核酸(Short hairpin RNA)以抑制人類為小管相關蛋白1A/1B-輕鏈3(microtubule-associated protein 1A/1B-light chain 3, LC3)的基因表現，觀察是否GLP-1對於脂肪肝的影響在自噬作用被抑制時有無改變。結果顯示，GLP-1有效減少大鼠肝細胞與該細胞株內的脂肪堆積，且GLP-1可以增加自噬體與LC3的表現。另外，GLP-1也經由pAMPK調控自噬作用，因為抑制AMPK可以減少GLP-1對自噬作用的增強效果。而GLP-1已可經由增加Bcl-2而改善細胞生存能力。並且在Hoechst 33342染色及流式細胞儀實驗顯示GLP-1同事也抑制了細胞凋亡。GLP-1也可以回復因脂肪堆積導致的自噬作用流通(autophagic flux)並增加自噬體與溶酶體(lysosome)的融合作用。GLP-1也部分增加PPARr以調控自噬作用。最後LC3基因敲落(knockdown)會導致GLP-1對脂肪肝治療效果消失。這些都顯示GLP-1改善脂肪肝是經由自噬作用的調控，包括藉著活化AMPK，維持細胞生存能力，避免細胞凋亡，以及改善自噬作用流通與自噬體與溶酶體的融合。
第二部分，我們在大鼠施行了十二指腸空腸繞道手術(Duodenojejunal bypass, DJB)，DJB是現今許多種不同型態減重手術中的重要一部分，包括在Roux-en Y胃繞道(gastric bypass)，迷你胃繞道(minigastric bypass)，膽胰分流手術(biliopancreatic diversion)，十二指腸倒置手術(duodenal switch)與十二指腸空腸繞道合併胃袖狀切除手術(DJB plus sleeve gastrectomy)等。這些手術術後常發現脂肪肝炎症狀減輕，但是機轉不明。這個實驗中，我們研究在高脂飲食餵養的肥胖大鼠中，DJB對NASH的影響。結果顯示，DJB有效改善體重，胰島素抗性，脂質代謝，與脂肪肝的嚴重度。其中，DJB有效減低非酒精性脂肪肝病變活性指數(NAFLD activity score)，且減小脂肪堆積及脂肪細胞大小，因為與治療Pioglitazone(一個胰島素敏感度增進劑)的效果非常類似，因此可以推論DJB藉由改善胰島素抗性以減少脂肪肝炎。另外，DJB也減低肝臟星狀細胞(hepatic stellate cell)活性，減低腫瘤壞死因子alpha(tumor necrosis factor-alpha)，也可增強肝細胞自噬作用。

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease ranging from simple hepatic steatosis, nonalcoholic steatohepatitis (NASH) and eventually liver fibrosis. Current treatments include diet modification, exercise, and weight reduction. Though some novel therapeutic agents are undergoing clinical trial, the US Food and Drug Association has not approved any drugs for NAFLD so far. The present thesis investigated the practical therapeutic options for NAFLD using glucagon-like peptide-1 (GLP-1) and explored its mechanism relating to cell autophagy in the first part. In the second part, we performed duodenal-jejunal bypass surgery as an innovative surgical intervention to reduce insulin resistance for treatment of NASH.
Human and animal studies have indicated that glucagon-like peptide-1 (GLP-1) has a significant therapeutic effect on nonalcoholic fatty liver disease (NAFLD). Hepatic autophagy plays a crucial role in oxidative stress and lipid metabolism. Whether GLP-1 affects hepatic steatosis through modification of cell autophagy is unclear. We first investigated the effects of GLP-1 on hepatic fat resolution and cell autophagy. Male Sprague Dawley model rats with 12-week high-fat diet–induced NAFLD were treated with GLP-1 to reveal the effect on liver fat accumulation and autophagosome augmentation. Human hepatocellular carcinoma (HepG2) and alpha mouse liver 12 cell lines (AML12) were loaded with oleic acid (OA) or palmitic acid (PA) to establish steatotic hepatocyte model cells. Cells were treated with GLP-1. AML12 cells were transfected with short hairpin RNA against human microtubule-associated protein 1A/1B-light chain 3 (LC3) B for 48 h. Whether autophagy inhibition influenced GLP-1 effect on the hepatic fat resolution were investigated further. In our results, GLP-1 significantly reduced hepatic steatosis in rat liver and HepG2. GLP-1 enhanced the autophagosome number and LC3 expression. GLP-1 also activated pAMPK and autophagy, but the augmentation in autophagy was reduced when AMPK was inhibited. GLP-1 improved cell viability by increasing Bcl-2. By using Hoechst 33342 staining and flow cytometry study, GLP-1 was also demonstrated to inhibit cell apoptosis. GLP-1 also reversed the impaired autophagic flux and enhanced autophagosome–lysosome fusion. LC3 knockdown led to a loss of the effects of GLP-1 on the hepatic fat resolution. GLP-1 also activated PPARγ and influenced autophagy. In first part, we concluded that GLP-1 increased autophagy through activation of AMPK, maintained cell viability, and prevented apoptosis. Lipotoxicity-induced autophagic flux impairment could be reversed by GLP-1 by improving autophagosome–lysosome fusion ability.
In the second part, we performed the Duodenal–jejunal bypass (DJB) which is an important component of many types of current bariatric surgery including Roux-en-Y gastric bypass, mini-gastric bypass, biliopancreatic diversion, duodenal switch, and DJB plus sleeve gastrectomy. Surgery is often observed to ameliorate nonalcoholic steatohepatitis (NASH), but without a clearly delineated mechanism. In this study, we investigated the effects of DJB in diet-induced obese rats with NASH. In our results, compared with the HF group, the DJB group showed improved body weight, insulin sensitivity, lipid metabolism, and steatosis severity. The DJB group exhibited a significantly lower nonalcoholic fatty liver disease activity score than the HF and PGZ group. Furthermore, DJB significantly reduced fat mass and adipocyte size. These effects were also observed in the PGZ group. Therefore, we speculated that the improvements induced by DJB are closely related to an alteration in insulin sensitivity. Moreover, DJB reduced hepatic stellate cell activity and tumor necrosis factor-alpha expression and enhanced hepatocyte autophagy.

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