非酒精性脂肪肝病 (Non-alcoholic fatty liver disease, NAFLD) 是最常見與肝臟脂質累積相關的疾病，其與代謝症候群如肥胖和胰島素阻抗等具有密切關係。紫檀芪 (pterostilbene, Pt) 是天然存在於藍莓中的一種酚類化合物，具有抗氧化、抗癌和改善胰島素阻抗等作用。本研究探討Pt及其衍生物3'-hydroxypterostilbene (OHPt) 對游離脂肪酸 (free fatty acid, FFA) 誘導HepG2細胞脂質堆積及高脂飲食 (high fat diet, HFD) 誘導C57BL/6J小鼠NAFLD與腸道微菌叢失調之影響。Pt和OHPt顯著降低FFA誘導HepG2細胞中的脂質蓄積，且透過SIRT1/AMPK及胰島素訊息傳遞路徑改善FFA誘導HepG2細胞脂肪變性並增加脂解作用。在體內研究中，給予Pt和OHPt減少了餵養HFD小鼠的體重、體脂肪與脂肪細胞大小，使血清中與血脂、血糖、動脈粥樣硬化及肝臟發炎反應相關之生化值下降，以及減緩肝臟脂肪油滴累積與發炎細胞浸潤，調控SIRT1/AMPK途徑，抑制SREBP-1及SREBP-2途徑，減少脂肪合成，刺激脂肪酸β-氧化，活化胰島素訊息傳遞路徑與緊密連接蛋白，減輕胰島素阻抗並保持腸道屏障完整性，抑制細菌內毒素和NF-κB發炎途徑，降低發炎反應。Pt和OHPt顯著提升肥胖小鼠腸道菌群中Bacteroidetes及Akkermansia muciniphila益菌數，顯著降低Firmicutes、F/B ratio及Erysipelotrichaceae Allobaculum菌群數，提高代謝產物短鏈脂肪酸，以及豐富肥胖小鼠盲腸菌群中Porphyromonadaceae Parabacteroides和Ruminococcaceae Oscillospira益菌菌群數量，並減少與肥胖及NAFLD相關的Ruminococcaceae和Erysipelotrichaceae Allobaculum，改善由HFD所造成的腸道微菌叢失調。綜合以上所述，Pt和OHPt在體外與體內模式中，皆可有效減緩脂質累積，且可改善HFD誘導引起的肥胖、胰島素阻抗、NAFLD及腸道微菌叢失調，OHPt的功效優於Pt，可為預防和預後NAFLD，提供更多元的選擇。

Non-alcoholic fatty liver disease (NAFLD) is the most common disease associated with liver lipid accumulation, and it is closely related to metabolic syndrome, such as obesity and insulin resistance. Pterostilbene (Pt) is a phenolic compound naturally found in blueberries. It has anti-oxidant, anti-cancer and anti-insulin resistance properties. The present study was carried out to investigate the effects of Pt and its derivative 3'-hydroxypterostilbene (OHPt) on free fatty acids (FFA)-induced steatosis in HepG2 cell model and high fat diet (HFD)-induced NAFLD and gut dysbiosis in C57BL/6J mice. Pt and OHPt significantly reduced FFA-induced lipid accumulation in HepG2 cells, and ameliorated FFA-induced steatosis in HepG2 cells and enhanced lipolysis through SIRT1/AMPK and insulin signaling pathways. In the in vivo study, Pt and OHPt treatment decreased the body weight, body fat and adipocyte size in HFD-fed mice, reduced serum biochemical parameters related to blood lipids, blood glucose, atherosclerosis index and liver inflammation, and reduced the accumulation of fatty oil droplets and the infiltration of inflammatory cells in the liver. The data showed that Pt and OHPt up-regulated SIRT1/AMPK pathway and subsequently down regulated the protein expression of SREBP‑1 and SREBP‑2 to activate fatty acid β-oxidation to inhibit fatty acid synthesis. Pt and OHPt administration activated the insulin signaling pathway and tight junction protein and ameliorated the insulin resistance and intestinal barrier defect in the HFD-fed mice, and through the regulation of lipopolysaccharide and NF-κB activation to inhibit chronic inflammation. Pt and OHPt had an impact on gut microbiota, increased relative abundance of Bacteroidales and Akkermansia muciniphila, decreasing Firmicutes, F/B ratio and Erysipelotrichaceae Allobaculum but also increased the SCFAs content in obese mice, and Porphyromonadaceae Parabacteroides and Ruminococcaceae Oscillospira were increased, while Ruminococcaceae and Erysipelotrichaceae Allobaculum were decreased in obese mice cecal microbiota, and then improve HFD induced gut dysbiosis. Based on the above results, Pt and OHPt can effectively reduced lipid accumulation in vitro and in vivo models, and ameliorate HFD-induced obesity, insulin resistance, NAFLD and gut dysbiosis. Besides, OHPt is more effective than Pt and can provide more options for the prevention and prognosis of NAFLD.

行政院衛生福利部。2021。中華民國109年國人主要死因統計資料。
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