非酒精性脂肪肝(Nonalcoholic fatty liver disease, NAFLD)是近幾年全球逐漸盛行的肝臟疾病，是基於過多的脂肪堆積在肝臟中造成，並與現代人日常高熱量、高糖飲食息息相關，不及時治療可能會造成纖維化、肝功能異常，甚至最終導致肝硬化、肝癌。Krüppel Like Factor 10 (KLF10)是一個會參與肝功能和疾病的重要晝夜規律的調節的轉錄因子，又稱為轉化生長因子(Transforming Growth Factor, TGF)早期誘導基因(TGF inducible early gene 1, TIEG1)能夠調節葡萄糖和脂質代謝、細胞生長和腫瘤生成等基因表達。然而，Klf10 是否會受到攝取糖分的影響去調節NAFLD仍不清楚。目前尚未有U.S. FDA認可的NAFLD治療藥物，並且近年來食物療法受到極大的關注，紫檀芪是一種從藍莓中提取的天然物，以及蟲草素是蟲草屬真菌中特有的成分，兩者在先前研究已知具有優秀的抗氧化及抗發炎能力，根據先前研究推測紫檀芪可能會誘導的氧化壓力的減少，因此紫檀芪對果糖誘導的肝臟脂質積累起到保護作用。本篇研究探討 Klf10 剔除後給予高蔗糖飲食 (High Sucrose Diet, HSD) 是否會產生加劇NAFLD的產生，而同時利用天然物的合併處理下是否能逆轉嚴重的肝臟損傷，並以體外細胞研究Klf10在NAFLD發展過程中的調控角色以及天然物治療的機制。
本研究使用8週大的 C57BL/6 Wild type 以及 Klf10(-/-)基因剔除小鼠給予高蔗糖飼料並每天口服管餵不同劑量的紫檀芪以及蟲草素，持續8週，研究NAFLD的病程發展以及評估天然物治療效果。小鼠犧牲後採集血液、心臟、肝臟、脾臟、肺臟、胰臟和睪丸。檢測血清中的GOT、GPT、三酸甘油酯(TG)、膽固醇、葡萄糖的濃度，以及肝臟組織中三酸甘油酯(TG)、膽固醇的含量，並觀察全器官的組織H&E染色切片，以NAFLD Activity Score (NAS)量化評估n損傷程度，再透過Masson’s Trichrome和Oil Red O染色觀察肝臟組織的纖維化和脂質累積的產生。體外試驗使用人類肝臟細胞HepaRG，並利用KLF10 inhibitor抑制KLF10蛋白的功能表現，透過流式細胞儀、免疫螢光染色分析及西方墨點法去探討高濃度的果糖並共同暴露治療效果較佳的紫檀芪減緩肝細胞中發炎與細胞自噬發生的機制，以及Klf10基因在保護肝臟疾病發展的角色。
結果顯示，高蔗糖飲食顯著增加了小鼠的體重和肝臟重量，並導致血清中的天門冬胺酸轉氨酶（GOT）、丙胺酸轉氨酶（GPT）、三酸甘油酯（TG）、總膽固醇（TCHO）和葡萄糖濃度升高。同時，肝臟組織出現脂肪變性、發炎反應和細胞氣球樣變化。然而，加入紫檀芪或蟲草素後，小鼠的體血清生化指標接近正常水平，肝臟病理變化明顯改善。紫檀芪和蟲草素的實驗結果相似，均顯示了對高糖飲食誘導的肝臟脂肪變性，兩天然物相比之下，紫檀芪的效果更為顯著，更顯示了多器官損傷的保護作用。體外實驗進一步證實了紫檀芪能有效逆轉高濃度果糖處理所引起的肝細胞脂質堆積和自噬作用，這些結果支持了在動物實驗的發現。
綜合上述結果，本研究證實了Klf10基因剔除加劇了高糖誘導的脂肪肝和纖維化，紫檀芪和蟲草素在預防和治療高糖飲食誘導的脂肪肝的潛在保護效果，以紫檀芪的效果更為顯著。Klf10基因剔除小鼠中磷酸化SREBP-1c上調和脂質生成增加。紫檀芪透過活化AMPK誘導自噬從而減少了肝細胞中的脂肪堆積。這些結果表明，Klf10在脂質生成中起著關鍵作用，並且可能影響自噬作用以作為治療NAFLD的潛在靶點。

Non-alcoholic fatty liver disease (NAFLD) can lead to fibrosis, liver failure, cirrhosis, and hepatocellular carcinoma. The global prevalence of NAFLD has sharply increased in recent years, affecting approximately 25% of the population and posing significant health risks. Krüppel-like factor 10 (KLF10) is a transcription factor that regulates genes involved in glucose and lipid metabolism, cell growth, and tumorigenesis. However, its role in NAFLD, particularly concerning sugar consumption and autophagy, remains unclear. Despite the absence of a U.S. FDA-approved treatment for NAFLD, natural products have gained attention for their antioxidant and anti-inflammatory properties. This study investigates the potential mechanism by which Klf10 knockout (KO) mice exacerbate NAFLD following high sucrose feeding and evaluates the therapeutic effects of pterostilbene and cordycepin. We conducted in vivo studies on 8-week-old B6 wild-type (WT) and Klf10 KO mice fed with either a control or high sucrose diet, supplemented or not with pterostilbene or cordycepin for 8 weeks. Additionally, in vitro studies using the HepaRG cell line aimed to elucidate the interplay between the Klf10 gene and pterostilbene. The results indicated increased severity of NAFLD in Klf10 KO mice, evidenced by elevated serum levels of GOT, GPT, and cholesterol, and exacerbated steatosis. Pterostilbene co-treatment showed better therapeutic potential compared to cordycepin. High fructose consumption induced liver lipogenesis and inhibited autophagy, whereas pterostilbene modulated autophagy via AMPK activation, leading to LC3 induction. These findings suggest that Klf10 deficiency aggravates sugar-triggered NAFLD, increasing liver steatosis and fibrosis. Elevated SREBP-1c levels drive lipogenesis, while pterostilbene demonstrates promising therapeutic actions.

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