以脫細胞化肝臟間質為基底之奈米藥物應用於代謝失能脂肪肝病

Abstract

近年來人們在營養攝取過剩以及缺乏運動下，罹患非酒精性脂肪肝病 (Nonalcoholic fatty liver disease; NAFLD) 的比例逐年攀升。而在最近的研究中也發現其對身體的傷害不僅僅限於肝臟且有可能擴展至全身性的代謝功能失常，因此近來更將 NAFLD 進一步定義為代謝失能相關脂肪肝病 (Metabolic dysfunction-associated steatotic liver disease; MASLD)。然而目前在臨床測試藥物的結果仍無法證明其有效性。為了能更有效的解決 MASLD，本研究擬嘗試開發一套能對 MASLD 有顯著回復效果的奈米藥物。 本研究旨在開發一種新穎的奈米藥物，進入肝臟後並促進病患之脂肪肝回復成健康肝臟。研究分為兩個部分：第一部分是奈米藥物的開發：利用脫細胞化肝臟間質 (Decellularized liver matrix; DLM) 與單寧酸 (Tannic acid; TA) 形成奈米藥物，並對其進行性質檢測；第二部分則是對該奈米藥物進行體外和體內試驗。在體外實驗中分別使用誘導性多能幹細胞 (induced pluripotent stem cells; iPSC) 所誘導而成之肝細胞以及大鼠初代成熟肝細胞與該奈米藥物進行共培養，並檢測其細胞活性和肝細胞機能。此外，本研究亦建立小鼠 MASLD 模型，並評估該奈米藥物對於 MASLD 小鼠代謝機能回復的能力。 在本研究的結果中可以發現 TA 與 DLM 確實具備合成奈米粒子的能力；且在投入到 MASLD 體外模型時，除了由於 TA 活化了 AMPK pathway 而展現了降低脂質堆積以及提升肝細胞機能的能力外、TA-DLM 奈米藥物也展現了相較於只投入 TA 有著更為有效的表現。最後再將 TA-DLM 奈米藥物投入到 MASLD 體內模型時，該奈米藥物也展現了改善肝內脂質堆積以及全身性的脂質代謝的潛力。本研究的成果有望為 MASLD 的治療提供新的方法和展望，並為 MASLD 治療領域帶來重要的突破。

In recent years, the incidence of nonalcoholic fatty liver disease (NAFLD) has been increasing due to excessive nutritional intake and lack of exercise. Recent studies show that NAFLD can cause systemic metabolic dysfunction, leading to its redefinition as metabolic dysfunction-associated steatotic liver disease (MASLD). However, current clinical trials have not proven effective. This study aims to develop a nanomedicine with significant recovery effects on MASLD. This study aims to develop a novel nanomedicine that enters the liver and promotes the recovery of fatty liver to a healthy liver in patients. The research is divided into two parts: the first part involves the development of the nanomedicine by forming nanoparticles using decellularized liver matrix (DLM) and tannic acid (TA) and characterizing their properties. The second part involves in vitro and in vivo experiments with the nanomedicine. In the in vitro experiments, hepatocytes derived from induced pluripotent stem cells (iPSC) and primary mature rat hepatocytes are co-cultured with the nanomedicine, and their cell viability and liver functions are detected. Additionally, a mouse MASLD model is established to evaluate the ability of the nanomedicine to restore metabolic function in MASLD mice. The results indicate that TA and DLM can synthesize nanoparticles. In the in vitro MASLD model, TA activates the AMPK pathway, reducing lipid accumulation and enhancing hepatocyte function. The TA-DLM nanomedicine outperformed TA alone. In the in vivo MASLD model, TA-DLM nanomedicine improved intrahepatic lipid accumulation and systemic lipid metabolism. Therefore, this study offers new methods and prospects for MASLD treatment, potentially leading to significant breakthroughs in the field.