Corylin對於非酒精性脂肪肝疾病的治療作用和相關機制

Abstract

非酒精性脂肪肝(nonalcoholic fatty liver disease; NAFLD)是造成代謝綜合症和第二型糖尿病的主因，臨床主要病徵為代謝失調，如高血糖、高血脂症和胰島素阻抗。補骨脂寧(Corylin)是一種從補骨脂 (Psoralea corylifolia L.)萃取出的異黃酮類化合物，多項研究已證實Corylin具有抗氧化及抗發炎作用，並且可以降低肥胖和胰島素阻抗發生。然而，Corylin 對於肝臟代謝的調控作用及機制尚不清楚，因此本研究目的是探討 Corylin 對非酒精脂肪肝疾病的影響。首先，在細胞實驗中使用棕櫚酸 (Palmitic acid, PA) 誘導人類肝細胞 (HepG2) 進行研究；在動物實驗部分，利用高脂飼料誘導小鼠肥胖的模式，藉由同時餵食Corylin 10週，藉此探討Corylin對於NAFLD的作用，透過評估肝細胞中油滴累積、胰島素阻抗性和非酒精性脂肪肝疾病的相關生化數值和蛋白質表達量，觀察Corylin是否可以抑制非酒精性脂肪肝的形成。本篇研究結果顯示，在細胞實驗結果方面，Corylin 具有減少脂質合成、保護棕櫚酸誘導粒線體功能的失調、降低氧化性壓力(oxidative stress)、並增加肝細胞葡萄糖攝取的能力和胰島素敏感度。在動物實驗部分，Corylin的餵食也顯示能有效減少高脂飲食誘導小鼠的體重增加、改善胰島素敏感度、抑制肝臟油滴堆積和纖維化的嚴重程度。AMP active protein kinase (5' adenosine monophosphate-activated protein kinase, AMPK)參與多種生理代謝，在細胞能量穩定中發揮作用，在肝臟中負責調控脂質和醣類代謝，本篇研究結果顯示Corylin 藉由增加AMPK的活化，抑制肝細胞中經由PA造成的油滴累積，改善粒線體活性和減少ROS的產生。綜合上述結果，我們推測Corylin 可以作為改善非酒精性脂肪肝疾病的新治療藥物選擇。

Nonalcoholic fatty liver disease (NAFLD) is a major cause of metabolic syndrome and type II diabetes, and it presents with metabolic disorders, such as hyperglycemia, hyperlipidemia, and insulin resistance. Corylin, a flavonoid compound extracted from Psoralea corylifolia L., has been shown to have antioxidant, anti-inflammatory effects and can reduce obesity and insulin resistance. However, it remains unknown whether Corylin could modulate the metabolism of liver, so the objective of this study is to explore the effect of Corylin on NAFLD. The anti-NAFLD effects of Corylin on fat accumulation, insulin resistance, and NAFLD-related physiological parameters and protein levels were assessed in high-fat diet (HFD)-induced obese mice in vivo and in palmitate (PA)-treated HepG2 cells in vitro. The present study showed that Corylin strikingly increased insulin sensitivity, glycogen synthesis and reduced body weight, fat accumulation, reactive oxygen species (ROS) and fibrosis in HFD-treated mice. In addition, Corylin also decreased lipid synthesis and improved mitochondria dysfunction, glucose uptake ability and insulin sensitivity in PA-induced HepG2 cells. Corylin significantly decreased the expression of lipid metabolism-related proteins level and improved the expression of glucose metabolism-related proteins level. The above effects of Corylin on NAFLD inhibition were through AMP-activated protein kinase (AMPK) pathway. Based on the above results, we speculate that Corylin can be used as a new treatment option for NAFLD.