虾青素抗非酒精性脂肪肝纤维化效应及分子机制研究

Hepatic fibrosis is critical in the development of cirrhosis in non-alcoholic fatty liver disease (NAFLD), regulation of hepatic stellate cell (HSC) activation is an effective measure for the prevention and treatment of hepatic fibrosis in NAFLD. Transcription factor FoxO1 plays an important role in the HSC activation. Previous study of our lab have found that astaxanthin has potential anti-NAFLD effect, which significantly suppressed high glucose induced fatty acid synthesis and lipid accumulation in HepG2 cell. In the present study, we will explore the mechanism which astaxanthin regulates HSC activation by investigating the role of PI3K-Akt-FoxO1 signaling pathway and related microRNA (miRNA) in HSC activation, cytokine secretion and collagen synthesis using primary rat HSC and human LX-2 HSC cell lines.In addition, we will investigate the effect of astaxanthin on the process of NAFLD and the expression of fibrogenesis related cytokines, confirm its anti-fibrogenic effect and molecular mechanism using high-fat high-carbohydrate (HFHC) diet or methionine and choline deficient (MCD) diet induced animal models. This research will provide evidence for the clinical and nutritional application of astaxanthin in prevention and treatment of NAFLD.

肝纤维化是非酒精性脂肪性肝病（NAFLD）发展成为肝硬化的关键环节，调控肝星状细胞（HSC）活化是防治NAFLD肝纤维化的有效措施，而转录因子FoxO1在HSC活化中发挥了重要作用。我们以往的研究发现虾青素可降低高糖诱导的HepG2细胞脂肪酸合成和脂质沉积，提示虾青素可能具有潜在的抗NAFLD作用。本课题利用大鼠原代HSC和人LX-2 HSC两种细胞系、高脂高糖饮食和蛋氨酸-胆碱缺乏饮食诱导的两种动物模型，拟研究1）磷脂酰肌醇3-激酶（PI3K）-蛋白激酶B（Akt）-FoxO1信号通路及相关miRNA在HSC活化、细胞因子分泌及胶原合成中的作用，阐明虾青素调节HSC活化的机制；2）虾青素对NAFLD进程及肝纤维化相关因子表达的影响，验证虾青素抗NAFLD肝纤维化效应及分子机制。本研究将为虾青素抗NAFLD的临床应用及营养膳食防治NAFLD提供理论依据。

肝纤维化是非酒精性脂肪性肝病（NAFLD）发展成为肝硬化的关键环节，调控肝星状细胞（HSC）活化是防治NAFLD肝纤维化的有效措施。本课题利用人LX-2 HSC细胞系、高脂高糖饮食和蛋氨酸-胆碱缺乏饮食诱导的动物模型，拟研究：1）磷脂酰肌醇3-激酶（PI3K）-蛋白激酶B（Akt）信号通路在HSC活化、细胞因子分泌及胶原合成中的作用，阐明虾青素调节HSC活化的机制；2）虾青素对NAFLD进程及肝纤维化相关因子表达的影响，验证虾青素抗NAFLD肝纤维化效应及分子机制。结果发现：1）虾青素可通过改善肝脏功能、血脂水平及抑制炎症因子释放等途径减缓高脂（HF）饮食诱导的NAFLD；2）虾青素可改善肝功能，且可能通过调控α-SMA和Ⅰ型胶原基因的表达减缓蛋氨酸—胆碱缺乏（MCD）饮食诱导的非酒精性脂肪肝纤维化进程；3）虾青素可通过PI3K/Akt信号通路抑制肝星状细胞活化，发挥抗非酒精性脂肪肝纤维化效应。上述结果提示虾青素可抑制或减缓NAFLD肝纤维化进程，其机制可能与抑制PI3K/Akt信号通路，调控α-SMA和Ⅰ型胶原等基因表达，进而调节血脂水平，抑制炎症因子释放等途径有关。本研究将为虾青素抗NAFLD临床应用及营养膳食防治NAFLD提供科学依据。