非酒精性脂肪性肝（NAFLD）的主要病理特征是肝脏脂肪堆积，其可导致肝硬化和肝癌，对人类健康危害巨大，目前尚无有效治疗手段。本课题组近十余年来对五环三萜的研究表明，该类天然产物在防治高血脂症和NAFLD方面具有非常好的临床应用前景。前期工作通过体内外研究和临床试验证明齐墩果酸具有显著的降血酯和抗NAFLD功效。初步的机制研究表明，齐墩果酸等五环三萜可能是继DK-3之后发现的第二类外源性的雌激素相关受体alpha（ERRalpha）激动剂。其可能通过激活ERRalpha而促进线粒体生成和脂肪酸氧化代谢(“燃烧”脂肪)，同时也抑制脂肪酸合成，进而减少肝脏脂肪堆积而发挥抗NAFLD功效。本项目拟开展深入、系统的五环三萜新靶标确证、抗NAFLD活性评价（包括临床验证试验）、作用机制、结构优化及抗NAFLD新药发现研究，为NAFLD等脂代谢异常相关疾病的药物干预提供源头创新基础和候选新药。

The major pathological characteristic of nonalcoholic fatty liver disease (NAFLD) is liver fat accumulation that could lead to cirrhosis and liver cancer. Thus, NAFLD is a burgeoning health problem, and therapeutic options are limited. In the past decade, our studies on pentacyclic triterpenes have shown that this class of natural products have great therapeutic potential, especially for the treatment of metabolic diseases such as hyperlipidemia and NAFLD. Our previous in vitro and in vivo studies together with clinical studies showed that oleanolic acid had significant lipid-lowering and anti-NAFLD effects. Preliminary mechanistic studies showed that oleanolic acid and related pentacyclic triterpenes might be the second class of estrogen related receptor alpha (ERRalpha) agonist following DK-3 that is the first reported ERRalpha agonist. It might activate ERRalpha to increase mitochondrial biogenesis and oxidative metabolism, and inhibit fatty acid biosynthesis, and thus leading to reduced fat deposition in the liver. This project will be focused on target identification, mechanistic studies, anti-NAFLD biological evaluation (including human studies), structural modifications and drug discovery of pentacyclic triterpenes. Together, we hope to realize the original innovations in drug development for NAFLD and other disorders of lipid metabolism, and to provide "first-in-class" drug candidates.