Abstract：
Farnesoid X receptor (FXR) is a nuclear receptor that regulates the synthesis and enterohepatic circulation of bile acids (BAs). It also regulates lipid and carbohydrate metabolism, making FXR ligands potential therapeutic agents for systemic and/or hepatic metabolic disorders. We previously synthesized a series of FXR antagonists and showed that oral administration of FLG249 reduced the expression of several FXR target genes in the mouse ileum. Here, we investigated the effects of FLG249 on lipid metabolism in mice fed a high-fat diet (HFD). When FLG249 was administered for 4 weeks to HFD-induced obese mice, it altered the expression of genes related to BA metabolism, ceramide synthesis and fatty acid β-oxidation, improving lipid metabolism in the liver and ileum without decreasing body weight. These findings suggest that FLG249 has the potential to be a low toxicity pharmaceutical compound and likely acts as a nonsteroidal FXR antagonist to improve lipid metabolism disorders.
摘要：
法尼醇X受体（FXR）是调节胆汁酸（BA）合成和肝肠循环的核受体。它还调节脂质和碳水化合物的代谢，使FXR配体成为全身性和/或肝代谢紊乱的潜在治疗剂。我们先前合成了一系列FXR拮抗剂，并显示口服FLG249可降低小鼠回肠中几种FXR靶基因的表达。这里,我们研究了FLG249对高脂饮食（HFD）小鼠脂质代谢的影响。当向HFD诱导的肥胖小鼠施用FLG2494周时，它改变了与BA代谢相关的基因的表达，神经酰胺合成与脂肪酸β-氧化,改善肝脏和回肠的脂质代谢而不降低体重。这些发现表明，FLG249具有成为低毒性药物化合物的潜力，并且可能充当非甾体FXR拮抗剂以改善脂质代谢紊乱。
