Evans Mark J, Mahaney Paige E, Borges-Marcucci Lisa, Lai KehDih, Wang Shuguang, Krueger Julie A, Gardell Stephen J, Huard Christine, Martinez Robert, Vlasuk George P, Harnish Douglas C
Department of Cardiovascular and Metabolic Diseases, Wyeth Research, 500 Arcola Rd, Collegeville, PA 19426, USA.
Am J Physiol Gastrointest Liver Physiol. 2009 Mar;296(3):G543-52. doi: 10.1152/ajpgi.90585.2008. Epub 2009 Jan 8.
The nuclear hormone receptor farnesoid X receptor (FXR) plays a critical role in the regulation of bile acid, triglyceride (TG), and cholesterol homeostasis. WAY-362450 (FXR-450/XL335) is a potent synthetic FXR agonist as characterized in luciferase reporter assays and in mediating FXR target gene regulation in primary human and immortalized mouse hepatocytes. In vivo, WAY-362450 dose dependently decreased serum TG levels after 7 days of oral dosing in western diet-fed low-density lipoprotein receptor-/- mice and in the diabetic mouse strains KK-Ay and db/db comparable to that achieved with the peroxisome proliferator activated receptor-alpha agonist, fenofibrate. WAY-362450 treatment also reduced serum cholesterol levels via reductions in LDLc, VLDLc, and HDLc lipoprotein fractions that were not accompanied by hepatic cholesterol accumulation. This cholesterol lowering was dependent on FXR as demonstrated in a hypothyroid-induced hypercholesterolemia setting in FXR-/- mice. In fructose-fed models, WAY-362450 also decreased TG and VLDLc levels in rats and hamsters but significantly increased HDLc levels in rats while reducing HDLc levels in hamsters. The differential effect of WAY-362450 on HDLc is likely due to a murine-specific induction of endothelial lipase and scavenger receptor-BI that does not occur in rats. These studies demonstrate a consistent ability of WAY-362450 to lower both serum TG and cholesterol levels and suggest that synthetic FXR agonists may have clinical utility in the treatment of mixed dyslipidemia.
核激素受体法尼酯X受体（FXR）在胆汁酸、甘油三酯（TG）和胆固醇稳态的调节中起关键作用。WAY-362450（FXR-450/XL335）是一种强效的合成FXR激动剂，在荧光素酶报告基因检测以及在原代人肝细胞和永生化小鼠肝细胞中介导FXR靶基因调控方面均有相关特性描述。在体内，在喂食西方饮食的低密度脂蛋白受体敲除小鼠以及糖尿病小鼠品系KK-Ay和db/db中，口服给药7天后，WAY-362450剂量依赖性地降低血清TG水平，效果与过氧化物酶体增殖物激活受体α激动剂非诺贝特相当。WAY-362450治疗还通过降低低密度脂蛋白胆固醇（LDLc）、极低密度脂蛋白胆固醇（VLDLc）和高密度脂蛋白胆固醇（HDLc）脂蛋白组分来降低血清胆固醇水平，且未伴随肝脏胆固醇积累。在FXR敲除小鼠的甲状腺功能减退诱导的高胆固醇血症模型中证实，这种胆固醇降低依赖于FXR。在喂食果糖的模型中，WAY-362450也降低了大鼠和仓鼠的TG和VLDLc水平，但显著提高了大鼠的HDLc水平，同时降低了仓鼠的HDLc水平。WAY-362450对HDLc的不同影响可能是由于小鼠特异性诱导内皮脂肪酶和清道夫受体-BI所致，而这种情况在大鼠中不会发生。这些研究证明了WAY-362450具有一致的降低血清TG和胆固醇水平的能力，并表明合成FXR激动剂在治疗混合性血脂异常方面可能具有临床应用价值。
