NGM Biopharmaceuticals, Inc., South San Francisco, CA 94080.
NGM Biopharmaceuticals, Inc., South San Francisco, CA 94080
J Lipid Res. 2019 Mar;60(3):550-565. doi: 10.1194/jlr.M089961. Epub 2019 Jan 24.
Fibroblast growth factor (FGF)19, an endocrine hormone produced in the gut, acts in the liver to control bile acid synthesis. NGM282, an engineered FGF19 analog, is currently in clinical development for treating nonalcoholic steatohepatitis. However, the molecular mechanisms that integrate FGF19 with cholesterol metabolic pathways are incompletely understood. Here, we report that FGF19 and NGM282 promote HDL biogenesis and cholesterol efflux from the liver by selectively modulating LXR signaling while ameliorating hepatic steatosis. We further identify ABCA1 and FGF receptor 4 as mediators of this effect, and that administration of a HMG-CoA reductase inhibitor or a blocking antibody against proprotein convertase subtilisin/kexin type 9 abolished FGF19-associated elevations in total cholesterol, HDL cholesterol (HDL-C), and LDL cholesterol in mice. Moreover, we show that a constitutively active MEK1, but not a constitutively active STAT3, mimics the effect of FGF19 and NGM282 on cholesterol change. In dyslipidemic mice fed a Western diet, treatment with NGM282 dramatically reduced atherosclerotic lesion area in aortas. Administration of NGM282 to healthy volunteers for 7 days resulted in a 26% increase in HDL-C levels compared with placebo. These findings outline a previously unrecognized role for FGF19 in the homeostatic control of cholesterol and may have direct impact on the clinical development of FGF19 analogs.
成纤维细胞生长因子 19（FGF19）是一种在肠道中产生的内分泌激素，在肝脏中发挥作用以控制胆汁酸合成。NGM282 是一种工程化的 FGF19 类似物，目前正在临床开发中用于治疗非酒精性脂肪性肝炎。然而，将 FGF19 与胆固醇代谢途径整合的分子机制尚不完全清楚。在这里，我们报告 FGF19 和 NGM282 通过选择性调节 LXR 信号来促进 HDL 的生成和肝脏中的胆固醇流出，同时改善肝脂肪变性。我们进一步确定 ABCA1 和 FGF 受体 4 是这种作用的介导物，并且 HMG-CoA 还原酶抑制剂或针对前蛋白转化酶枯草溶菌素/克酶 9 的阻断抗体的给药消除了 FGF19 相关的总胆固醇、HDL 胆固醇（HDL-C）和 LDL 胆固醇在小鼠中的升高。此外，我们表明组成型激活的 MEK1，但不是组成型激活的 STAT3，模拟了 FGF19 和 NGM282 对胆固醇变化的作用。在喂食西方饮食的血脂异常小鼠中，NGM282 的治疗使主动脉粥样硬化病变面积显著减少。NGM282 对健康志愿者的 7 天给药与安慰剂相比使 HDL-C 水平增加了 26%。这些发现概述了 FGF19 在胆固醇稳态控制中的先前未被认识到的作用，并且可能对 FGF19 类似物的临床开发有直接影响。
