FGF21 acts as a negative regulator of bile acid synthesis
FGF21 acts as a negative regulator of bile acid synthesis
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DOI：
10.1530/joe-17-0727
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发表时间：
2018-05-01
影响因子：
4
通讯作者：
Veniant, Murielle M.
中科院分区：
文献类型：
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作者：
Chen, Michelle M.;Hale, Clarence;Veniant, Murielle M.
成纤维细胞生长因子21（FGF 21）是体内葡萄糖和脂质稳态的有效调节剂;已知其最密切相关的亚家族成员FGF 19是胆汁酸合成的关键负调节剂。为了描述FGF 21是否也在胆汁酸代谢中发挥功能性作用，我们评估了短期和长期暴露于天然FGF 21和长效FGF 21类似物对原代肝细胞以及啮齿动物和猴模型中肝脏信号转导、基因表达和肠肝胆汁酸水平的影响。在原代肝细胞和不同啮齿动物模型中，FGF 21急性诱导ERK磷酸化并抑制Cyp 7A 1 mRNA表达，但效力低于重组人FGF 19。在喂食标准食物饮食的小鼠中长期施用FGF 21导致肝脏和小肠中胆汁酸水平降低50-60%，并因此导致胆汁酸池大小降低60%。同时，结肠和粪便胆汁酸减少，而粪便胆固醇和脂肪酸排泄量升高。长效FGF 21类似物在降低小鼠胆汁酸水平方面显示出优于重组人FGF 21和FGF 19，且作用持续时间长。在肥胖食蟹猴中长期施用长效FGF 21类似物抑制血浆总胆汁酸和7 α-羟基-4-异戊烯-3-酮水平，7 α-羟基-4-异戊烯-3-酮是胆汁酸合成的生物标志物。总的来说，这些数据揭示了以前未鉴定的FGF 21在胆汁酸代谢中作为胆汁酸合成的负调节剂的作用。
Fibroblast growth factor 21 (FGF21) is a potent regulator of glucose and lipid homeostasis in vivo; its most closely related subfamily member, FGF19, is known to be a critical negative regulator of bile acid synthesis. To delineate whether FGF21 also plays a functional role in bile acid metabolism, we evaluated the effects of short-and long-term exposure to native FGF21 and long-acting FGF21 analogs on hepatic signal transduction, gene expression and enterohepatic bile acid levels in primary hepatocytes and in rodent and monkey models. FGF21 acutely induced ERK phosphorylation and inhibited Cyp7A1 mRNA expression in primary hepatocytes and in different rodent models, although less potently than recombinant human FGF19. Long-term administration of FGF21 in mice fed a standard chow diet resulted in a 50-60% decrease in bile acid levels in the liver and small intestines and consequently a 60% reduction of bile acid pool size. In parallel, colonic and fecal bile acid was decreased, whereas fecal cholesterol and fatty acid excretions were elevated. The long-acting FGF21 analog showed superiority to recombinant human FGF21 and FGF19 in decreasing bile acid levels with long duration of effect action in mice. Long-term administration of the long-acting FGF21 analogs in obese cynomolgus monkeys suppressed plasma total bile acid and 7 alpha-hydroxy-4-cholesten-3-one levels, a biomarker for bile acid synthesis. Collectively, these data reveal a previously unidentified role of FGF21 in bile acid metabolism as a negative regulator of bile acid synthesis.