Paracrine Fibroblast Growth Factor 1 Functions as Potent Therapeutic Agent for Intrahepatic Cholestasis by Downregulating Synthesis of Bile Acid
Paracrine Fibroblast Growth Factor 1 Functions as Potent Therapeutic Agent for Intrahepatic Cholestasis by Downregulating Synthesis of Bile Acid
复制标题
旁分泌成纤维细胞生长因子 1 通过下调胆汁酸的合成作为肝内胆汁淤积的有效治疗剂
DOI：
10.3389/fphar.2019.01515
复制
发表时间：
2019-12-20
影响因子：
5.6
通讯作者：
Niu, Jianlou
中科院分区：
文献类型：
--
作者：
Lin, Huan;Zhou, Chuanren;Niu, Jianlou
内分泌成纤维细胞生长因子（FGF）19已被证明能够维持胆汁酸（BA）的稳态，因此有望成为胆汁淤积性肝病的潜在治疗剂。然而，旁分泌FGF是否具有这种BA调节活性仍有待确定。在我们的研究中，我们发现，旁分泌成纤维细胞生长因子1（FGF 1）选择性下调α-萘异硫氰酸酯（ANIT）诱导的肝内胆汁淤积症小鼠的肝脏，这表明这种旁分泌FGF与异常BA代谢的病理相关性。因此，我们评估了工程化的FGF 1突变体-FGF 1 ΔHBS对肝脏BA代谢的影响，发现该蛋白比没有任何肝脏促有丝分裂活性的FGF 19显示出更强的BA生物合成抑制作用。此外，长期给予FGF 1 ΔHBS通过减少肝脏BA积累来保护肝脏免受ANIT诱导的损伤。综上所述，这些数据表明，FGF 1 ΔHBS可能作为一种有效的治疗剂用于肝内胆汁淤积性肝病。
Endocrine fibroblast growth factor (FGF) 19 has been shown to be capable of maintaining bile acid (BA) homeostasis and thus hold promise to be a potential therapeutic agent for cholestasis liver disease. However, whether paracrine FGFs possess this BA regulatory activity remains to be determined. In our study, we identified that paracrine fibroblast growth factor 1 (FGF1) was selectively downregulated in the liver of alpha naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis mice, suggesting a pathological relevance of this paracrine FGF with abnormal BA metabolism. Therefore, we evaluated the effects of engineered FGF1 mutant - FGF1ΔHBS on the metabolism of hepatic BA and found that this protein showed a more potent inhibitory effect of BA biosynthesis than FGF19 without any hepatic mitogenic activity. Moreover, the chronic administration of FGF1ΔHBS protected liver against ANIT-induced injury by reducing hepatic BA accumulation. Taken together, these data suggest that FGF1ΔHBS may function as a potent therapeutic agent for intrahepatic cholestasis liver disease.