Paracrine Fibroblast Growth Factor 1 Functions as Potent Therapeutic Agent for Intrahepatic Cholestasis by Downregulating Synthesis of Bile Acid

Huan Lin; Chuanren Zhou; Yushu Hou; Qi Li; Guanting Qiao; Yang Wang; Zhifeng Huang; Jianlou Niu

doi:10.3389/fphar.2019.01515

Paracrine Fibroblast Growth Factor 1 Functions as Potent Therapeutic Agent for Intrahepatic Cholestasis by Downregulating Synthesis of Bile Acid

Front Pharmacol. 2019 Dec 20:10:1515. doi: 10.3389/fphar.2019.01515. eCollection 2019.

Authors

Huan Lin^{1

2}, Chuanren Zhou¹, Yushu Hou¹, Qi Li¹, Guanting Qiao¹, Yang Wang³, Zhifeng Huang¹, Jianlou Niu¹

Affiliations

¹ School of Pharmacy, Wenzhou Medical University, Wenzhou, China.
² Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Biomedical Collaborative Innovation Center of Wenzhou, Wenzhou, China.
³ School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.

Abstract

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 - FGF1^ΔHBS 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 FGF1^ΔHBS protected liver against ANIT-induced injury by reducing hepatic BA accumulation. Taken together, these data suggest that FGF1^ΔHBS may function as a potent therapeutic agent for intrahepatic cholestasis liver disease.

Keywords: alpha naphthylisothiocyanate; bile acid; cholestatic liver disease; fibroblast growth factor 1; intrahepatic cholestasis; negative regulator.