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 - 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.
Highlights
As synthesized from cholesterol in the liver, bile acids (BAs) are normally stored in the gallbladder
We found that serum levels of Alanine transaminase (ALT), aspartate transaminase (AST), and total BA were markedly upregulated with concomitant increases of hepatic BAs in these mice (Figures 1A, D)
We found that only mRNA level of fibroblast growth factor 1 (FGF1) in the liver was selectively downregulated (51% reduction relative to vehicle group) compared to other paracrine fibroblast growth factor (FGF) (Figure 1E; Table S2)
Summary
As synthesized from cholesterol in the liver, bile acids (BAs) are normally stored in the gallbladder. After meal, it is released into the small intestine to facilitate the digestion and absorption of dietary lipids (de Aguiar Vallim et al, 2013). Cholestasis is one of the most life-threatening liver diseases that is characterized with impaired bile flow and intrahepatic retention of toxic BAs. The occurrence and development of this disease. Up to 40% of patients’ response poorly to UDCA therapy (Lindor, 2007; Hirschfield et al, 2018). For patients with late-stage cholestasis, the only available option is liver transplantation (Lindor, 2007). There is still an unmet need for more effective therapeutic agents to relief cholestatic liver disease
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