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

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

Cystic fibrosis-related liver disease: Clinical presentations, diagnostic and monitoring approaches in the era of CFTR modulator therapies

“…Although obeticholic acid was found to be beneficial in patients with other chronic liver diseases, it was associated with serious adverse events [151]. FGF19 analogs are also a potential candidates [152] and other fibroblast growth factors such as FGF1, which is a PPARγ target, are potent potential therapeutic agents [153,154]. It has been suggested that vitamin D may alter gut microbiota, downregulate pro-inflammatory cytokines and IL-8 production, and prevent liver fibrosis by inhibiting the TGFβ1/SMAD signaling pathway [155][156][157][158].…”

Spaceflight alters host-gut microbiota interactions

“…This is consistent with the mitochondrial dysfunction highlighted as characteristic of spaceflight pathogenicity in recent multiomic analysis performed by de Silveira et at 18 , who also characterised compromised liver function in mice and astronauts after spaceflight compared ground controls, including upregulation of Fgf21 , a negative repressor of bile synthesis 122 , and accumulation of total cholesterol (higher low-density lipoprotein cholesterol but decreased high-density lipoprotein cholesterol). Here, another potent repressor of Cyp7A1 bile synthesis, fibroblast growth factor 1 ( fgf1 ) 123 , was upregulated in the liver of mice after 29 days of spaceflight, and the more well known Fgf21 16 was significantly upregulated in the liver after both 29 days and 56 days of spaceflight.…”

FGF1 Signaling Modulates Biliary Injury and Liver Fibrosis in the Mdr2−/− Mouse Model of Primary Sclerosing Cholangitis

“…( 37 ) Also, FGF1 improves intrahepatic cholestasis by down‐regulation of bile acid (BA) levels. ( 38 ) The beneficial effects of FGF1 and other FGF isoforms (e.g., FGF21) on steatosis and steatohepatitis were also observed in mouse models of nonalcoholic fatty liver diseases. ( 39 ) Another study has shown that elevated levels of FGF19 suppress BA synthesis through inhibition of the CYP7A1 (cytochrome P450 family 7 subfamily A member 1) gene, thus providing beneficial effects for patients with PBC.…”