However, the recent identification of a new type of genetic progressive familial intrahepatic cholestasis (PFIC) linked to FXR mutations has strengthen also the bona fide beneficial effects of target therapies that by-pass FXR activation, directly promoting the action of its target, namely the enterokine FGF19, in the repression of hepatic BAs synthesis with reduction of total BA levels in the liver and serum, accomplishing one of the major goals in cholestasis.
In this context, therapeutic approaches including the use of new hydrophilic BA such as the conjugation-resistant nor- ursodeoxycholic acid, nuclear receptor (FXR, PPAR-alpha) agonists, FGF19 analogues, inhibitors of the apical sodium-depend bile acid transporter (ASBT) and modulators of the inflammatory cascade triggered by BA are being studied as novel treatments of cholestasis.
These findings demonstrate that the regulation of BA synthesis in response to cholestasis is primarily controlled by circulating FGF19 and that under cholestatic conditions, the FGF19-BA synthesis feedback mechanism remains intact.
Here we analyzed hepatic expression of FGF19 and other genes relevant to the adaptive response to cholestasis in tissues from non-cirrhotic (n = 24) and cirrhotic (n = 21) patients along with control tissues (n = 21).