Novel and Emerging Therapies for Cholestatic Liver Diseases

Jordan Goldstein; Cynthia Levy


Liver International. 2018;38(9):1520-1535. 

In This Article

Bile Acid Homoeostasis, Signalling Pathways and Targets for Therapy

Given the liver involvement in their synthesis and transport, the liver is exposed to very high concentrations of bile acids. While their detergent-like properties help with digestion, leakage and accumulation of bile acids in hepatocytes at higher concentrations may lead to activation of cholangiocytes, causing chronic inflammation, proliferation, apoptosis and subsequently fibrosis.[6–8] Bile acids are thought to play a key role in the progression of both PBC and PSC.

The primary bile acids, cholic acid and chenodeoxycholic acid, are synthesized in the liver from cholesterol by the rate limiting enzyme cytochrome P450 7A1-hydroxylase (CYP7A1). Prior to secretion into the bile canaliculi, they undergo conjugation with taurine or glycine to form bile salts which decrease passive reabsorption. Once in the bowel, these primary bile salts undergo dehydroxylation and deconjugation by the gut microbiota, forming the secondary acids deoxycholic acid, lithocholic acid and UDCA. Although a small amount of bile acids are reabsorbed passively in the upper intestine, 90%–95% of them are reabsorbed in the terminal ileum through the apical sodium-dependent bile acid transporter (ASBT).[9,10] Bile acids then enter the portal circulation via transport by organic solute transporter (OST) α/β and are subsequently taken back into the hepatocyte through the sodium-taurocholate cotransporting polypeptide (NTCP) or the organic anion-transporting polypeptide (OATP). This process is known as the enterohepatic circulation and it is tightly regulated by numerous feedback mechanisms to protect the hepatocytes from bile acid-induced cytotoxicity (Figure 1).

Figure 1.

Enterohepatic circulation (EC) involves the production and maintenance of bile flow from production through recycling in the liver, biliary system, and intestines. EC begins with the production of the primary BA, CA and CDCA, via the rate limiting enzyme CYP7A1. After conjugation the BA are secreted into the bile canaliculi, mainly through BSEP, where a portion of the bile undergoes re-uptake via the periductular capillary plexus and subsequent resecretion (cholehepatic shunting); this increases bile flow and augments the bicarbonate-rich choleresis (bicarbonate umbrella). After assisting with digestion in the intestines, BA are reabsorbed via ABST. BA bind FXR in both the intestines and liver causing subsequent downregulation of CYP7A1. BA make their way back to the liver by portal circulation and are recycled, completing EC. AE2, apical chloride/bicarbonate exchanger; ASBT, apical sodium-dependent bile acid transporter; BA, bile acid; BSEP, bile salt export pump; CA, cholic acid; CDCA, chenodeoxycholic acid; CFTR, cystic fibrosis transmembrane conductance regulator; Cl-, chloride; CYP7A1, cytochrome P450 7A1-hydroxylase; FGF4, fibroblast growth factor 14; FGF19, fibroblast growth factor 19; FXR, farnesoid X receptor; HCO3-, bicarbonate; MDR1, multidrug resistance protein 1; MDR3, multidrug resistance protein 3; MRP2, multidrug resistance-associated protein 2; NTCP, sodium-taurocholate cotransporting polypeptide; OATP, organic anion transporting polypeptide; OST, organic solute transporter; PPAR, peroxisome proliferator-activated receptor

The main negative feedback mechanism regulating bile acid homoeostasis is via the farnesoid X nuclear receptor (FXR). In the enterocytes, bile acids bind FXR, triggering a signalling cascade which ultimately downregulates CYP7A1, thus decreasing the synthesis of bile acids. Importantly, one of the pathways to suppress CYP7A1 activity is through upregulation of the enteral hormone fibroblast growth factor 19 (FGF-19). Once secreted in the portal circulation, FGF-19 reaches the hepatocyte, where it binds to its receptor, the fibroblast growth factor 4/β klotho complex, to inhibit CYP7A1 gene transcription. Furthermore, FXR activation leads to downregulation of the intestinal bile acid transporter ASBT, the hepatic uptake transporters NTCP and OATP and upregulation of the hepatic efflux transporters bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2).[11,12]

Other important defence mechanisms include (1) the bicarbonate umbrella, (2) cholehepatic shunting, and (3) anti-inflammatory signalling. The bicarbonate umbrella, thought to be defective in PBC and PSC, refers to the alkalinization of bile via increased bicarbonate secretion. The elevated pH shifts bile acids towards an ionized form, decreasing their ability to diffuse and lessening their cytotoxic effects.[13,14] Similarly, cholehepatic shunting occurs when bile acids are recirculated between hepatocytes and cholangiocytes through the periductular capillary plexus, thus increasing bile flow and augmenting bicarbonate-rich choleresis.[11,15] Finally, bile acids can modulate inflammatory pathways via binding to a variety of nuclear and surface receptors (ie FXR, TGR5 and PXR) throughout the intestines and bile ducts.[16] By altering or overwhelming these defence mechanisms, PBC and PSC can further progress.