FXR agonists represent an attractive class of drugs for pati

FXR agonists represent an attractive class of drugs for patients with PFIC. Synthetic and semi-synthetic FXR agonists, with higher affinity and potency to activate FXR, have been successfully tested in animal models of cholestasis. In these murine models, the semi-synthetic steroidal FXR ligand obeticholic rotenone (OCA, or 6-ethylchenodeoxycholic acid [6-ECDCA]) was able to restore reduced bile flow and improve cholestasis outcome [27], [98]. In phase II clinical trials, significant improvements were observed in the levels of ALP, serum bilirubin, γ-glutamyl transpeptidase and ALT. However, the increased frequency of pruritus along with the dyslipidaemia, a well-known cardiovascular risk, among cholestatic patients included in the clinical trial raise concerns with regard to the clinical application of this compound [39]. Interestingly, in Abcb4-/- mice, OCA did not show beneficial anti-cholestatic effects, although ileal FGF15 was induced and hepatic Cyp7a1 repressed. The complete absence of biliary phospholipids in the Abcb4 model may explain these discrepancies. Moreover, the dual FXR/TGR5 agonist, INT-767, improved the cholestasis phenotype along with robustly induced bicarbonate-rich choleresis and reduction of biliary BA output [2]. Analysis of the liver gene expression in cholestatic rats treated with the non-steroidal FXR agonist GW4064 demonstrated a decreased expression of BA biosynthetic genes together with an increased upregulation of genes involved in BA transport, including the phospholipid floppase MDR2. Nevertheless, the short terminal half-life of GW4064 has restricted its clinical utility [29]. Notably, when FXR was selectively overexpressed in the intestine of various mouse models of intrahepatic and extrahepatic cholestasis, BA pool size was substantially reduced and cholestasis improved [33], [63], suggesting that ileal FXR stimulation alone may be sufficient to counteract cholestasis. Pharmacological FXR activation leads to increased production of the FGF19 hormone, which reduces hepatic BA synthesis. FGF19 overexpression in mice has been associated with the development of HCC, therefore the activation of FXR with FXR agonist therapy raises unproven safety clinical concerns due to potential predisposition to the development of liver cancer. Recently, a non-tumorigenic FGF19-like peptide, which lacks the proliferative potency of their endogenous mother compounds [69], [87] was designed. Whereas it is not able to affect proliferation, it reduces BA production in humans [134]. Moreover, this peptide effectively reversed the cholestatic liver injury phenotype in Abcb4-/- mice [92], through the suppression of Cyp7a1 and total BA pools; therefore, it could be potentially good not only in the treatment of PFIC with Abcb4 mutations, but also PFIC with Atp8b1 and Abcb11 mutations. In a phase I trial on human volunteers, FGF19 mimetics resulted in a robust suppression of endogenous BA synthesis without showing apparent side effects [69]. Finally, in a very recent phase II clinical trial in primary biliary cholangitis patients unresponsive to UDCA treatment, FGF19 mimetics was able to decrease total BA and AP levels. Overall, further studies are still required for effective treatment in the management of PFIC.
Funding A. Moschetta is funded by Italian Association for Cancer Research (AIRC, IG 18987), NR-NET FP7 Marie Curie ITN (project number 606806), Intercept Pharmaceuticals Inc, San Diego CA, NGM Biopharmaceuticals, San Francisco CA, Italian Ministry of Health (Young Researchers Grant GR-2010-2314703).
Conflict of interest
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Introduction Alcoholic liver disease (ALD) could be caused by chronic and overt alcohol consumption, and is currently one of the major causes of liver morbidity and mortality worldwide. ALD represents a wide spectrum of morphological changes that can occur in varying degrees, including fatty liver, hepatic inflammation, alcoholic hepatitis, and alcoholic cirrhosis [1]. The mechanisms by which alcohol consumption leads to ALD remain elusive. Currently, ethanol is considered to generate hepatotoxicity by altering hepatic lipid metabolism and increasing endotoxin release from the gut, contributing to inflammation and oxidative stress [1], [2], [3], [4]. Additionally, environmental and genetic factors, including gender, ethnicity, nutritional factors, oxidative stress, and hepatic co-morbidities, may play a crucial role in ALD development [4], [5].