Non-steroidal FXR agonist cilofexor improves cholestatic liver injury in the Mdr2-/- mouse model of sclerosing cholangitis

Fuchs, Claudia D.; Sroda, Natalie; Scharnagl, Hubert; Gupta, Ruchi S.; Minto, Wesley; Stojaković, Tatjana; Liles, John T.; Budas, Grant R.; Hollenback, David; Trauner, Michael

doi:10.1016/j.jhepr.2023.100874

Cited by 5 publications

(3 citation statements)

References 40 publications

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“…Interestingly, OCA treatment did not improve the cholestatic phenotype of cytochrome P450 2C70 ( Cyp2c70 ) deficient mice with a humanized more hydrophobic bile salt pool [29]. The nonsteroidal FXR agonist cilofexor also improved cholestatic liver injury in multidrug resistance protein 2 ( Mdr2 ) knock-out mice, marked by amongst others improved ALP and ALT, and reduced hepatic fibrosis [30 ▪ ]. To date, novel FXR agonists are still being discovered.…”

Section: Pre-clinical Researchmentioning

confidence: 99%

Targeting bile salt homeostasis in biliary diseases

Trampert,

Kunst,

van de Graaf

2024

Current Opinion in Gastroenterology

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Purpose of review Advances in the understanding of bile salt synthesis, transport and signalling show the potential of modulating bile salt homeostasis as a therapeutic strategy in cholestatic liver diseases. Here, recent developments in (pre)clinical research in this field is summarized and discussed. Recent findings Inhibition of the apical sodium-dependent bile salt transporter (ASBT) and Na+-taurocholate cotransporting polypeptide (NTCP) seems effective against cholestatic liver diseases, as well as Farnesoid X receptor (FXR) agonism or a combination of both. While approved for the treatment of primary biliary cholangitis (PBC) and intrahepatic cholestasis of pregnancy (ICP), ursodeoxycholic acid (UDCA) has retrospectively shown carefully promising results in primary sclerosing cholangitis (PSC). The side chain shortened derivate norUDCA is of further therapeutic interest since its mechanisms of action are independent of the bile salt transport machinery. In the pathogenesis of sclerosing cholangiopathies, a skewed T-cell response with alterations in gut microbiota and bile salt pool compositions are observed. In PSC pathogenesis, the bile salt receptor Takeda G-protein-coupled receptor 5 (TGR5) in cholangiocytes is implicated, whilst in immunoglobulin G4-related cholangitis the autoantigens annexin A11 and laminin 511-E8 are involved in protecting cholangiocytes. Summary Modulating bile salt homeostasis has proven a promising treatment strategy in models of cholestasis and are continuously being further developed. Confirmatory clinical studies are needed in order to assess the proposed treatment strategies in patients allowing for a broader therapeutic arsenal in the future.

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Section: Pre-clinical Researchmentioning

confidence: 99%

Targeting bile salt homeostasis in biliary diseases

Trampert,

Kunst,

van de Graaf

2024

Current Opinion in Gastroenterology

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“…In a phase II study, patients with noncirrhotic MASH given 24‐week therapy with cilofexor showed significant improvement in hepatic steatosis, liver biochemistry, and bile acids 88 . Cilofexor improved cholestatic liver enzymes and noninvasive markers of liver fibrosis in patients with primary sclerosing cholangitis 89 . Similarly, cilofexor improved insulin sensitivity and liver enzymes in patients with nondiabetic MASLD 89 .…”

Section: Small Molecule Developmentsmentioning

confidence: 99%

“…Cilofexor improved cholestatic liver enzymes and noninvasive markers of liver fibrosis in patients with primary sclerosing cholangitis 89 . Similarly, cilofexor improved insulin sensitivity and liver enzymes in patients with nondiabetic MASLD 89 . Cilofexor reduced hepatic fat content and serum Gamma Glutamyl Transferase (γ‐GT) in patients with MASH; pruritus was noted as a minor side‐effect 88,90 .…”

Section: Small Molecule Developmentsmentioning

confidence: 99%

Advancements in metabolic‐associated steatotic liver disease research: Diagnostics, small molecule developments, and future directions

Eeda,

Patil,

Joshi

et al. 2024

Hepatology Research

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Metabolic (dysfunction) associated steatotic liver disease (MASLD) formerly known as non‐alcoholic fatty liver disease (NAFLD) is a growing global health concern with no approved pharmacological treatments. At the same time, there are no standard methods to definitively screen for the presence of MASLD because of its progressive nature and symptomatic commonality with other disorders. Recent advances in molecular understanding of MASLD pathophysiology have intensified research on development of new drug molecules, repurposing of existing drugs approved for other indications, and an educated use of dietary supplements for its treatment and prophylaxis. This review focused on depicting the latest advancements in MASLD research related to small molecule development for prophylaxis or treatment and diagnosis, with emphasis on mechanistic basis at the molecular level.This article is protected by copyright. All rights reserved.

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