Tropifexor-Mediated Abrogation of Steatohepatitis and Fibrosis Is Associated With the Antioxidative Gene Expression Profile in Rodents

Hepatology Communications
Eloy D HernandezBryan Laffitte

Abstract

Farnesoid X receptor (FXR) agonism is emerging as an important potential therapeutic mechanism of action for multiple chronic liver diseases. The bile acid-derived FXR agonist obeticholic acid (OCA) has shown promise in a phase 2 study in patients with nonalcoholic steatohepatitis (NASH). Here, we report efficacy of the novel nonbile acid FXR agonist tropifexor (LJN452) in two distinct preclinical models of NASH. The efficacy of tropifexor at <1 mg/kg doses was superior to that of OCA at 25 mg/kg in the liver in both NASH models. In a chemical and dietary model of NASH (Stelic animal model [STAM]), tropifexor reversed established fibrosis and reduced the nonalcoholic fatty liver disease activity score and hepatic triglycerides. In an insulin-resistant obese NASH model (amylin liver NASH model [AMLN]), tropifexor markedly reduced steatohepatitis, fibrosis, and profibrogenic gene expression. Transcriptome analysis of livers from AMLN mice revealed 461 differentially expressed genes following tropifexor treatment that included a combination of signatures associated with reduction of oxidative stress, fibrogenesis, and inflammation. Conclusion: Based on preclinical validation in animal models, tropifexor is a promising investigatio...Continue Reading

References

May 21, 1999·Science·M MakishimaB Shan
May 21, 1999·Science·D J ParksJ M Lehmann
Aug 9, 2002·Journal of Medicinal Chemistry·Roberto PellicciariTimothy M Willson
May 18, 2004·The Journal of Clinical Investigation·Mitsuhiro WatanabeJohan Auwerx
May 26, 2005·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·David E KleinerUNKNOWN Nonalcoholic Steatohepatitis Clinical Research Network
Jan 18, 2006·Proceedings of the National Academy of Sciences of the United States of America·Yanqiao ZhangPeter A Edwards
Oct 31, 2008·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Yan-Dong WangWendong Huang
Sep 18, 2009·Trends in Pharmacological Sciences·Stefano FiorucciSabrina Cipriani
Mar 2, 2011·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Zobair M YounossiZachary Goodman
Jan 24, 2012·American Journal of Physiology. Gastrointestinal and Liver Physiology·James L TrevaskisJonathan D Roth
Mar 15, 2012·Nature Reviews. Molecular Cell Biology·Anna C Calkin, Peter Tontonoz
May 23, 2012·Molecular and Cellular Endocrinology·Tsutomu MatsubaraFrank J Gonzalez
Feb 19, 2013·Journal of Lipid Research·George N IoannouChristopher Savard
Jul 28, 2013·American Journal of Physiology. Gastrointestinal and Liver Physiology·Jason R ClapperJonathan D Roth
Aug 29, 2013·Nature Reviews. Gastroenterology & Hepatology·Frank G SchaapPeter L M Jansen
Sep 18, 2013·Nature Reviews. Gastroenterology & Hepatology·Rohit Loomba, Arun J Sanyal
Oct 19, 2013·The Journal of Clinical Investigation·Ichiaki ItoJunn Yanagisawa
Nov 12, 2013·Lancet·Roger Williams, Richard Horton
Apr 29, 2014·Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association·Siddharth SinghRohit Loomba
Jan 23, 2016·Nature Reviews. Drug Discovery·Giovanni MussoRoberto Gambino
Nov 30, 2016·World Journal of Gastroenterology : WJG·Evangelia MakriKonstantinos Tziomalos
Jul 18, 2017·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Naga ChalasaniArun J Sanyal
Jul 27, 2017·Digestive Diseases and Sciences·George CholankerilAijaz Ahmed
Nov 13, 2017·Journal of Hepatology·Prasanna K SanthekadurArun J Sanyal
Dec 1, 2017·Expert Opinion on Drug Discovery·Banumathi K ColeAjit Dash
Nov 21, 2018·Cell·Marcus GrohmannTony Tiganis

❮ Previous
Next ❯

Citations

Dec 6, 2019·Hepatology International·Katharina C ReimerFrank Tacke
Jun 17, 2020·Expert Opinion on Pharmacotherapy·Joeri LambrechtFrank Tacke
Mar 31, 2020·Journal of Gastroenterology·Mette Vesterhus, Tom Hemming Karlsen
Oct 6, 2020·Frontiers in Medicine·Mary Stofan, Grace L Guo
Jul 8, 2020·BMC Gastroenterology·Henrik H HansenKristoffer T G Rigbolt
Sep 29, 2020·Frontiers in Pharmacology·Chao LiYunlun Li
Jun 14, 2020·Diseases·Ludovico AbenavoliPietro Invernizzi
Jan 20, 2021·BMJ : British Medical Journal·Maria Letizia PetroniGiulio Marchesini
Nov 3, 2020·World Journal of Gastroenterology : WJG·Alejandro Campos-MurguíaRicardo U Macías-Rodríguez
Feb 20, 2021·Journal of Clinical and Translational Hepatology·Vinka Rupcic RubinRobert Smolic
Apr 25, 2021·Liver International : Official Journal of the International Association for the Study of the Liver·Yongtao XiaoWei Cai
Jun 17, 2021·Nature Reviews. Endocrinology·Daniel Ferguson, Brian N Finck
Mar 31, 2021·Journal of Pediatric Gastroenterology and Nutrition·Yang LiuWei Cai
Aug 4, 2021·Metabolism: Clinical and Experimental·Margaux NawrotBart Staels
Jan 16, 2020·Journal of Medicinal Chemistry·Donatella ChianelliValentina Molteni

❮ Previous
Next ❯

Datasets Mentioned

BETA
GSE129389

Methods Mentioned

BETA
RNAseq

Clinical Trials Mentioned

NCT02855164

Software Mentioned

GraphPad
Cuffnorm
STAR
Cuffdiff
GraphPad Prism
Tropifexor
Aperio

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.