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A dual farnesoid X receptor/soluble epoxide hydrolase modulator treats non-alcoholic steatohepatitis in mice.

Authors
  • Hye Khan, Md Abdul1
  • Schmidt, Jurema2
  • Stavniichuk, Anna1
  • Imig, John D1
  • Merk, Daniel3
  • 1 Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
  • 2 Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany. , (Germany)
  • 3 Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany; Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Switzerland. Electronic address: [email protected] , (Switzerland)
Type
Published Article
Journal
Biochemical pharmacology
Publisher
New York, NY : Elsevier Science Inc
Publication Date
May 23, 2019
Volume
166
Pages
212–221
Identifiers
DOI: 10.1016/j.bcp.2019.05.023
PMID: 31129048
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are the most prevalent metabolic liver disorders and a serious global health burden. NAFLD/NASH pathogenesis and progression are highly multi-factorial and likely demand a combination of multiple mechanisms to provide a more effective treatment. We have developed a dual farnesoid X receptor agonist (FXRA)/soluble epoxide hydrolase inhibitor (sEHi) to simultaneously address two validated and complementary modes of action in NASH treatment. Here we report the in vivo profiling for this FXRA/sEHi in toxin- and diet-induced rodent NASH models. In streptozotocin-induced NASH as a proof-of-concept study, the experimental FXRA/sEHi drug robustly prevented hepatic steatosis and fibrosis, and improved lipid homeostasis as well as biochemical markers of liver health. In methionine-choline-deficient high-fat diet-induced NASH, FXRA/sEHi treatment reduced hepatic steatosis and fibrosis to levels similar to healthy animals and demonstrated anti-inflammatory activity confirming that dual FXRA/sEHi modulation produces a triad of complementary anti-NASH effects. Our results validate dual FXRA/sEHi modulation as an effective therapeutic strategy to treat NASH and advocates for a combinational drug therapeutic approach for multifactorial liver diseases. Copyright © 2019 Elsevier Inc. All rights reserved.

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