1. Academic Validation
  2. Improvement of NASH and liver fibrosis through modulation of the gut-liver axis by a novel intestinal FXR agonist

Improvement of NASH and liver fibrosis through modulation of the gut-liver axis by a novel intestinal FXR agonist

  • Biomed Pharmacother. 2024 Feb 29:173:116331. doi: 10.1016/j.biopha.2024.116331.
An-Na Moon 1 François Briand 2 Natalia Breyner 2 Dong-Keun Song 3 Martin Rønn Madsen 4 Hongbin Kim 5 Keonwoo Choi 5 Yoonsuk Lee 6 Wan Namkung 7
Affiliations

Affiliations

  • 1 College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, South Korea; iLeadBMS Co., Ltd., 614 Dongtangiheung-ro, Hwaseong-si 18469, South Korea.
  • 2 Physiogenex, 280 rue de l'Hers, ZAC de la Masquère, Escalquens 31750, France.
  • 3 iLeadBMS Co., Ltd., 614 Dongtangiheung-ro, Hwaseong-si 18469, South Korea.
  • 4 Gubra, Hørsholm Kongevej 11B, Hørsholm 2970, Denmark.
  • 5 KINS, Korean Institute of Nonclinical Study, 172 Dolma-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13505, South Korea.
  • 6 iLeadBMS Co., Ltd., 614 Dongtangiheung-ro, Hwaseong-si 18469, South Korea. Electronic address: ivo.lee@ileadbms.com.
  • 7 College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, South Korea. Electronic address: wnamkung@yonsei.ac.kr.
Abstract

Farnesoid X receptor (FXR) plays a pivotal role in the regulation of bile acid homeostasis and is involved in the pathogenesis of nonalcoholic steatohepatitis (NASH). Although FXR agonists effectively alleviate pathological features of NASH, adverse effects such as disturbance of Cholesterol homeostasis and occurrence of pruritus remain to be addressed. Here, we identified a novel FXR Agonist, ID119031166 (ID166), and explored the pharmacological benefits of ID166 in the treatment of NASH. ID166, a potent and selective non-bile acid FXR Agonist, exhibits preferential distribution in the intestine and shows no agonist activity against potential itch receptors including Mas-related G protein-coupled receptor X4 (MRGPRX4). Interestingly, ID166 significantly attenuated total nonalcoholic fatty liver disease (NAFLD) activity and liver fibrosis in a free choice diet-induced NASH hamster model. In addition, ID166 drastically modulated the relative abundance of five gut microbes and reduced the increase in plasma total bile acid levels to normal levels in NASH hamsters. Moreover, long-term treatment with ID166 significantly improved key histological features of NASH and liver fibrosis in a diet-induced NASH mouse model. In the NASH mouse livers, RNA-seq analysis revealed that ID166 reduced the gene expression changes associated with both NASH and liver fibrosis. Notably, ID166 exhibited no substantial effects on scratching behavior and serum IL-31 levels in mice. Our findings suggest that ID166, a novel FXR Agonist with improved pharmacological properties, provides a preclinical basis to optimize clinical benefits for NASH drug development.

Keywords

Bile acid; FXR; Gut; Microbiota; NASH; Pruritus.

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