Article
Biochemistry & Molecular Biology
Pin-Ho Pan, Ya-Yu Wang, Shih-Yi Lin, Su-Lan Liao, Yu-Fang Chen, Wei-Chi Huang, Chun-Jung Chen, Wen-Ying Chen
Summary: 18-β-Glycyrrhetinic acid has promising hepatoprotective effects against cholestatic liver injury, improving liver histology and reducing oxidative stress, inflammation, apoptosis, impaired autophagy, and fibrosis.
Review
Pharmacology & Pharmacy
Danmei Yu, Zhou Lu, Ruyu Wang, Yusen Xiang, Hongtao Li, Jiani Lu, Lijun Zhang, Hongzhuan Chen, Weihua Li, Xin Luan, Lili Chen
Summary: Farnesoid X receptor (FXR) is considered a tumor suppressor for colorectal and liver cancers. The interaction between FXR, bile acids, and gut microbiota is closely associated with an increased risk of these cancers. Combination therapy using FXR agonists is receiving attention as a potential treatment approach for improved efficacy and reduced side effects.
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Tong Qin, Xuefeng Gao, Lei Lei, Jing Feng, Wenxuan Zhang, Yuhua Hu, Zhufang Shen, Zhenming Liu, Yi Huan, Song Wu, Jie Xia, Liangren Zhang
Summary: In this study, a novel potential drug target for nonalcoholic fatty liver disease (NAFLD) named Farnesoid X receptor (FXR) agonist was discovered through the development of a multi-stage computational workflow. The compound identified as the representative showed potent FXR agonistic activity in HEK293T cells and demonstrated positive effects on hypercholesterolemia, hepatic steatosis, hyperglycemia, and insulin resistance (IR) in high-fat-diet induced obese (DIO) mice.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Gastroenterology & Hepatology
Laura G. Di Pasqua, Marta Cagna, Giuseppina Palladini, Anna C. Croce, Massimiliano Cadamuro, Luca Fabris, Stefano Perlini, Luciano Adorini, Andrea Ferrigno, Mariapia Vairetti
Summary: The effects of two FXR agonists, OCA and INT-787, on hepatic levels of various proteins in a NASH model were compared. The results showed that INT-787 is superior to OCA in controlling specific cell types and clinically relevant anti-inflammatory and antifibrotic molecular mechanisms in NASH.
LIVER INTERNATIONAL
(2023)
Article
Gastroenterology & Hepatology
Xiaokui Huo, Dawei Li, Fan Wu, Shenghui Li, Yanling Qiao, Chao Wang, Yan Wang, Changjiang Zhou, Liqun Sun, Zhilin Luan, Qiulong Yan, Jiayue Wang, Yu Zhang, Ting Zhao, Yue An, Baojing Zhang, Xiangge Tian, Zhenlong Yu, Xiaochi Ma
Summary: The study found that Candida spp had a higher abundance in patients with IBD. It was revealed that Candida metapsilosis M2006B significantly attenuated colitis in mice by activating farnesoid X receptor (FXR). The research identified two acyclic sesquiterpenoids (F4 and F5) as major active metabolites of M2006B that effectively treated experimental colitis by selectively activating FXR.
Article
Gastroenterology & Hepatology
Stefania Grimaudo, Paola Dongiovanni, Jussi Pihlajamaki, Mohammed Eslam, Hannele Yki-Jarvinen, Rosaria Maria Pipitone, Guido Baselli, Calogero Camma, Vito Di Marco, Marco Enea, Miriam Longo, Grazia Pennisi, Daniele Prati, Rossella Zito, Anna Ludovica Fracanzani, Antonio Craxi, Jacob George, Stefano Romeo, Luca Valenti, Salvatore Petta
Summary: The NR1H4 gene rs35724 C allele is protective against severity of steatosis, steatohepatitis, and liver fibrosis, but is associated with higher total circulating cholesterol levels. Patients carrying the NR1H4 rs35724 C allele show increased hepatic mRNA levels of FXR and genes involved in bile acid synthesis. This suggests that increased hepatic FXR expression due to the NR1H4 rs35724 C allele may have potential therapeutic implications for NAFLD.
LIVER INTERNATIONAL
(2021)
Article
Biochemistry & Molecular Biology
Qianqian Qiu, Yanjuan Wang, Guolong Gu, Fan Yu, Shichao Zhang, Yining Zhao, Bai Ling
Summary: This study introduced structural optimizations to convert auraptene (AUR) into compound 14, a potent FXR agonist with higher activity, which fits well with the binding pocket in molecular modeling study and demonstrates better therapeutic effect in acetaminophen-induced acute liver injury model compared to AUR.
BIOORGANIC CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Zi-Lin Ren, Chang-Xiang Li, Chong-Yang Ma, Dan Chen, Jia-Hui Chen, Wen-Xiu Xu, Cong-Ai Chen, Fa-Feng Cheng, Xue-Qian Wang
Summary: Non-alcoholic fatty liver disease (NAFLD) affects a significant population worldwide and has implications beyond the liver, including the brain. The bile acid signaling pathway plays a crucial role in the development of NAFLD and brain disorders. Bile acids can send messages to the brain through direct or indirect channels, potentially impacting brain health.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Guoshun Luo, Xin Lin, Zhenbang Li, Maoxu Xiao, Xinyu Li, Dayong Zhang, Hua Xiang
Summary: FXR agonists are potential therapeutics for metabolic diseases by affecting bile acid, lipid, and glucose homeostasis, but full agonists may have side effects due to lack of selectivity. Partially activating FXR is important for novel modulators development. A new FXR agonist, 11k, showed lower maximum efficacy but similar potency in cellular FXR-dependent gene modulation and lipid-reducing activity, demonstrating promising in vivo FXR agonistic activity with desirable pharmacokinetic characteristics.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Gastroenterology & Hepatology
Kyounghwa Jung, Minwook Kim, Juhoon So, Seung-Hoon Lee, Sungjin Ko, Donghun Shin
Summary: This study identifies that activation of farnesoid X receptor (FXR) impairs biliary epithelial cell (BEC)-driven liver regeneration by enhancing PTEN activity. FXR activation reduces hepatic progenitor cell proliferation and increases cell death by inhibiting the PI3K-AKT-mTOR signaling pathway.
Article
Chemistry, Medicinal
Wenxin Wang, Zhijun Cao, Zhongcheng Yang, Ya Chen, Huixin Yao, Danting Zhou, Peixin Ou, Wanqiu Huang, Shixuan Jiao, Siliang Chen, Lianru Chen, Yuxia Liu, Jianming Mao, Jiayi Xie, Ruojing Xiang, Yuanqian Yang, Yisi Chen, Yonghong Yang, Liyun Tan, Haolong Tang, Luyong Zhang, Zheng Li
Summary: In this study, a novel sulfonamide FXR agonist 19 was synthesized through structure-based scaffold hopping strategy and showed promising therapeutic potential for NASH treatment with acceptable safety profiles.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Katrin Panzitt, Martin Wagner
Summary: The liver serves as a central metabolic hub that coordinates nutritional inputs and metabolic outputs. FXR in the liver and intestine plays a crucial role in regulating postprandial nutrient disposal. Aside from classical roles, FXR also has effects on amino acid, protein metabolism, autophagic turnover, and inflammation, which are less studied. Additionally, understanding of how FXR signaling is affected by posttranslational modifications and different isoforms is important for potential pharmaceutical targeting in clinical applications.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2021)
Article
Food Science & Technology
Peng Cao, Jun Gan, Sanlan Wu, Yixin Hu, Bin Xia, Xiaoyue Li, Hongan Zeng, Bingyu Cheng, Huifan Yu, Fei Li, Luqin Si, Jiangeng Huang
Summary: Tectorigenin (TG), a natural isoflavone, has protective effects on alpha-naphthylisothiocyanate-induced cholestatic liver injury by restoring abnormal markers and maintaining bile acid homeostasis through FXR-mediated bile acid efflux and Nrf2-mediated antioxidative pathways.
FOOD AND CHEMICAL TOXICOLOGY
(2023)
Review
Chemistry, Medicinal
Kang Wang, Yuecan Zhang, Guangji Wang, Haiping Hao, Hong Wang
Summary: Nonalcoholic fatty liver disease is a common liver disease without approved pharmacotherapy. Farnesoid X receptor (FXR) is considered a promising therapeutic target, but currently developed drugs have shown limited efficacy in clinical trials. This review summarizes the development of the FXR agonist obeticholic acid and discusses its limitations in depth.
MEDICINAL RESEARCH REVIEWS
(2023)
Article
Cell Biology
Bethan L. Clifford, Leslie R. Sedgeman, Kevin J. Williams, Pauline Morand, Angela Cheng, Kelsey E. Jarrett, Alvin P. Chan, Madelaine C. Brearley-Sholto, Annika Wahlstrom, Julianne W. Ashby, William Barshop, James Wohlschlegel, Anna C. Calkin, Yingying Liu, Anders Thorell, Peter J. Meikle, Brian G. Drew, Julia J. Mack, Hanns-Ulrich Marschall, Elizabeth J. Tarling, Peter A. Edwards, Thomas Q. de Aguiar Vallim
Summary: FXR agonists are used to treat NAFLD by controlling hepatic lipid absorption and fatty acid synthesis, specifically reducing levels of MUFA and PUFA in the liver. This reduction is mediated by repression of specific genes and is independent of other regulatory factors like SHP and SREBP1c. Additionally, tissue-specific FXR KO mice studies show that hepatic FXR controls lipogenic genes while intestinal FXR controls lipid absorption.
