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Review
. 2024 Aug 1;15(4):1508-1536.
doi: 10.14336/AD.2023.0830.

Farnesoid X receptor: From Structure to Function and Its Pharmacology in Liver Fibrosis

Chuan Ding  1   2 , Zeping Wang  1 , Xinyue Dou  1 , Qiao Yang  1 , Yan Ning  1 , Shi Kao  1 , Xianan Sang  1 , Min Hao  1 , Kuilong Wang  1 , Mengyun Peng  1 , Shuosheng Zhang  3 , Xin Han  1   2 , Gang Cao  1   2
Affiliations
Review

Farnesoid X receptor: From Structure to Function and Its Pharmacology in Liver Fibrosis

Chuan Ding et al. Aging Dis. .

Abstract

The farnesoid X receptor (FXR), a ligand-activated transcription factor, plays a crucial role in regulating bile acid metabolism within the enterohepatic circulation. Beyond its involvement in metabolic disorders and immune imbalances affecting various tissues, FXR is implicated in microbiota modulation, gut-to-brain communication, and liver disease. The liver, as a pivotal metabolic and detoxification organ, is susceptible to damage from factors such as alcohol, viruses, drugs, and high-fat diets. Chronic or recurrent liver injury can culminate in liver fibrosis, which, if left untreated, may progress to cirrhosis and even liver cancer, posing significant health risks. However, therapeutic options for liver fibrosis remain limited in terms of FDA-approved drugs. Recent insights into the structure of FXR, coupled with animal and clinical investigations, have shed light on its potential pharmacological role in hepatic fibrosis. Progress has been achieved in both fundamental research and clinical applications. This review critically examines recent advancements in FXR research, highlighting challenges and potential mechanisms underlying its role in liver fibrosis treatment.

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Conflict of interest statement

Declaration of interests

The authors declare that there is no competition of interest.

Figures

Figure 1.
Figure 1.
Three different crystal form structures known to FXR (PDB ID is 4QE6). (A) Common architecture of FXR. (B) The approximate location of the apo-FXR and its bonded pocket that employs different conformation according to the species of ligands. (C) Activated conformation of FXR combined with CDCA (agonist-FXR). (D) Antagonistic conformation of FXR binding to GUDCA (antagonist-FXR).
Figure 2.
Figure 2.
Relationship between FXR and BAs. BAs are mainly synthesized by hepatocytes via the classical pathway or alternative pathway, all of which are regulated by FXRs expression. Activated FXRs can reduce the expression of BA synthases through SHP or FGFs. The relationship between FXR and BAs is mainly established through hepatoenteric circulation.
Figure 3.
Figure 3.
FXR in glucose lipid metabolism. In lipid metabolism, FXR reduces liver fat by inhibiting fat formation and promoting fatty acid oxidation; these functions are related to the expression of SREBP1 or PPARs, respectively; in glucose metabolism, FXR participates in glucose homeostasis through two pathways, namely, gluconeogenesis-related genes and glucagon-activated factors.
Figure 4.
Figure 4.
Overview of FXRs’ regulation of intestinal flora homeostasis and metabolic disorders. The imbalance between the body and the intestinal flora leads to the disturbance of normal physiological functions. The intestinal flora promotes fatty inflammation, steatosis, and obesity in an FXR-dependent manner. The activation of intestinal FXR can inhibit the abnormal proliferation of bacteria and reduce intestinal mucosal damage.
Figure 5.
Figure 5.
Role of FXRs in the liver. FXR activation is used in multiple liver diseases, such as liver injury, fibrosis, and even cancer, and the main mechanism is closely related to inflammation, steatosis, and apoptosis via related factors.
Figure 6.
Figure 6.
FXR in the gut-brain axis. FXRs interact and work together by regulating inflammatory responses, BAs, and the intestinal microbiome involved in entero-brain circulation.
Figure 7.
Figure 7.
Anti-fibrosis therapy in liver fibrosis. According to the pathogenesis, the treatment of liver fibrosis can be started from the cells involved in liver fibrosis. The main methods are inhibiting the damage and apoptosis of liver cells, promoting the type of transformation of immune cells, inhibiting the activation of HSCs, and promoting the apoptosis of activated HSCs.
Figure 8.
Figure 8.
Summary of the role of FXR in key cells in liver fibrosis. In the normal liver, hepatocytes provide energy and nutrients to nonparenchymal cells. Vitamin A stored in HSCs promotes the growth and proliferation of hepatocytes and macrophages, effectively maintaining homeostasis in the liver microenvironment. After liver injury, FXR was decreased significantly, accompanied by apoptosis of hepatocytes as well as the release of increased DAMPs and FFA content, resulting in macrophage activation. During this process, HSCs lose the storage function of vitamin A and contribute to the deposition of ECM, leading to liver fibrosis.
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Grants and funding

This work was financially supported by the National Natural Science Foundation of China (Nos. 81973481 and 82104394); the Natural Science Foundation of Zhejiang Province (Nos. LZ22H280001 and Y23H280022); Zhejiang Province Traditional Chinese Medicine Science and Technology Project (Nos. 2022ZQ033 and 2021ZQ023), and Zhejiang Chinese Medicine University university-level talent special project (Nos. 2021ZR06).

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