Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury
Abstract
:1. Introduction
2. FXR
2.1. Targeting FXR for BA Regulation in Cholestasis
2.2. Targeting FXR-Fibroblast Growth Factor (FGF) 15/19 Enterohepatic Pathway
2.3. Targeting Hydrophobic BA with Role in Hepatocellular Death, Activation of HSC and Fibrogenesis
3. Targeting FXR in Portal Hypertension Associated with Cholestasis-Induced Cirrhosis
4. FXR Involvement in Autophagy during Cholestasis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Dysfunction | Signaling Pathway/Genetic Defect | Drugs | References |
---|---|---|---|
Reduced FXR activity in hepatocytes | FXR/SHP/BA synthesis enzymes | Natural (UDCA) and synthetic (INT747, GW4046, WAY-62450) FXR ligands | [6,20,21,22,23,24,25,26,27,28] |
Reduced FXR expression in hepatocytes | ROS/NRF2/FXR | -Inhibitors of NRF2: Brusatol; | [29,30,31] |
-Inhibitors of ROS: N-acetyl cysteine | [32,33,34] | ||
Reduced expression of FXR in hepatocytes | FGF19/Src/FXR | FGF19-induced activation of Src to phosphorylate FXR | [35,36,37,38] |
Excessive hydrophobic BA in hepatocytes | HNF4α/SHP/ALR (hepatopoietin) | Activation of ALR, FOXA2, STAT3 | [39,40] |
Excessive total BA in hepatocytes | -Reduced expression/activity of enzymes that catabolize BA; | -Inducers of drug-metabolizing enzymes: CYP3A4, CYP7A1; | [41,42,43,44,45,46,47] |
-Increased expression/activities of enzymes of BA biosynthesis; | -Inhibitors of GGPP, FPP; | [48] | |
Impaired BA homeostasis | BA transport proteins: | -Inducers of BA exporters (BSEP, MRP4) and HCO3- excretion (AE2); | [49,50,51] |
-Inhibitors of NTCP (recovers BA from intestine): rifampicin | [47,51] | ||
Impaired autophagy | AMPK/Autophagy/FXR | -Activators of AMPK: betulinic acid, AICAR | [52,53] |
Impaired autophagy | ROS/NRF2/Autophagy/FXR | -Inhibitors of ROS-generating oxidative enzymes | [33,54] |
Study | NCT Number | Conditions | Treatments |
---|---|---|---|
OCA in PSC cholangitis | NCT02177136 | PSC | OCA vs. Placebo |
A post-authorization noninterventional observational of patients with PBC cholangitis treated with OCA in real time. | NCT03703076 | PBC | OCA vs. Placebo |
Phase 4 study of OCA evaluating clinical outcomes in patients with PBC | NCT0238111 | Liver cirrhosis, biliary | OCA vs. Placebo |
Prospective, multicenter cohort study on PBC | NCT04076527 | PBC | UDCA vs. Ocaliva |
Study of OCA evaluating pharmacokinesis and safety in patients with PBC and hepatic impairment | NCT03633227 | Liver cirrhosis, biliary | OCA vs. Placebo |
Study of OCA in combination with BZF evaluating efficacy, safety, and tolerability in patients with PBC | NCT04594694 | Liver, cirrhosis, biliary | OCA + BZF vs. OCA only, BZF only, Placebo |
Linerixibat and OCA drug interaction study in healthy subjects | NCT04053023 | Cholestasis | GSK2330672 + OCA vs. each drug alone, or Placebo |
Phase 3 study of OCA in patients with PBC | NCT01473524 | PBC | OCA vs. Placebo |
OCA in bariatric and gallstone disease | NCT01625026 | Gall stones, obesity | OCA vs. Placebo |
Effect of OCA on transport of BA in PBC examined by 11C-cholyl-sarcosine PET/CT | NCT03253276 | PBC | OCA vs. Placebo |
Study of INT 747 in combination with URSO in patients with PBC | NCT00550862 | PBC | INT-747, URSO/UDCA vs. Placebo |
Study of OCA combination with UDCA in patients with PBC | NCT04956328 | PBC | OCA + UDCA vs. Placebo, OCA only, UDCA only. |
Study of INT-747 as monotherapy in participants with PBC | NCT00570765 | PBC | INT-747 vs. Placebo |
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Petrescu, A.D.; DeMorrow, S. Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury. Cells 2021, 10, 1846. https://doi.org/10.3390/cells10081846
Petrescu AD, DeMorrow S. Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury. Cells. 2021; 10(8):1846. https://doi.org/10.3390/cells10081846
Chicago/Turabian StylePetrescu, Anca D., and Sharon DeMorrow. 2021. "Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury" Cells 10, no. 8: 1846. https://doi.org/10.3390/cells10081846