Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury

Petrescu, Anca D.; DeMorrow, Sharon

doi:10.3390/cells10081846

Cited by 23 publications

(18 citation statements)

References 113 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Especially, Farnesoid X receptor (FXR) as a nuclear receptor, and Takeda G protein coupled receptor 5 (TGR5) as a membrane bound receptor are extensively investigated [43]. It is possible that bile acids trigger ROS production and inflammasome activation after binding to FXR or TGR5 [44]. Differences in the response of HSC, KC and hepatocytes to distinct bile acids may be due to different receptor profiles [45].…”

Section: Discussionmentioning

confidence: 99%

Bile Acids Activate NLRP3 Inflammasome, Promoting Murine Liver Inflammation or Fibrosis in a Cell Type-Specific Manner

Holtmann

Inzaugarat

Knorr

et al. 2021

Cells

View full text Add to dashboard Cite

Bile acids (BA) as important signaling molecules are considered crucial in development of cholestatic liver injury, but there is limited understanding on the involved cell types and signaling pathways. The aim of this study was to evaluate the inflammatory and fibrotic potential of key BA and the role of distinct liver cell subsets focusing on the NLRP3 inflammasome. C57BL/6 wild-type (WT) and Nlrp3−/− mice were fed with a diet supplemented with cholic (CA), deoxycholic (DCA) or lithocholic acid (LCA) for 7 days. Additionally, primary hepatocytes, Kupffer cells (KC) and hepatic stellate cells (HSC) from WT and Nlrp3−/− mice were stimulated with aforementioned BA ex vivo. LCA feeding led to strong liver damage and activation of NLRP3 inflammasome. Ex vivo KC were the most affected cells by LCA, resulting in a pro-inflammatory phenotype. Liver damage and primary KC activation was both ameliorated in Nlrp3-deficient mice or cells. DCA feeding induced fibrotic alterations. Primary HSC upregulated the NLRP3 inflammasome and early fibrotic markers when stimulated with DCA, but not LCA. Pro-fibrogenic signals in liver and primary HSC were attenuated in Nlrp3−/− mice or cells. The data shows that distinct BA induce NLRP3 inflammasome activation in HSC or KC, promoting fibrosis or inflammation.

show abstract

Section: Discussionmentioning

confidence: 99%

Bile Acids Activate NLRP3 Inflammasome, Promoting Murine Liver Inflammation or Fibrosis in a Cell Type-Specific Manner

Holtmann

Inzaugarat

Knorr

et al. 2021

Cells

View full text Add to dashboard Cite

show abstract

“…The farnesoid X receptor (FXR) has been shown to play an important role in hepatic inflammation, fibrosis, and vasculature remodeling, and FXR agonists have recently been studied in a variety of diseases, including primary biliary cholangitis and non-alcoholic steatohepatitis (83)(84)(85)(86). In addition, animal studies have shown that FXR agonists may also help improve PH.…”

Section: Fxr Agonistsmentioning

confidence: 99%

Current and investigational drugs in early clinical development for portal hypertension

2022

View full text Add to dashboard Cite

IntroductionThe development of portal hypertension leads to a majority of complications associated with chronic liver disease. Therefore, adequate treatment of portal hypertension is crucial in the management of such patients. Current treatment options are limited and consist mainly of medications that decrease the hyperdynamic circulation, such as non-selective beta blockers, and treatment of hypervolemia with diuretics. Despite these options, mortality rates have not improved over the last two decades. Newer, more effective treatment options are necessary to help improve survival and quality of life in these patients.Areas coveredMultiple preclinical models and clinical studies have demonstrated potential efficacy of a variety of new treatment modalities. We introduce treatment options including the use of vasodilation promotors, vasoconstriction inhibitors, anticoagulants, antiangiogenics, and anti-inflammatory drugs. We examine the most recent studies for treatment options within these drug classes and offer insights as to which show the most promise in this field.MethodologyPublished studies that identified novel medical treatment options of portal hypertension were searched using PubMed (https://pubmed.ncbi.nlm.nih.gov/). Clinical trials listed in Clinicaltrials.gov were also searched with a focus on more recent and ongoing studies, including those with completed recruitment. Searching with key terms including “portal hypertension” as well as individually searching specific treatment medications that were listed in other publications was carried out. Finally, current societal guidelines and recent review articles relevant to the management of portal hypertension were evaluated, and listed references of interest were included.ConclusionMany ongoing early phase studies demonstrate promising results and may shape the field of portal hypertension management in future. As concrete results become available, larger RCTs will be required before making definitive conclusions regarding safety and efficacy and whether or not they can be incorporated into routine clinical practice. Statins, anticoagulants, and PDE inhibitors have been among the most studied and appear to be most promising.

show abstract

“…They are either ligand-dependent or -independent transcription factors that play key roles in almost every mammalian physiology. Dysfunctions of nuclear receptor (NR) signaling pathways often become culprits that lead to many human diseases including liver diseases [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. For a long time, autophagy regulation has been considered to exclusively occur in cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Regulation of Hepatic Autophagy by Nuclear Receptors

Kim

Lee

2022

Cells

View full text Add to dashboard Cite

Autophagy is an adaptive self-eating process involved in degradation of various cellular components such as carbohydrates, lipids, proteins, and organelles. Its activity plays an essential role in tissue homeostasis and systemic metabolism in response to diverse challenges, including nutrient depletion, pathogen invasion, and accumulations of toxic materials. Therefore, autophagy dysfunctions are intimately associated with many human diseases such as cancer, neurodegeneration, obesity, diabetes, infection, and aging. Although its acute post-translational regulation is well described, recent studies have also shown that autophagy can be controlled at the transcriptional and post-transcriptional levels. Nuclear receptors (NRs) are in general ligand-dependent transcription factors consisting of 48 members in humans. These receptors extensively control transcription of a variety of genes involved in development, metabolism, and inflammation. In this review, we discuss the roles and mechanisms of NRs in an aspect of transcriptional regulation of hepatic autophagy, and how the NR-driven autophagy pathway can be harnessed to treat various liver diseases.

show abstract

Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury

Cited by 23 publications

References 113 publications

Bile Acids Activate NLRP3 Inflammasome, Promoting Murine Liver Inflammation or Fibrosis in a Cell Type-Specific Manner

Bile Acids Activate NLRP3 Inflammasome, Promoting Murine Liver Inflammation or Fibrosis in a Cell Type-Specific Manner

Current and investigational drugs in early clinical development for portal hypertension

Transcriptional Regulation of Hepatic Autophagy by Nuclear Receptors

Contact Info

Product

Resources

About