FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption

Clifford, Bethan; Sedgeman, Leslie R.; Williams, Kevin J.; Morand, Pauline; Cheng, Angela; Jarrett, Kelsey E; Chan, Alvin P.; Brearley-Sholto, Madelaine C.; Wahlström, Annika; Ashby, Julianne W.; Barshop, William D.; Wohlschlegel, James A.; Calkin, Anna C.; Liu, Yingying; Thorell, Anders; Meikle, Peter J.; Drew, Brian G.; Mack, Julia J.; Marschall, Hanns‐Ulrich; Tarling, Elizabeth J.; Edwards, Peter A.; Vallim, Thomas Q. de Aguiar

doi:10.1016/j.cmet.2021.06.012

Cited by 226 publications

(164 citation statements)

References 61 publications

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“…Fanitol X receptor (FXR) is a nuclear receptor widely expressed in the liver and small intestinal mucosa that plays an essential role in the sensation of bile acid signals. Fanitol X receptor senses bile acid signals and regulates their secretion by negative feedback, resulting in decreased intestinal lipid absorption, downregulation of the expression of key lipogenic genes in the liver, and reduced hepatic lipid levels in the end (69). The beneficial effects of the ligation of FXR with bile acids on metabolism also include promoting fatty acid oxidation in the liver, regulating glycogenolysis and gluconeogenesis, as well as restoring insulin sensitivity in muscle and adipose tissue (12).…”

Section: Liver Fibrosis Driven By Dietary Intake-derived Lipid Synthesis Fanitol X Receptor and Fxr Agonistsmentioning

confidence: 99%

Liver Fibrosis and MAFLD: From Molecular Aspects to Novel Pharmacological Strategies

Cai

et al. 2021

Front. Med.

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Metabolic-associated fatty liver disease (MAFLD) is a new disease definition, and this nomenclature MAFLD was proposed to renovate its former name, non-alcoholic fatty liver disease (NAFLD). MAFLD/NAFLD have shared and predominate causes from nutrition overload to persistent liver damage and eventually lead to the development of liver fibrosis and cirrhosis. Unfortunately, there is an absence of effective treatments to reverse MAFLD/NAFLD-associated fibrosis. Due to the significant burden of MAFLD/NAFLD and its complications, there are active investigations on the development of novel targets and pharmacotherapeutics for treating this disease. In this review, we cover recent discoveries in new targets and molecules for antifibrotic treatment, which target pathways intertwined with the fibrogenesis process, including lipid metabolism, inflammation, cell apoptosis, oxidative stress, and extracellular matrix formation. Although marked advances have been made in the development of antifibrotic therapeutics, none of the treatments have achieved the endpoints evaluated by liver biopsy or without significant side effects in a large-scale trial. In addition to the discovery of new druggable targets and pharmacotherapeutics, personalized medication, and combinatorial therapies targeting multiple profibrotic pathways could be promising in achieving successful antifibrotic interventions in patients with MAFLD/NAFLD.

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Section: Liver Fibrosis Driven By Dietary Intake-derived Lipid Synthesis Fanitol X Receptor and Fxr Agonistsmentioning

confidence: 99%

Liver Fibrosis and MAFLD: From Molecular Aspects to Novel Pharmacological Strategies

Cai

et al. 2021

Front. Med.

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“…FXR activation with the FXR agonist GSK2324 controls hepatic lipids via reduced absorption and selective decreases in fatty acid synthesis. The results in tissue-specific FXR KO mice show that hepatic FXR controls lipogenic genes, whereas intestinal FXR controls lipid absorption [ 289 ]. FXR activation by chenodeoxycholic acid (CDCA) in Zucker (fa/fa) obese rats reverse insulin resistance and hepatic steatosis [ 290 ].…”

Section: Clinical Research Findings Involving Metabolic Therapeutic Targetsmentioning

confidence: 99%

The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD

Hong

Chen

et al. 2021

Oxidative Medicine and Cellular Longevity

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The overproduction of reactive oxygen species (ROS) and consequent oxidative stress contribute to the pathogenesis of acute and chronic liver diseases. It is now acknowledged that nonalcoholic fatty liver disease (NAFLD) is characterized as a redox-centered disease due to the role of ROS in hepatic metabolism. However, the underlying mechanisms accounting for these alternations are not completely understood. Several nuclear receptors (NRs) are dysregulated in NAFLD, and have a direct influence on the expression of a set of genes relating to the progress of hepatic lipid homeostasis and ROS generation. Meanwhile, the NRs act as redox sensors in response to metabolic stress. Therefore, targeting NRs may represent a promising strategy for improving oxidation damage and treating NAFLD. This review summarizes the link between impaired lipid metabolism and oxidative stress and highlights some NRs involved in regulating oxidant/antioxidant turnover in the context of NAFLD, shedding light on potential therapies based on NR-mediated modulation of ROS generation and lipid accumulation.

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“…Farnesoid X receptor (FXR) is a Bsep transcriptional regulator. Recent studies show that FXR activation decreases intestinal lipid absorption and hepatic triglyceride levels to protect against NAFLD [ 46 ], and stimulating the FXR/BSEP pathway may promote the secretion of accumulated bile [ 47 ]. Boldine infusion can instantly increase the bile flow not only in healthy rats, but also in multidrug resistance-associated protein 2 (Mrp2) animals with deficiency or ethinylestradiol-induced cholestasis, without the increase in bile acid or glutathione biliary excretion.…”

Section: Amelioration Of Nafldmentioning

confidence: 99%

Natural Aporphine Alkaloids with Potential to Impact Metabolic Syndrome

et al. 2021

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The incidence and prevalence of metabolic syndrome has steadily increased worldwide. As a major risk factor for various diseases, metabolic syndrome has come into focus in recent years. Some natural aporphine alkaloids are very promising agents in the prevention and treatment of metabolic syndrome and its components because of their wide variety of biological activities. These natural aporphine alkaloids have protective effects on the different risk factors characterizing metabolic syndrome. In this review, we highlight the activities of bioactive aporphine alkaloids: thaliporphine, boldine, nuciferine, pronuciferine, roemerine, dicentrine, magnoflorine, anonaine, apomorphine, glaucine, predicentrine, isolaureline, xylopine, methylbulbocapnine, and crebanine. We particularly focused on their impact on metabolic syndrome and its components, including insulin resistance and type 2 diabetes mellitus, endothelial dysfunction, hypertension and cardiovascular disease, hyperlipidemia and obesity, non-alcoholic fatty liver disease, hyperuricemia and kidney damage, erectile dysfunction, central nervous system-related disorder, and intestinal microbiota dysbiosis. We also discussed the potential mechanisms of actions by aporphine alkaloids in metabolic syndrome.

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FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption

Cited by 226 publications

References 61 publications

Liver Fibrosis and MAFLD: From Molecular Aspects to Novel Pharmacological Strategies

Liver Fibrosis and MAFLD: From Molecular Aspects to Novel Pharmacological Strategies

The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD

Natural Aporphine Alkaloids with Potential to Impact Metabolic Syndrome

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