Nuclear Receptors: From Structure to the Clinic


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A subsequent question remains whether some drug effects can now be assigned to FXR activation. Fluticasone propionate and mometasone furoate are both anti-inflammatory drugs, which can be linked to FXR activation since FXR is known for its anti-inflammatory effect Of particular interest is the drug gliquidone, an oral drug used to treat patients suffering from type 2 diabetes mellitus Likewise, findings of several studies support a role for FXR in glucose homeostasis, that could work in synergy to reduce glucose levels even further Another interesting drug to discuss is triclosan, an antibacterial agent found in many consumer products, for instance first aid products, toothpaste, mouthwash and soap.

Many of these products are used regularly, and as a consequence, people may be exposed to FXR activators regularly. Furthermore, triclosan is rapidly absorbed through skin and can enter the bloodstream for systemic circulation. Interestingly, a recent study in which mice were briefly exposed to relatively low triclosan concentrations showed adverse health effects in mice with colitis, as demonstrated by increased gut inflammation and enhanced colon cancer cell growth Moreover, triclosan treated mice showed accelerated hepatocellular carcinoma development Similarly, FXR deficiency also leads to increased inflammation and enhances tumour growth in gut and liver 45 , This may at least cause some of the negative effects observed after long-term exposure to triclosan.

However, further research has to reveal whether there is a connection between these drugs and FXR. Screens like the one described in this paper could provide insight in multiple drug targeting and will give us a more complete understanding of the requirements of FXR ligand binding.

Avermectin B1a, bepridil, fluticasone proprionate, gliquidone, triclosan and nicardipine were purchased from Sigma-Aldrich.

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Stable cell lines were generated by colony picking using cloning rings over well separated colonies as described before Cells were harvested by centrifugation and the resulting pellet was suspended in FACS uptake buffer 0. Huh7 cells were plated in wells. Expression levels of all samples were normalized to the geometrical mean of housekeeping genes. Raw data was converted using LC conversion software and samples were individually checked for their baseline and amplification efficiency using LinRegPCR software.

Trauner, M. Bile acids as regulators of hepatic lipid and glucose metabolism. Digestive diseases 28 , — Watanabe, M. The Journal of clinical investigation , — Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation.

Publications

Nature , — Fang, S. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nature medicine 21 , — Zhang, Y. Arteriosclerosis, thrombosis, and vascular biology 26 , — Yang, Z.


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Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease. Modica, S. Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis. Sinal, C. Cell , — Goodwin, B. Molecular cell 6 , — Gupta, S. Journal of Biological Chemistry , — Inagaki, T. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Chiang, J.

Bile acids: regulation of synthesis. Journal of lipid research 50 , — Boyer, J.

The association between nuclear receptors and ocular diseases

Wagner, M. Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice. Gastroenterology , — Guo, G.

Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity. M Mudaliar, S. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease.

Hirschfield, G. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Houck, K. Intestinal Farnesoid X Receptor activation by pharmacological inhibition of the Organic Solute Transporter alpha-beta. Lindenburg, L. Engineering genetically encoded FRET sensors. Sensors 14 , — Van der Velden, L. Hepatology 57 , — Boran, A.

Systems approaches to polypharmacology and drug discovery. Curr Opin Drug Disc 13 , — Network analysis of FDA approved drugs and their targets. Anighoro, A. Polypharmacology: Challenges and Opportunities in Drug Discovery.

Grober, J. Lee, F. FXR, a multipurpose nuclear receptor. Nature , — Fang, S. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nature medicine 21 , — Zhang, Y. Arteriosclerosis, thrombosis, and vascular biology 26 , — Yang, Z. Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease.

Modica, S. Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis. Sinal, C. Cell , — Goodwin, B. Molecular cell 6 , — Gupta, S. Journal of Biological Chemistry , — Inagaki, T. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis.

Chiang, J. Bile acids: regulation of synthesis.

Journal of lipid research 50 , — Boyer, J. Wagner, M. Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice. Gastroenterology , — Guo, G. Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity. M Mudaliar, S. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Hirschfield, G.

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Nuclear Receptors, Volume by David W. Russell | | Booktopia

Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Houck, K. Intestinal Farnesoid X Receptor activation by pharmacological inhibition of the Organic Solute Transporter alpha-beta.

Nuclear Receptors: From Structure to the Clinic Nuclear Receptors: From Structure to the Clinic
Nuclear Receptors: From Structure to the Clinic Nuclear Receptors: From Structure to the Clinic
Nuclear Receptors: From Structure to the Clinic Nuclear Receptors: From Structure to the Clinic
Nuclear Receptors: From Structure to the Clinic Nuclear Receptors: From Structure to the Clinic
Nuclear Receptors: From Structure to the Clinic Nuclear Receptors: From Structure to the Clinic
Nuclear Receptors: From Structure to the Clinic Nuclear Receptors: From Structure to the Clinic

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