AKR1B7 Is Induced by the Farnesoid X Receptor and Metabolizes Bile Acids

Schmidt, Daniel R.; Schmidt, Samuel; Holmstrom, Sam R.; Makishima, Makoto; Yu, Ruth T.; Cummins, Carolyn L.; Mangelsdorf, David J.; Kliewer, Steven A.

doi:10.1074/jbc.m110.181230

Cited by 35 publications

(40 citation statements)

References 32 publications

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“…We noted that while this article was in preparation, Schmidt et al reported that treatment of mice with GW4064 for 4 or 12 h induced Akr1b7 mRNA levels in the liver and intestine ( 16 ). Consistent with these data, we demonstrated that oral gavage of C57BL/6 mice with GW4064 for 7 days signifi cantly induces both mRNA and protein levels of Akr1b7 .…”

Section: Hepatic Expression Of Akr1b7 Ameliorates Hepatic Lipid Accumsupporting

confidence: 78%

“…Very recently, AKR1B7 was shown to convert 3-keto lithocholic acid (LCA) to less toxic 3 ␤ -hydroxy LCA and was induced in enterohepatic tissues when FXR was activated following acute treatment with an FXR agonist ( 16 ). In this report, we show that activation of FXR induces AKR1B7 mRNA and protein levels in both the intestine and liver.…”

Section: Glucose/insulin/pyruvate Tolerance Tests and Hepatic Glycogementioning

confidence: 62%

“…Recent data suggest that certain bile acids are substrates for Akr1b7 ( 16 ). Bile acids are known to activate FXR, a nuclear receptor that has both hypoglycemic and hypolipidimic effects.…”

Section: Discussionmentioning

confidence: 99%

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Aldo-keto reductase 1B7 is a target gene of FXR and regulates lipid and glucose homeostasis

Yin

et al. 2011

Journal of Lipid Research

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Section: Hepatic Expression Of Akr1b7 Ameliorates Hepatic Lipid Accumsupporting

confidence: 78%

Section: Glucose/insulin/pyruvate Tolerance Tests and Hepatic Glycogementioning

confidence: 62%

See 1 more Smart Citation

Aldo-keto reductase 1B7 is a target gene of FXR and regulates lipid and glucose homeostasis

Yin

et al. 2011

Journal of Lipid Research

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“…In addition, Akr1b7 is important for metabolizing 3-keto bile acids to 3b-hydroxy bile acids. Toxic bile acids, such as desoxycorticosterone acetate, are converted to less toxic 3b bile acids, such as 3bDCA, by Akr1b7 (Schmidt et al, 2011). The present data indicates for the first time that Akr1b3 is expressed mainly in brain.…”

Section: Discussionmentioning

confidence: 99%

Tissue Distribution, Ontogeny, and Chemical Induction of Aldo-Keto Reductases in Mice

Pratt-Hyatt¹,

Lickteig²,

Klaassen³

2013

Drug Metab Dispos

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Aldo-keto reductases (Akrs) are a conserved group of NADPHdependent oxido-reductase enzymes. This study provides a comprehensive examination of the tissue distribution of the 16 substrate-metabolizing Akrs in mice, their expression during development, and whether they are altered by chemicals that activate distinct transcriptional factor pathways. Akr1c6, 1c14, 1c20, and 1c22 are primarily present in liver; Akr1a4, 1c18, 1c21, and 7a5 in kidney; Akr1d1 in liver and kidney; Akr1b7 in small intestine; Akr1b3 and Akr1e1 in brain; Akr1b8 in testes; Akr1c14 in ovaries; and Akrs1c12, 1c13, and 1c19 are expressed in numerous tissues. Liver expression of Akr1d1 and Akr1c is lowest during prenatal and postnatal development. However, by 20 days of age, liver Akr1d1 increases 120-fold, and Akr1c mRNAs increase as much as 5-fold (Akr1c19) to 1000-fold (Akr1c6). Treatment of mice with chemical activators of transcription factors constitutive androgen receptor (CAR), pregnane X receptor (PXR), and the nuclear factor-erythroid-2 (Nrf2) transcription factor alters liver mRNAs of Akrs. Specifically, CAR activation by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) increases mRNAs of Akr1b7, Akr1c6, Akr1c19, and Akr1d1, whereas PXR activation by 5-pregnenolone-16a-carbonitrile (PCN) increases the mRNA of Akr1b7 and suppresses mRNAs of Akr1c13 and Akr1c20. The Nrf2 activator 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) induces mRNAs of Akr1c6 and Akr1c19. Moreover, Nrf2-null and Nrf2 overexpressing mice demonstrate that this induction is Nrf2-dependent.

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“…For example the case has been made for orally administered fish oil poly unsaturated fatty acids (PUFAs), such as DHA, acting physiologically at GPR120 (Oh et al, 2010; Talukdar et al, 2011). Other beneficial dietary FFAs, such as conjugated linoleic acid, are also FFA GPCR agonists (Schmidt et al, 2011). Given the apparent lack of selectivity of FFA GPCRs for a range of “good” and “bad” long chain FFAs, it will be necessary to test the extent to which the specific benefits of PUFAs derive from binding FFA1 or GPR120 receptors.…”

Section: Long Chain Ffa Gpcrs As Therapeutic Targetsmentioning

confidence: 99%

Drug Discovery Opportunities and Challenges at G Protein Coupled Receptors for Long Chain Free Fatty Acids

Holliday¹,

Watson²,

Brown³

2012

Front. Endocrin.

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Discovery of G protein coupled receptors for long chain free fatty acids (FFAs), FFA1 (GPR40) and GPR120, has expanded our understanding of these nutrients as signaling molecules. These receptors have emerged as important sensors for FFA levels in the circulation or the gut lumen, based on evidence from in vitro and rodent models, and an increasing number of human studies. Here we consider their promise as therapeutic targets for metabolic disease, including type 2 diabetes and obesity. FFA1 directly mediates acute FFA-induced glucose-stimulated insulin secretion in pancreatic beta-cells, while GPR120 and FFA1 trigger release of incretins from intestinal endocrine cells, and so indirectly enhance insulin secretion and promote satiety. GPR120 signaling in adipocytes and macrophages also results in insulin sensitizing and beneficial anti-inflammatory effects. Drug discovery has focused on agonists to replicate acute benefits of FFA receptor signaling, with promising early results for FFA1 agonists in man. Controversy surrounding chronic effects of FFA1 on beta-cells illustrates that long term benefits of antagonists also need exploring. It has proved challenging to generate highly selective potent ligands for FFA1 or GPR120 subtypes, given that both receptors have hydrophobic orthosteric binding sites, which are not completely defined and have modest ligand affinity. Structure activity relationships are also reliant on functional read outs, in the absence of robust binding assays to provide direct affinity estimates. Nevertheless synthetic ligands have already helped dissect specific contributions of FFA1 and GPR120 signaling from the many possible cellular effects of FFAs. Approaches including use of fluorescent ligand binding assays, and targeting allosteric receptor sites, may improve further pre-clinical ligand development at these receptors, to exploit their unique potential to target multiple facets of diabetes.

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AKR1B7 Is Induced by the Farnesoid X Receptor and Metabolizes Bile Acids

Cited by 35 publications

References 32 publications

Aldo-keto reductase 1B7 is a target gene of FXR and regulates lipid and glucose homeostasis

Aldo-keto reductase 1B7 is a target gene of FXR and regulates lipid and glucose homeostasis

Tissue Distribution, Ontogeny, and Chemical Induction of Aldo-Keto Reductases in Mice

Drug Discovery Opportunities and Challenges at G Protein Coupled Receptors for Long Chain Free Fatty Acids

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