ArticleToxicology and applied pharmacology2014
Activation of the constitutive androstane receptor inhibits gluconeogenesis without affecting lipogenesis or fatty acid synthesis in human hepatocytes.
Article in Toxicology and applied pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 36 citations in OpenAlex.
- Article
- Mapping transcriptional heterogeneity and metabolic networks in fatty livers at single-cell resolution.iScience · 2023Article
- Clinical Relevance of the Constitutive Androstane Receptor.Drug metabolism and disposition: the biological fate of chemicals · 2022Review
- Human CYP2B6 produces oxylipins from polyunsaturated fatty acids and reduces diet-induced obesity.PloS one · 2022Article
- Identifying CAR Modulators Utilizing a Reporter Gene Assay.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Induction of Constitutive Androstane Receptor during the Development of Oxidative Stress.Bulletin of experimental biology and medicine · 2021Article
- Negative Regulation of Human Hepatic Constitutive Androstane Receptor by Cholesterol Synthesis Inhibition: Role of Sterol Regulatory Element Binding Proteins.Drug metabolism and disposition: the biological fate of chemicals · 2021Article
- Article
- Constitutive Androstane Receptor: A Peripheral and a Neurovascular Stress or Environmental Sensor.Cells · 2020Review
- Review
- The Roles of Xenobiotic Receptors: Beyond Chemical Disposition.Drug metabolism and disposition: the biological fate of chemicals · 2018Review
- The Role of PPAR and Its Cross-Talk with CAR and LXR in Obesity and Atherosclerosis.International journal of molecular sciences · 2018Review
- Small-molecule modulators of PXR and CAR.Biochimica et biophysica acta · 2016Review
- RNA-Seq reveals common and unique PXR- and CAR-target gene signatures in the mouse liver transcriptome.Biochimica et biophysica acta · 2016Article
- Nonsterol Isoprenoids Activate Human Constitutive Androstane Receptor in an Isoform-Selective Manner in Primary Cultured Mouse Hepatocytes.Drug metabolism and disposition: the biological fate of chemicals · 2016Article
- Quantitative High-Throughput Luciferase Screening in Identifying CAR Modulators.Methods in molecular biology (Clifton, N.J.) · 2016Article
- Genome-wide analysis of human constitutive androstane receptor (CAR) transcriptome in wild-type and CAR-knockout HepaRG cells.Biochemical pharmacology · 2015Article
- Small-molecule modulators of the constitutive androstane receptor.Expert opinion on drug metabolism & toxicology · 2015Review
- Quantitative high-throughput identification of drugs as modulators of human constitutive androstane receptor.Scientific reports · 2015Article
- Targeting xenobiotic receptors PXR and CAR in human diseases.Drug discovery today · 2015Review
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
objectiveAccumulating evidence suggests that activation of mouse constitutive androstane receptor (mCAR) alleviates type 2 diabetes and obesity by inhibiting hepatic gluconeogenesis, lipogenesis, and fatty acid synthesis. However, the role of human (h) CAR in energy metabolism is largely unknown. The present study aims to investigate the effects of selective hCAR activators on hepatic energy metabolism in human primary hepatocytes (HPH).
methodsLigand-based structure-activity models were used for virtual screening of the Specs database (www.specs.net) followed by biological validation in cell-based luciferase assays. The effects of two novel hCAR activators (UM104 and UM145) on hepatic energy metabolism were evaluated in HPH.
resultsReal-time PCR and Western blotting analyses reveal that activation of hCAR by UM104 and UM145 significantly repressed the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, two pivotal gluconeogenic enzymes, while exerting negligible effects on the expression of genes associated with lipogenesis and fatty acid synthesis. Functional experiments show that UM104 and UM145 markedly inhibit hepatic synthesis of glucose but not triglycerides in HPH. In contrast, activation of mCAR by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, a selective mCAR activator, repressed the expression of genes associated with gluconeogenesis, lipogenesis, and fatty acid synthesis in mouse primary hepatocytes, which were consistent with previous observations in mouse model in vivo.
conclusionOur findings uncover an important species difference between hCAR and mCAR in hepatic energy metabolism, where hCAR selectively inhibits gluconeogenesis without suppressing fatty acid synthesis. IMPLICATIONS: Such species selectivity should be considered when exploring CAR as a potential therapeutic target for metabolic disorders.
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