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Dash, Amit K.
- The Constitutive Androstane Receptor (CAR): A Nuclear Receptor in Health and Disease
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Authors
Amit K. Dash
1,
Ashutosh S. Yende
1,
Sudhir Kumar
1,
Shashi Kala Singh
1,
Deepak Kotiya
1,
Manjul Rana
1,
Rakesh K. Tyagi
1
Affiliations
1 Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi-110067, IN
1 Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi-110067, IN
Source
Journal of Endocrinology and Reproduction, Vol 18, No 2 (2014), Pagination: 59-74Abstract
Constitutive Androstane Receptor (CAR, NR1I3), a member of the nuclear receptor superfamily of transcription factors, has emerged as one of the key regulators of the drug and xenobiotic metabolism. The unique feature that separates CAR from other members of the superfamily is that it remains active in the absence of ligand and is further regulated by activators. From its first isolation in 1994, a number of studies related to its distribution, characteristics, functions, and relation to other members of the superfamily have been conducted that place it centrally, governing many key events of the body. Human CAR is expressed relatively higher in liver and epithelial cells of the small intestine villi and less in heart, muscle, kidney, brain and lung. Though there are some controversies regarding its subcellular localization in different cell lines, in general, the subcellular localization of CAR is reported to be predominantly cytoplasmic, in complex with co-chaperone partners HSP90 and CCRP (cytoplasmic CAR retention protein). To execute transcription functions, nuclear translocation is a prerequisite event for a NR, including CAR. In this context, existence of two pathways is suggested, i) direct mechanism of action; and ii) indirect mechanism of action that is governed via nuclear translocation of CAR. Additionally, existence of species-specific differences in its modulation with ligands acting either as an agonist, antagonist or inverse agonist is also apparent. Like the other xenobiotic receptor PXR, CAR also functions as an alternative 'xenosensor' to defend the body against persistent chemical insults. It responds to diverse array of chemically distinct compounds, including endobiotics and xenobiotics, to regulate the clearance of noxious chemicals and toxic metabolites in liver and intestine via induction of genes involved in their metabolism. The usefulness of targeting CAR in metabolic diseases including bilirubinemia, obesity, type 2 diabetes mellitus, atherosclerosis, preeclampsia, hypertension, cholestasis and also in liver cancer is being extensively studied in animal models. However, to determine the human relevance it requires further investigation. Though a large number of natural and synthetic compounds act as modulators of CAR, designing new derivatives with defined therapeutic benefit need to be investigated. The purpose of this review is to highlight the general aspects of nuclear receptor CAR, its mechanism of action and importance in human health and disease.Keywords
Nuclear Receptors, Transcription Factors, Constitutive Androstane Receptor, Xenosensor, Drug Metabolism, Metabolic Diseases, Sub-Cellular Localization, Cancer.References
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- A Compendium of Nuclear Receptors:The Superfamily of Ligand-Modulated Transcription Factors
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1 Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi – 110067, IN
1 Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi – 110067, IN
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Journal of Endocrinology and Reproduction, Vol 20, No 1 (2016), Pagination: 1-27Abstract
The ‘Nuclear Receptor Super-family’ is a group of ligand-modulated transcription factors with 48 members identified in human genome. Members of this family of receptors are now established to be involved in regulation of a plethora of physiological processes in the paradigms of development, reproduction, metabolism and homeostasis. Also, in the myriads of patho-physiological processes, these receptors have consistently exhibited enormous potential as targets for the treatment of diseases such as cancers, osteoporosis, diabetes, obesity, coronary heart disease, asthma, hypertension, thyroid conditions and multiple other metabolic disorders. In recent times, it is estimated that about 15% of the clinical drugs, used in treatments of different ailments, target nuclear receptors. These receptors include steroid/thyroid hormone receptors and orphan/adopted receptors that function as intra-cellular transcription factors to regulate expression of several hundreds of genes in response to their cognate ligands. Interestingly, nuclear receptors are also being assigned a novel role in serving as ‘epigenetic marks’ for the retention and transmission of cellular ‘transcriptional memory’. These receptors function primarily either as homodimers or heterodimers with Retinoid X Receptor (RXR) or sometimes as monomers. Being ‘drug responsive’ these receptors offer attractive targets for drug discovery since their activities can be favorably modulated by interacting ligands. However, many of the newly discovered members of this family of receptors remain incompletely understood, both in terms of physiological roles and activating ligands. In brief, nuclear receptors represent enormous potential for drug discovery and are continuously being examined to unravel the mysteries underlying their mechanisms of action. It has been well-over three decades since the cloning of steroid/nuclear receptors in the 1980s. Therefore, it’s only appropriate to prepare a comprehensive review that provides a compendium of facts and events from receptor cloning and characterization to establishment of receptor domain structures, physiological functioning and consequences of receptor malfunctioning. This review is expected to serve as a refreshing compendium of nuclear receptors for both, the beginners, as well as experts working in the areas of nuclear receptor biology.Keywords
Classification, Diseases, Diversity, Drug Targets, Epigenetics, Nuclear Receptors, Transcription Factors, Structure.References
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