CIDeRplusGeneral Information:
| Id: | 8,285 |
| Diseases: |
Cardiovascular disease
Diabetes mellitus, type II - [OMIM] Fatty liver disease, nonalcoholic Insulin resistance |
| Mammalia | |
| review | |
| Reference: | Kempson SA et al.(2014) The betaine/GABA transporter and betaine: roles in brain, kidney, and liver Front Physiol 5: 159 [PMID: 24795654] |
Interaction Information:
| Comment | The physiological roles of the betaine/GABA transporter (BGT1; slc6a12) are still being debated. BGT1 is a member of the solute carrier family 6 (the neurotransmitter, sodium symporter transporter family) and mediates cellular uptake of betaine and GABA in a sodium- and chloride-dependent process. |
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Formal Description Interaction-ID: 83895 |
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| Comment | The physiological roles of the betaine/GABA transporter (BGT1; slc6a12) are still being debated. BGT1 is a member of the solute carrier family 6 (the neurotransmitter, sodium symporter transporter family) and mediates cellular uptake of betaine and GABA in a sodium- and chloride-dependent process. |
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Formal Description Interaction-ID: 84155 |
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| Comment | Hepatocytes express high levels of both BGT1 and the only enzyme that can metabolize betaine, namely betaine:homocysteine-S-methyltransferase (BHMT1). The BHMT1 enzyme removes a methyl group from betaine and transfers it to homocysteine, a potential risk factor for cardiovascular disease. |
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Formal Description Interaction-ID: 84156 |
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| Drugbank entries | Show/Hide entries for BHMT |
| Comment | Osmotic stress occurs in several tissues and has been studied most extensively in cells in the inner medulla of the kidney. In humans these cells are normally exposed to low oxygen tension, ammonia, and very high levels (600 mOsm) of both NaCl and urea when urine is maximally concentrated. Numerous perturbations can result from the hypertonic effect of high NaCl and the denaturing effect of high urea. These include production of reactive oxygen species, cytoskeletal rearrangements, inhibition of DNA replication, transcription, and translation, and damage to DNA and mitochondria. Adaptation is essential for survival and the adaptations by medullary cells are extensive. Many are driven by the transcription factor TonEBP/NFAT5. |
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Formal Description Interaction-ID: 84157 |
gene/protein decreases_activity of process |
| Comment | Osmotic stress occurs in several tissues and has been studied most extensively in cells in the inner medulla of the kidney. In humans these cells are normally exposed to low oxygen tension, ammonia, and very high levels (600 mOsm) of both NaCl and urea when urine is maximally concentrated. Numerous perturbations can result from the hypertonic effect of high NaCl and the denaturing effect of high urea. These include production of reactive oxygen species, cytoskeletal rearrangements, inhibition of DNA replication, transcription, and translation, and damage to DNA and mitochondria. Adaptation is essential for survival and the adaptations by medullary cells are extensive. Many are driven by the transcription factor TonEBP/NFAT5. |
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Formal Description Interaction-ID: 84164 |
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| Comment | Betaine, which is found in many foods including spinach and wheat, is one of the important osmolytes in the kidney medulla. |
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Formal Description Interaction-ID: 84165 |
drug/chemical compound decreases_activity of process |
| Comment | In mice betaine was reported to have anti-epileptic properties. |
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Formal Description Interaction-ID: 84166 |
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| Comment | Betaine can elevate growth hormone levels and activate IGF-1 signaling pathways in pig, mouse and rat tissues. |
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Formal Description Interaction-ID: 84167 |
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| Comment | Betaine can elevate growth hormone levels and activate IGF-1 signaling pathways in pig, mouse and rat tissues. |
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Formal Description Interaction-ID: 84168 |
drug/chemical compound increases_activity of |
| Comment | Betaine, sorbitol, myo-inositol, taurine, and glycerolphosphorylcholine are the predominant osmolytes in the mammalian kidney and MDCK cells. |
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Formal Description Interaction-ID: 84169 |
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| Comment | Betaine, sorbitol, myo-inositol, taurine, and glycerolphosphorylcholine are the predominant osmolytes in the mammalian kidney and MDCK cells. |
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Formal Description Interaction-ID: 84170 |
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| Comment | Betaine, sorbitol, myo-inositol, taurine, and glycerolphosphorylcholine are the predominant osmolytes in the mammalian kidney and MDCK cells. |
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Formal Description Interaction-ID: 84171 |
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| Comment | Betaine, sorbitol, myo-inositol, taurine, and glycerolphosphorylcholine are the predominant osmolytes in the mammalian kidney and MDCK cells. |
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Formal Description Interaction-ID: 84172 |
drug/chemical compound decreases_activity of process |
| Comment | Hypertonicity increases betaine transport, primarily in the basolateral plasma membrane, by activating transcription of the BGT1 gene. This increases abundance of BGT1 mRNA more than 10-fold and increases the transportcapacity 5-10 fold. Activation of transcription is achieved by tonicity-responsive enhancer sequences (TonE1 and TonE2) that are present in the promoter region of the BGT1 gene and specifically bind the TonE-binding proteins (TonEBP/NFAT5’s). Up- and down-regulation of BGT1 mRNA transcription in response to changes in medullary tonicity has been confirmed also in vivo. |
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Formal Description Interaction-ID: 84173 |
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| Comment | TonEBP/NFAT5 is not exclusive for the BGT1 gene, it also regulates several other osmolyte transporter genes including the sodium/myo-inositol cotransporter 1 (SMIT1; slc5a3), and the taurine transporter (TAUT; slc6a6), as well as aldose reductase which converts glucose to sorbitol. |
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Formal Description Interaction-ID: 84174 |
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| Comment | TonEBP/NFAT5 is not exclusive for the BGT1 gene, it also regulates several other osmolyte transporter genes including the sodium/myo-inositol cotransporter 1 (SMIT1; slc5a3), and the taurine transporter (TAUT; slc6a6), as well as aldose reductase which converts glucose to sorbitol. |
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Formal Description Interaction-ID: 84175 |
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| Comment | TonEBP/NFAT5 is not exclusive for the BGT1 gene, it also regulates several other osmolyte transporter genes including the sodium/myo-inositol cotransporter 1 (SMIT1; slc5a3), and the taurine transporter (TAUT; slc6a6), as well as aldose reductase which converts glucose to sorbitol. |
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Formal Description Interaction-ID: 84176 |
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| Drugbank entries | Show/Hide entries for AKR1B1 |
| Comment | Betaine-homocysteine-S-methyltransferase (BHMT1) removes a methyl group from betaine and is the major betaine catabolizing enzyme in liver. Expression of BHMT1 mRNA in isolated hepatocytes was decreased by hypertonicity consistent with preservation of betaine content for osmoregulation. The reverse occurred during hypotonicity, consistent with removal of intracellular betaine. In experiments in vivo, chronic plasma hyposmolarity in rats was accompanied by decreases in mRNA for TonEBP, SMIT1, and BGT1 in liver. Taken together, these findings are a good illustration of the importance of volume regulation for cell survival. |
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Formal Description Interaction-ID: 84177 |
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| Drugbank entries | Show/Hide entries for BHMT |
| Comment | Betaine-homocysteine-S-methyltransferase (BHMT1) removes a methyl group from betaine and is the major betaine catabolizing enzyme in liver. Expression of BHMT1 mRNA in isolated hepatocytes was decreased by hypertonicity consistent with preservation of betaine content for osmoregulation. The reverse occurred during hypotonicity, consistent with removal of intracellular betaine. In experiments in vivo, chronic plasma hyposmolarity in rats was accompanied by decreases in mRNA for TonEBP, SMIT1, and BGT1 in liver. Taken together, these findings are a good illustration of the importance of volume regulation for cell survival. |
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Formal Description Interaction-ID: 84178 |
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| Comment | Betaine supplements have been reported to improve liver function in non-alcoholic fatty liver disease. |
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Formal Description Interaction-ID: 84179 |
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| Comment | In addition to its role as an osmolyte, betaine's metabolic role has been shown to be important in protection of the liver and other tissues and in alleviating cardiovascular risk factors such as homocysteine. |
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Formal Description Interaction-ID: 84180 |
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| Comment | In response to the chronic hyperglycemia found in diabetics, glucose flux through the polyol pathway is increased and accounts for about one third of total glucose consumption. In this pathway aldose reductase converts glucose to sorbitol and the resultant accumulation of intracellular sorbitol causes hyperosmotic stress. Aldose reductase occurs not only in the renal medulla but also in other organs and has long been believed to be responsible for secondary diabetic complications such as retinopathy, neuropathy, nephropathy, and caractogenesis. |
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Formal Description Interaction-ID: 84181 |
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| Comment | In response to the chronic hyperglycemia found in diabetics, glucose flux through the polyol pathway is increased and accounts for about one third of total glucose consumption. In this pathway aldose reductase converts glucose to sorbitol and the resultant accumulation of intracellular sorbitol causes hyperosmotic stress. Aldose reductase occurs not only in the renal medulla but also in other organs and has long been believed to be responsible for secondary diabetic complications such as retinopathy, neuropathy, nephropathy, and caractogenesis. |
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Formal Description Interaction-ID: 84182 |
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| Comment | In response to the chronic hyperglycemia found in diabetics, glucose flux through the polyol pathway is increased and accounts for about one third of total glucose consumption. In this pathway aldose reductase converts glucose to sorbitol and the resultant accumulation of intracellular sorbitol causes hyperosmotic stress. Aldose reductase occurs not only in the renal medulla but also in other organs and has long been believed to be responsible for secondary diabetic complications such as retinopathy, neuropathy, nephropathy, and caractogenesis. |
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Formal Description Interaction-ID: 84183 |
process polyol pathway increases_activity of process |
| Comment | In response to the chronic hyperglycemia found in diabetics, glucose flux through the polyol pathway is increased and accounts for about one third of total glucose consumption. In this pathway aldose reductase converts glucose to sorbitol and the resultant accumulation of intracellular sorbitol causes hyperosmotic stress. Aldose reductase occurs not only in the renal medulla but also in other organs and has long been believed to be responsible for secondary diabetic complications such as retinopathy, neuropathy, nephropathy, and caractogenesis. |
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Formal Description Interaction-ID: 84184 |
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| Drugbank entries | Show/Hide entries for AKR1B1 |
| Comment | A number of studies have reported a strong association between localized hypertonicity and inflammation. |
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Formal Description Interaction-ID: 84185 |
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