Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism
<p>Abstract</p> <p>Background</p> <p>The metabolic function of PEPCK-C is not fully understood; deletion of the gene for the enzyme in mice provides an opportunity to fully assess its function.</p> <p>Methods</p> <p>The gene for the cytosolic for...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2005-11-01
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| Series: | Nutrition & Metabolism |
| Online Access: | http://www.nutritionandmetabolism.com/content/2/1/33 |
| _version_ | 1818515678393532416 |
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| author | Kalhan Satish C Conlon Ronald A Lepage David F Yang Jianqi Johnson Mark T Hakimi Parvin Reshef Lea Tilghman Shirley M Hanson Richard W |
| author_facet | Kalhan Satish C Conlon Ronald A Lepage David F Yang Jianqi Johnson Mark T Hakimi Parvin Reshef Lea Tilghman Shirley M Hanson Richard W |
| author_sort | Kalhan Satish C |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>The metabolic function of PEPCK-C is not fully understood; deletion of the gene for the enzyme in mice provides an opportunity to fully assess its function.</p> <p>Methods</p> <p>The gene for the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK-C) was deleted in mice by homologous recombination (PEPCK-C<sup>-/- </sup>mice) and the metabolic consequences assessed.</p> <p>Results</p> <p>PEPCK-C<sup>-/-</sup> mice became severely hypoglycemic by day two after birth and then died with profound hypoglycemia (12 mg/dl). The mice had milk in their stomachs at day two after birth and the administration of glucose raised the concentration of blood glucose in the mice but did not result in an increased survival. PEPCK-C<sup>-/- </sup>mice have two to three times the hepatic triglyceride content as control littermates on the second day after birth. These mice also had an elevation of lactate (2.5 times), β-hydroxybutyrate (3 times) and triglyceride (50%) in their blood, as compared to control animals. On day two after birth, alanine, glycine, glutamine, glutamate, aspartate and asparagine were elevated in the blood of the PEPCK-C<sup>-/- </sup>mice and the blood urea nitrogen concentration was increased by 2-fold. The rate of oxidation of [2-<sup>14</sup>C]-acetate, and [5-<sup>14</sup>C]-glutamate to <sup>14</sup>CO<sub>2 </sub>by liver slices from PEPCK-C<sup>-/- </sup>mice at two days of age was greatly reduced, as was the rate of fatty acid synthesis from acetate and glucose. As predicted by the lack of PEPCK-C, the concentration of malate in the livers of the PEPCK-C<sup>-/- </sup>mice was 10 times that of controls.</p> <p>Conclusion</p> <p>We conclude that PEPCK-C is required not only for gluconeogenesis and glyceroneogenesis but also for <it>cataplerosis </it>(i.e. the removal of citric acid cycle anions) and that the failure of this process in the livers of PEPCK-C<sup>-/- </sup>mice results in a marked reduction in citric acid cycle flux and the shunting of hepatic lipid into triglyceride, resulting in a fatty liver.</p> |
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| format | Article |
| id | doaj.art-e59fbd2ce5ac4a799b71668d2c8ca71b |
| institution | Directory Open Access Journal |
| issn | 1743-7075 |
| language | English |
| last_indexed | 2024-12-11T00:31:54Z |
| publishDate | 2005-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Nutrition & Metabolism |
| spelling | doaj.art-e59fbd2ce5ac4a799b71668d2c8ca71b2022-12-22T01:27:19ZengBMCNutrition & Metabolism1743-70752005-11-01213310.1186/1743-7075-2-33Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolismKalhan Satish CConlon Ronald ALepage David FYang JianqiJohnson Mark THakimi ParvinReshef LeaTilghman Shirley MHanson Richard W<p>Abstract</p> <p>Background</p> <p>The metabolic function of PEPCK-C is not fully understood; deletion of the gene for the enzyme in mice provides an opportunity to fully assess its function.</p> <p>Methods</p> <p>The gene for the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK-C) was deleted in mice by homologous recombination (PEPCK-C<sup>-/- </sup>mice) and the metabolic consequences assessed.</p> <p>Results</p> <p>PEPCK-C<sup>-/-</sup> mice became severely hypoglycemic by day two after birth and then died with profound hypoglycemia (12 mg/dl). The mice had milk in their stomachs at day two after birth and the administration of glucose raised the concentration of blood glucose in the mice but did not result in an increased survival. PEPCK-C<sup>-/- </sup>mice have two to three times the hepatic triglyceride content as control littermates on the second day after birth. These mice also had an elevation of lactate (2.5 times), β-hydroxybutyrate (3 times) and triglyceride (50%) in their blood, as compared to control animals. On day two after birth, alanine, glycine, glutamine, glutamate, aspartate and asparagine were elevated in the blood of the PEPCK-C<sup>-/- </sup>mice and the blood urea nitrogen concentration was increased by 2-fold. The rate of oxidation of [2-<sup>14</sup>C]-acetate, and [5-<sup>14</sup>C]-glutamate to <sup>14</sup>CO<sub>2 </sub>by liver slices from PEPCK-C<sup>-/- </sup>mice at two days of age was greatly reduced, as was the rate of fatty acid synthesis from acetate and glucose. As predicted by the lack of PEPCK-C, the concentration of malate in the livers of the PEPCK-C<sup>-/- </sup>mice was 10 times that of controls.</p> <p>Conclusion</p> <p>We conclude that PEPCK-C is required not only for gluconeogenesis and glyceroneogenesis but also for <it>cataplerosis </it>(i.e. the removal of citric acid cycle anions) and that the failure of this process in the livers of PEPCK-C<sup>-/- </sup>mice results in a marked reduction in citric acid cycle flux and the shunting of hepatic lipid into triglyceride, resulting in a fatty liver.</p>http://www.nutritionandmetabolism.com/content/2/1/33 |
| spellingShingle | Kalhan Satish C Conlon Ronald A Lepage David F Yang Jianqi Johnson Mark T Hakimi Parvin Reshef Lea Tilghman Shirley M Hanson Richard W Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism Nutrition & Metabolism |
| title | Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism |
| title_full | Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism |
| title_fullStr | Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism |
| title_full_unstemmed | Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism |
| title_short | Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism |
| title_sort | phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism |
| url | http://www.nutritionandmetabolism.com/content/2/1/33 |
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