Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism

被引：98

作者：

Hakimi P. ^{[1
]}

Johnson M.T. ^{[2
]}

Yang J. ^{[1
]}

Lepage D.F. ^{[3
]}

Conlon R.A. ^{[3
]}

Kalhan S.C. ^{[2
,4
]}

Reshef L. ^{[5
]}

Tilghman S.M. ^{[6
]}

Hanson R.W. ^{[1
,4
]}

机构：

[1] Department of Biochemistry, Case Western Reserve University, School of Medicine, Cleveland, OH

[2] Department of Pediatrics, Case Western Reserve University, School of Medicine, Cleveland, OH

[3] Department of Genetics, Case Western Reserve University, School of Medicine, Cleveland, OH

[4] Schwartz Center for Metabolism and Nutrition, MetroHealth Medical Center, Cleveland, OH

[5] Department of Biochemistry, Hebrew University, Hadassah Medical School, Jerusalem

[6] Department of Molecular Biology, Princeton University, Princeton, NJ

来源：

Nutrition & Metabolism | / 2卷 / 1期

关键词：

Brown Adipose Tissue; Oxalacetate; Citric Acid Cycle; Pyruvate Carboxylase; Liver Slice;

D O I：

10.1186/1743-7075-2-33

中图分类号：

学科分类号：

摘要：

Background: 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. Methods: 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-/- mice) and the metabolic consequences assessed. Results: PEPCK-C-/- 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-/- 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-/- mice and the blood urea nitrogen concentration was increased by 2-fold. The rate of oxidation of [2-14C]-acetate, and [5-14C]-glutamate to 14CO2 by liver slices from PEPCK-C-/- 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 -/- mice was 10 times that of controls. Conclusion: We conclude that PEPCK-C is required not only for gluconeogenesis and glyceroneogenesis but also for cataplerosis (i.e. the removal of citric acid cycle anions) and that the failure of this process in the livers of PEPCK-C-/- mice results in a marked reduction in citric acid cycle flux and the shunting of hepatic lipid into triglyceride, resulting in a fatty liver. © 2005 Hakimi et al; licensee BioMed Central Ltd.

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