A Role for Mitochondrial Phosphoenolpyruvate Carboxykinase (PEPCK-M) in the Regulation of Hepatic Gluconeogenesis |
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Authors: | Romana Stark Fitsum Guebre-Egziabher Xiaojian Zhao Colleen Feriod Jianying Dong Tiago C Alves Simona Ioja Rebecca L Pongratz Sanjay Bhanot Michael Roden Gary W Cline Gerald I Shulman Richard G Kibbey |
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Institution: | From the Departments of ‡Internal Medicine and ;§Cellular and Molecular Physiology and ;the ¶Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520.;‖Isis Pharmaceuticals, Carlsbad, California 92010, and ;the **Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf 40225, Germany |
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Abstract: | Synthesis of phosphoenolpyruvate (PEP) from oxaloacetate is an absolute requirement for gluconeogenesis from mitochondrial substrates. Generally, this reaction has solely been attributed to the cytosolic isoform of PEPCK (PEPCK-C), although loss of the mitochondrial isoform (PEPCK-M) has never been assessed. Despite catalyzing the same reaction, to date the only significant role reported in mammals for the mitochondrial isoform is as a glucose sensor necessary for insulin secretion. We hypothesized that this nutrient-sensing mitochondrial GTP-dependent pathway contributes importantly to gluconeogenesis. PEPCK-M was acutely silenced in gluconeogenic tissues of rats using antisense oligonucleotides both in vivo and in isolated hepatocytes. Silencing PEPCK-M lowers plasma glucose, insulin, and triglycerides, reduces white adipose, and depletes hepatic glycogen, but raises lactate. There is a switch of gluconeogenic substrate preference to glycerol that quantitatively accounts for a third of glucose production. In contrast to the severe mitochondrial deficiency characteristic of PEPCK-C knock-out livers, hepatocytes from PEPCK-M-deficient livers maintained normal oxidative function. Consistent with its predicted role, gluconeogenesis rates from hepatocytes lacking PEPCK-M are severely reduced for lactate, alanine, and glutamine, but not for pyruvate and glycerol. Thus, PEPCK-M has a direct role in fasted and fed glucose homeostasis, and this mitochondrial GTP-dependent pathway should be reconsidered for its involvement in both normal and diabetic metabolism. |
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Keywords: | Diabetes Gluconeogenesis Glyceroneogenesis GTPase Intermediary Metabolism Metabolic Regulation Metabolic Tracers Metabolism Mitochondrial Metabolism Phosphoenolpyruvate Carboxykinase |
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