A Role for Mitochondrial Phosphoenolpyruvate Carboxykinase (PEPCK-M) in the Regulation of Hepatic Gluconeogenesis

Stark, Romana; Guebre-Egziabher, Fitsum; Zhao, Xiaojie; Feriod, Colleen; Dong, Jianying; Alves, Tiago C.; Ioja, Simona; Pongratz, Rebecca L.; Bhanot, Sanjay; Roden, Michael; Cline, Gary W.; Shulman, Gerald I.; Kibbey, Richard G.

doi:10.1074/jbc.c113.544759

Cited by 94 publications

(70 citation statements)

References 43 publications

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“…Also, PEPCK-M overexpression in the presence of PEPCK-C enhanced glucose production, suggesting a role for PEPCK-M in glucose homeostasis both through its intrinsic gluconeogenic potential and by complementing PEPCK-C, especially in species in which it is highly expressed, such as in humans. Reinforcing this concept, PEPCK-M silencing in rat liver severely reduced glucose production from lactate and amino acids (34). Another example of a role of PEPCK-M in cataplerosis is its involvement in the recycling of citric acid cycle anions in ␤-cells (5), linking PEPCK-M activity to the recycling of the GTP generated in the citric acid cycle (by succinyl-CoA synthase) to provide continuous TCA function and enhancing insulin secretion.…”

Section: Discussionmentioning

confidence: 95%

Mitochondrial Phosphoenolpyruvate Carboxykinase (PEPCK-M) Is a Pro-survival, Endoplasmic Reticulum (ER) Stress Response Gene Involved in Tumor Cell Adaptation to Nutrient Availability

Méndez-Lucas

Hyroššová

Novellasdemunt

et al. 2014

Journal of Biological Chemistry

163

136

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Background:The integrated stress response (ISR) is necessary to help the tumor adapt to its microenvironment. Results: ATF4 activates a PEPCK-M-dependent pro-survival pathway under amino acid deprivation or ER stress (ISR) by binding to its proximal promoter. Conclusion: PEPCK-M participates in supportive adaptations of cancer cells under stress. Significance: A previously unappreciated role for PEPCK-M in cancer cells opens a therapeutic window and enhances our understanding of cancer metabolism.

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Section: Discussionmentioning

confidence: 95%

Mitochondrial Phosphoenolpyruvate Carboxykinase (PEPCK-M) Is a Pro-survival, Endoplasmic Reticulum (ER) Stress Response Gene Involved in Tumor Cell Adaptation to Nutrient Availability

Méndez-Lucas

Hyroššová

Novellasdemunt

et al. 2014

Journal of Biological Chemistry

163

136

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“…GDH activity is highly controlled by allosteric regulation; mitochondrial GTP (mtGTP) inhibits GDH, whereas L-leucine activates GDH (22,23). mtGTP is an important mitochondrial energy sensor in both hepatocytes and pancreatic islet cells, reflecting the balance between tricarboxylic acid cycle and gluconeogenic fluxes implicated in glucose production, insulin secretion, and glucagon secretion (2,(24)(25)(26). In contrast, as an essential amino acid, L-leucine reflects high nutrient protein levels and can activate GDH even when mitochondrial energy is high.…”

Section: Discussionmentioning

confidence: 99%

“…Glucose in the medium from hepatocyte studies was measured using Genzyme Glucose-SL reagent, and glucose production was normalized to total protein levels as measured by Bradford assay. Urea production from hepatocytes was assessed by measuring urea in the medium by an enzymatic reaction coupling urease production of ammonia from urea to GDH and observing changes in NADH oxidation at 340 nm absorbance [buffer composition: 30 mM potassium phosphate (pH 7.6), 2.875 mM ADP, 0.9 mM NADH, 3.25 mM α-ketoglutarate; 12.5 U GDH, 1 U urease in a total reaction volume of 200 μL, 10 min incubation at room temperature] (27 2 , dried down in a speed-vacuum, and derivatized by adding one volume of acetic anhydride and pyridine and incubation at 65°C for 15 min. Derivatized samples were added to 75 μL of methanol, and 2 H enrichment was measured via GC/MS as previously described (28).…”

Section: Methodsmentioning

confidence: 99%

“…Accounting for nearly a third of hepatic metabolism, ureagenesis consumes three ATPs per urea produced and has an overall flux comparable to that of gluconeogenesis (1,2). Importantly, the ligation of citrulline to aspartate via argininosuccinate synthetase (ASS) hydrolyzes one ATP into AMP per turn of the ornithine cycle, making ASS a predominant hepatocellular contributor of AMP.…”

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confidence: 99%

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Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism

Madiraju

Alves

Zhao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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A key sensor of cellular energy status, AMP-activated protein kinase (AMPK), interacts allosterically with AMP to maintain an active state. When active, AMPK triggers a metabolic switch, decreasing the activity of anabolic pathways and enhancing catabolic processes such as lipid oxidation to restore the energy balance. Unlike oxidative tissues, in which AMP is generated from adenylate kinase during states of high energy demand, the ornithine cycle enzyme argininosuccinate synthetase (ASS) is a principle site of AMP generation in the liver. Here we show that ASS regulates hepatic AMPK, revealing a central role for ureagenesis flux in the regulation of metabolism via AMPK. Treatment of primary rat hepatocytes with amino acids increased gluconeogenesis and ureagenesis and, despite nutrient excess, induced both AMPK and acetyl-CoA carboxylase (ACC) phosphorylation. Antisense oligonucleotide knockdown of hepatic ASS1 expression in vivo decreased liver AMPK activation, phosphorylation of ACC, and plasma β-hydroxybutyrate concentrations. Taken together these studies demonstrate that increased amino acid flux can activate AMPK through increased AMP generated by ASS, thus providing a novel link between protein catabolism, ureagenesis, and hepatic lipid metabolism.argininosuccinate synthetase | AMPK | ureagenesis | amino acids | lipid metabolism M aintaining appropriate nitrogen balance is crucial to the fitness of an organism. The decision to deaminate amino acids to use their carbon skeleton for oxidative and/or synthetic purposes is tightly regulated. Excessive amino acid catabolism not only generates toxic nitrogenous waste but also could jeopardize the ability to generate or maintain protein levels.The liver is unique in its capacity to detoxify nitrogenous waste through the energy-requiring synthesis of urea. Accounting for nearly a third of hepatic metabolism, ureagenesis consumes three ATPs per urea produced and has an overall flux comparable to that of gluconeogenesis (1, 2). Importantly, the ligation of citrulline to aspartate via argininosuccinate synthetase (ASS) hydrolyzes one ATP into AMP per turn of the ornithine cycle, making ASS a predominant hepatocellular contributor of AMP. Hence, a metabolic signal generated through the AMP-generating ornithine cycle could be intrinsic to preserving nitrogen balance.In oxidative tissues such as muscle, AMPK helps balance energy homeostasis by detecting fluctuations in the [AMP]:[ATP] ratio. Phosphorylation of AMPK by upstream kinases such as liver kinase B1 enhance AMPK activity, and AMP binding to an allosteric site stabilizes a conformation that supports phosphorylation and protects AMPK from dephosphorylation (3). The canonical view of AMPK activation is that, following global shifts in energy balance (e.g., excessive energy demand during exercise), adenylate kinase (AK) increases AMP synthesis to salvage ATP from ADP (4). As a consequence, the AMPK-mediated phosphorylation of sterol regulatory element-binding protein 1 (SREBP-1), acetyl-CoA carboxylase 1 (ACC1), a...

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“…However, PF-4708671 failed to significantly reduce PEPCK or G6Pase protein expression despite lower mRNA expression of these enzymes. It is possible that G6Pase and PEPCK proteins are only reduced in specific cellular compartments [38][39][40]. Indeed, we have used a PEPCK1-specific antibody that recognises the cytosolic isoform, whereas PEPCK2 is predominantly a mitochondrial form.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

et al. 2016

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Aims/hypothesis The mammalian target of rapamycin complex 1 (mTORC1)/p70 ribosomal S6 kinase (S6K)1 pathway is overactivated in obesity, leading to inhibition of phosphoinositide 3-kinase (PI3K)/Akt signalling and insulin resistance. However, chronic mTORC1 inhibition by rapamycin impairs glucose homeostasis because of robust induction of liver gluconeogenesis. Here, we compared the effect of rapamycin with that of the selective S6K1 inhibitor, PF-4708671, on glucose metabolism in vitro and in vivo. Methods We used L6 myocytes and FAO hepatocytes to explore the effect of PF-4708671 on the regulation of glucose uptake, glucose production and insulin signalling. We also treated high-fat (HF)-fed obese mice for 7 days with PF-4708671 in comparison with rapamycin to assess glucose tolerance, insulin resistance and insulin signalling in vivo. Results Chronic rapamycin treatment induced insulin resistance and impaired glucose metabolism in hepatic and muscle cells. Conversely, chronic S6K1 inhibition with PF-4708671 reduced glucose production in hepatocytes and enhanced glucose uptake in myocytes. Whereas rapamycin treatment inhibited Akt phosphorylation, PF-4708671 increased Akt phosphorylation in both cell lines. These opposite effects of the mTORC1 and S6K1 inhibitors were also observed in vivo. Indeed, while rapamycin treatment induced glucose intolerance and failed to improve Akt phosphorylation in liver and muscle of HF-fed mice, PF-4708671 treatment improved glucose tolerance and increased Akt phosphorylation in metabolic tissues of these obese mice. Conclusions/interpretation Chronic S6K1 inhibition by PF-4708671 improves glucose homeostasis in obese mice through enhanced Akt activation in liver and muscle. Our results suggest that specific S6K1 blockade is a valid pharmacological approach to improve glucose disposal in obese diabetic individuals.

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A Role for Mitochondrial Phosphoenolpyruvate Carboxykinase (PEPCK-M) in the Regulation of Hepatic Gluconeogenesis

Cited by 94 publications

References 43 publications

Mitochondrial Phosphoenolpyruvate Carboxykinase (PEPCK-M) Is a Pro-survival, Endoplasmic Reticulum (ER) Stress Response Gene Involved in Tumor Cell Adaptation to Nutrient Availability

Mitochondrial Phosphoenolpyruvate Carboxykinase (PEPCK-M) Is a Pro-survival, Endoplasmic Reticulum (ER) Stress Response Gene Involved in Tumor Cell Adaptation to Nutrient Availability

Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism

Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

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