Diminished Hepatic Gluconeogenesis via Defects in Tricarboxylic Acid Cycle Flux in Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α)-deficient Mice

ABSTRACT Anabolic and catabolic signaling mediated via mTOR and AMPK (AMP-activated kinase) have to be intrinsically coupled to mitochondrial functions for maintaining homeostasis and mitigate cellular/organismal stress. Although glutamine is known to activate mTOR, whether and how differential mitochondrial utilization of glutamine impinges on mTOR signaling has been less explored. Mitochondrial SIRT4, which unlike other sirtuins is induced in a fed state, is known to inhibit catabolic signaling/pathways through the AMPK-PGC1α/SIRT1–peroxisome proliferator-activated receptor α (PPARα) axis and negatively regulate glutamine metabolism via the tricarboxylic acid cycle. However, physiological significance of SIRT4 functions during a fed state is still unknown. Here, we establish SIRT4 as key anabolic factor that activates TORC1 signaling and regulates lipogenesis, autophagy, and cell proliferation. Mechanistically, we demonstrate that the ability of SIRT4 to inhibit anaplerotic conversion of glutamine to α-ketoglutarate potentiates TORC1. Interestingly, we also show that mitochondrial glutamine sparing or utilization is critical for differentially regulating TORC1 under fed and fasted conditions. Moreover, we conclusively show that differential expression of SIRT4 during fed and fasted states is vital for coupling mitochondrial energetics and glutamine utilization with anabolic pathways. These significant findings also illustrate that SIRT4 integrates nutrient inputs with mitochondrial retrograde signals to maintain a balance between anabolic and catabolic pathways.

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Use of 14CO2 in estimating rates of hepatic gluconeogenesis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1992.263.1.e36 ◽

1992 ◽

Vol 263 (1) ◽

pp. E36-E41 ◽

Cited By ~ 3

Author(s):

E. Esenmo ◽

V. Chandramouli ◽

W. C. Schumann ◽

K. Kumaran ◽

J. Wahren ◽

...

Keyword(s):

Blood Glucose ◽

Specific Activity ◽

Tricarboxylic Acid Cycle ◽

Tricarboxylic Acid ◽

Hepatic Gluconeogenesis ◽

Acid Cycle ◽

Specific Activities ◽

Glucose Formation

Estimating the rate of hepatic gluconeogenesis in vivo from the incorporation of 14C from 14CO2 into glucose requires determination of the rates in liver of equilibration of oxaloacetate with fumarate, conversion of oxaloacetate to phosphoenolpyruvate (PEP), and conversion of PEP to pyruvate, all relative to the rate of tricarboxylic acid cycle flux. With the use of a model of mitochondrial metabolism and gluconeogenesis, expressions are derived relating specific activity of carboxyl of PEP from 14CO2 to those rates and specific activity of mitochondrial CO2. If those rates and specific activity of mitochondrial CO2 are known, specific activity of PEP, calculated using the expressions, should, on a mole basis, be one-half the specific activity of the glucose formed. At steady state, in the 60-h fasted individual, where glucose formation is solely by gluconeogenesis, twice estimated specific activity of PEP should then approximate that of blood glucose. Estimates of relative rates in 60-h fasted humans, previously made from distribution of 14C in glutamate from phenylacetylglutamine excreted when [3-14C]lactate and phenylacetate were given, were applied to the expressions. Specific activity of mitochondrial CO2 was equated to that of CO2 expired by 60-h fasted subjects given NaH14CO3 and alpha-[1-14C]ketoisocaproate. Predicted specific activities approximated actual specific activities of blood glucose when NaH14CO3 was administered. alpha-[1-14C]ketoisocaproate administrations gave underestimates. This is attributable to differences between specific activities of hepatic mitochondrial CO2 and expired CO2, which is evidenced by higher incorporations of 14C in glucose than in expired CO2 from alpha-[1-14C]ketoisocaproate than from NaH14CO3.(ABSTRACT TRUNCATED AT 250 WORDS

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Analysis of tricarboxylic acid cycle intermediates in dried blood spots by ultra-performance liquid chromatography-tandem mass spectrometry

Journal of Biochemical and Clinical Genetics ◽

10.24911/jbcgenetics/183-1563341940 ◽

2019 ◽

pp. 1

Author(s):

Lamia Dirbashi

Keyword(s):

Mass Spectrometry ◽

Tricarboxylic Acid Cycle ◽

Dried Blood Spots ◽

Ultra Performance Liquid Chromatography ◽

Tricarboxylic Acid ◽

Tandem Mass ◽

Acid Cycle ◽

Chromatography Tandem Mass Spectrometry ◽

Liquid Chromatography Tandem Mass ◽

Tricarboxylic Acid Cycle Intermediates

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Faculty Opinions recommendation of Crosstalk between the tricarboxylic acid cycle and peptidoglycan synthesis in Caulobacter crescentus through the homeostatic control of α-ketoglutarate.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.729075299.793537174 ◽

2017 ◽

Author(s):

Kevin D Young ◽

Matthew Jorgenson

Keyword(s):

Caulobacter Crescentus ◽

Tricarboxylic Acid Cycle ◽

Tricarboxylic Acid ◽

Homeostatic Control ◽

Acid Cycle ◽

Peptidoglycan Synthesis

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Modulation of tricarboxylic acid cycle dehydrogenases during hepatocarcinogenesis induced by hexachlorocyclohexane in mice

Experimental and Toxicologic Pathology ◽

10.1016/j.etp.2008.09.004 ◽

2009 ◽

Vol 61 (4) ◽

pp. 325-332 ◽

Cited By ~ 9

Author(s):

Devendra Kumar Bhatt ◽

Mehajbeen Bano

Keyword(s):

Tricarboxylic Acid Cycle ◽

Tricarboxylic Acid ◽

Acid Cycle

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Effects of sevoflurane anesthesia and abdominal surgery on the systemic metabolome: a prospective observational study

BMC Anesthesiology ◽

10.1186/s12871-021-01301-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yiyong Wei ◽

Donghang Zhang ◽

Jin Liu ◽

Mengchan Ou ◽

Peng Liang ◽

...

Keyword(s):

Abdominal Surgery ◽

General Anesthesia ◽

Tricarboxylic Acid Cycle ◽

Tricarboxylic Acid ◽

Metabolic Changes ◽

Sevoflurane Anesthesia ◽

Glutamate Metabolism ◽

Acid Cycle ◽

Link Type ◽

The Mean

Abstract Background Metabolic status can be impacted by general anesthesia and surgery. However, the exact effects of general anesthesia and surgery on systemic metabolome remain unclear, which might contribute to postoperative outcomes. Methods Five hundred patients who underwent abdominal surgery were included. General anesthesia was mainly maintained with sevoflurane. The end-tidal sevoflurane concentration (ETsevo) was adjusted to maintain BIS (Bispectral index) value between 40 and 60. The mean ETsevo from 20 min after endotracheal intubation to 2 h after the beginning of surgery was calculated for each patient. The patients were further divided into low ETsevo group (mean − SD) and high ETsevo group (mean + SD) to investigate the possible metabolic changes relevant to the amount of sevoflurane exposure. Results The mean ETsevo of the 500 patients was 1.60% ± 0.34%. Patients with low ETsevo (n = 55) and high ETsevo (n = 59) were selected for metabolomic analysis (1.06% ± 0.13% vs. 2.17% ± 0.16%, P < 0.001). Sevoflurane and abdominal surgery disturbed the tricarboxylic acid cycle as identified by increased citrate and cis-aconitate levels and impacted glycometabolism as identified by increased sucrose and D-glucose levels in these 114 patients. Glutamate metabolism was also impacted by sevoflurane and abdominal surgery in all the patients. In the patients with high ETsevo, levels of L-glutamine, pyroglutamic acid, sphinganine and L-selenocysteine after sevoflurane anesthesia and abdominal surgery were significantly higher than those of the patients with low ETsevo, suggesting that these metabolic changes might be relevant to the amount of sevoflurane exposure. Conclusions Sevoflurane anesthesia and abdominal surgery can impact principal metabolic pathways in clinical patients including tricarboxylic acid cycle, glycometabolism and glutamate metabolism. This study may provide a resource data for future studies about metabolism relevant to general anaesthesia and surgeries. Trial registration www.chictr.org.cn. identifier: ChiCTR1800014327.

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