Interaction between the Pentose Phosphate Pathway and Gluconeogenesis from Glycerol in the Liver

Jin, Eunsook S.; Sherry, A. Dean; Malloy, Craig R.

doi:10.1074/jbc.m114.577692

Cited by 28 publications

(62 citation statements)

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“…We also showed that viscerally obese individuals had a trend toward lower 13 C-labeled glucose isotopomers produced through the PPP or TCA cycle suggesting a possible link between excess VAT, inflammation, PPP dysregulation, and mitochondrial failure. Furthermore, we observed that refeeding results in lower 13 C enrichment in glucose through direct gluconeogenesis from [U- 13 C 3 ] glycerol, through PPP activity or through the TCA cycle prior to gluconeogenesis, compared with the fasting state, consistent with prior observations in non-obese refed rodents [17]. Overall, our findings provide intriguing evidence that excess VAT may act as a “constitutively fed state” and result in increased risk for hyperglycemia and type 2 diabetes through overstimulation of hepatic gluconeogenesis by chronic delivery of glycerol arising from mesenteric triglyceride turnover directly into the portal circulation and to the liver.…”

Section: 0 Discussionsupporting

confidence: 90%

“…Total 13 C enrichment in plasma glucose is measured by the sum of all glucose isotopomers with excess 13 C. Additional information about specific pathways is derived from specific glucose isotopomers [17, 18]. Initially, glycerol is phosphorylated in the liver by glycerol kinase and is converted to DHAP and GA3P.…”

Section: 0 Theory/calculationmentioning

confidence: 99%

“…Previs and colleagues found that a significant fraction of glucose derived from [U- 13 C] glycerol in rodents and non-human primates passed through the oxaloacetate pool in the TCA cycle prior to gluconeogenesis [16]. More recent studies in rodents [17] and healthy humans [18] demonstrated that most glycerol is metabolized directly to glucose but that a modest fraction enters the TCA cycle prior to re-synthesis to glucose and a small fraction of glycerol carbons are redistributed in the oxidative arm of the PPP. These observations are consistent with reports of bidirectional metabolism in the gluconeogenic and glycolytic pathways [19, 20].…”

Section: 0 Introductionmentioning

confidence: 99%

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Effects of visceral adiposity on glycerol pathways in gluconeogenesis

et al. 2017

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Objective To determine the feasibility of using oral 13C labeled glycerol at assess effects of visceral adiposity on gluconeogenic pathways in obese humans. Research Design and Methods Obese (BMI ≥30 kg/m2) participants without type 2 diabetes underwent visceral adipose tissue (VAT) assessment and stratification by median VAT into high VAT-fasting (n=3), low VAT-fasting (n=4), and high VAT-refed (n=2) groups. Participants ingested [U-13C3] glycerol and blood samples were subsequently analyzed at multiple time points over 3 hours by NMR spectroscopy. The fractions of plasma glucose (enrichment) derived from [U-13C3] glycerol via hepatic gluconeogenesis, pentose phosphate pathway (PPP), and tricarboxylic acid (TCA) cycle were assessed using 13C NMR analysis of glucose. Mixed linear models were used to compare 13C enrichment in glucose between groups. Results Mean age, BMI, and baseline glucose were 49 years, 40.1 kg/m2, and 98 mg/dl, respectively. Up to 20% of glycerol was metabolized in the TCA cycle prior to gluconeogenesis and PPP activity was minor (<1% of total glucose) in all participants. There was a 21% decrease in 13C enrichment in plasma glucose in the high VAT-fasting compared with low VAT-fasting group (p=0.03), suggesting dilution by endogenous glycerol. High VAT-refed participants had 37% less 13C enrichment in glucose compared with high VAT-fasting (p=0.02). There was a trend toward lower [1,2-13C2] (via PPP) and [5,6-13C2]/[4,5,6-13C3] (via TCA cycle) glucose in high VAT versus low VAT groups. Conclusions We applied a simple method to detect gluconeogenesis from glycerol in obese humans. Our findings provide preliminary evidence that excess visceral fat disrupts multiple pathways in hepatic gluconeogenesis from glycerol.

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Section: 0 Discussionsupporting

confidence: 90%

Section: 0 Theory/calculationmentioning

confidence: 99%

Section: 0 Introductionmentioning

confidence: 99%

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Effects of visceral adiposity on glycerol pathways in gluconeogenesis

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“…Analysis of hepatic PPP activity is based on the principle that the 13 C-labeling patterns in the "top" or "bottom" half of glucose carbons reflect the triose pool and that the relative concentrations of double-labeled trioses cannot be altered by transaldolase activity or incomplete equilibration at the level of triose phosphate isomerase (15). Transaldolase activity exchanges fructose 6-phosphate carbons 4 -6 with GA3P carbons.…”

Section: Methodsmentioning

confidence: 99%

“…Recently methods were introduced to study hepatic PPP by analysis of plasma glucose and hepatic fatty acid esterification in rodents receiving intragastric 13 C-labeled glycerol (15,16). After the administration of [U- 13 C 3 ]glycerol, different metabolic pathways in the liver generate unique 13 C-labeling patterns in the products of hepatic biosynthesis, glucose and TAGs, that are exported into circulation and readily sampled in venous blood.…”

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An Oral Load of [13C3]Glycerol and Blood NMR Analysis Detect Fatty Acid Esterification, Pentose Phosphate Pathway, and Glycerol Metabolism through the Tricarboxylic Acid Cycle in Human Liver

Jin

Sherry

Malloy

2016

Journal of Biological Chemistry

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Drugs and other interventions for high impact hepatic diseases often target biochemical pathways such as gluconeogenesis, lipogenesis, or the metabolic response to oxidative stress. However, traditional liver function tests do not provide quantitative data about these pathways. In this study, we developed a simple method to evaluate these processes by NMR analysis of plasma metabolites. Healthy subjects ingested [U-13 C 3 ]glycerol, and blood was drawn at multiple times. Each subject completed three visits under differing nutritional states. High resolution 13 C NMR spectra of plasma triacylglycerols and glucose provided new insights into a number of hepatic processes including fatty acid esterification, the pentose phosphate pathway, and gluconeogenesis through the tricarboxylic acid cycle. Fasting stimulated pentose phosphate pathway activity and metabolism of [U-13 C 3 ]glycerol in the tricarboxylic acid cycle prior to gluconeogenesis or glyceroneogenesis. Fatty acid esterification was transient in the fasted state but continuous under fed conditions. We conclude that a simple NMR analysis of blood metabolites provides an important biomarker of pentose phosphate pathway activity, triacylglycerol synthesis, and flux through anaplerotic pathways in mitochondria of human liver.

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Estimating pentose phosphate pathway activity from the analysis of hepatic glycogen ¹³C‐isotopomers derived from [U‐¹³C]fructose and [U‐¹³C]glucose

Belew

Nunzio

Tavares

et al. 2020

Magnetic Resonance in Med

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Purpose The pentose phosphate pathway (PPP) is an important component of hepatic intermediary metabolism. Jin et al developed an elegant 13C‐NMR method for measuring hepatic PPP flux by quantifying the distribution of glucose 13C‐isotopomers formed from [U‐13C]glycerol. We demonstrate that this approach can be extended to exogenous [U‐13C]fructose and [U‐13C]glucose precursors by 13C‐NMR analysis of glycogen. Methods Twelve male C57BL/6 mice fed standard chow were provided a 55/45 mixture of fructose and glucose at 30% w/v in the drinking water for 18 wk. On the evening before sacrifice, the fructose component was enriched with 20% [U‐13C]fructose for 6 mice, while the glucose component was enriched with 20% [U‐13C]glucose for the remaining 6 mice. Mice were allowed to feed and drink naturally overnight, and then, euthanized. Livers were freeze‐clamped and glycogen was extracted and derivatized for 13C NMR spectroscopy. Flux of each sugar into the PPP relative to its incorporation into glycogen was quantified from selected 13C glycogen isotopomer ratios. Results Both [U‐13C]fructose and [U‐13C]glucose precursors yielded glycogen 13C‐isotopomer distributions that were characteristic of PPP activity. The fraction of [U‐13C]glucose utilized by the PPP relative to its conversion to glycogen via the direct pathway was 14 ± 1%, while that from [U‐13C]fructose relative to its conversion to glycogen via the indirect pathway was significantly lower (10 ± 1%, P = .00032). Conclusions Hepatic PPP fluxes from both [U‐13C]glucose and [U‐13C]fructose precursors were assessed by 13C NMR analysis of glycogen 13C‐isotopomers. Glucose‐6‐phosphate generated via glucokinase and the direct pathway is preferentially utilized by the PPP.

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Interaction between the Pentose Phosphate Pathway and Gluconeogenesis from Glycerol in the Liver

Cited by 28 publications

References 21 publications

Effects of visceral adiposity on glycerol pathways in gluconeogenesis

Effects of visceral adiposity on glycerol pathways in gluconeogenesis

An Oral Load of [13C3]Glycerol and Blood NMR Analysis Detect Fatty Acid Esterification, Pentose Phosphate Pathway, and Glycerol Metabolism through the Tricarboxylic Acid Cycle in Human Liver

Estimating pentose phosphate pathway activity from the analysis of hepatic glycogen ¹³C‐isotopomers derived from [U‐¹³C]fructose and [U‐¹³C]glucose

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Interaction between the Pentose Phosphate Pathway and Gluconeogenesis from Glycerol in the Liver

Cited by 28 publications

References 21 publications

Effects of visceral adiposity on glycerol pathways in gluconeogenesis

Effects of visceral adiposity on glycerol pathways in gluconeogenesis

An Oral Load of [13C3]Glycerol and Blood NMR Analysis Detect Fatty Acid Esterification, Pentose Phosphate Pathway, and Glycerol Metabolism through the Tricarboxylic Acid Cycle in Human Liver

Estimating pentose phosphate pathway activity from the analysis of hepatic glycogen 13C‐isotopomers derived from [U‐13C]fructose and [U‐13C]glucose

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Estimating pentose phosphate pathway activity from the analysis of hepatic glycogen ¹³C‐isotopomers derived from [U‐¹³C]fructose and [U‐¹³C]glucose