Novel stable isotope methods to assess metabolic fluxes using microscale samples
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1 Novel stable isotope methods to assess metabolic fluxes using microscale samples Jamey D. Young Associate Professor and Chancellor s Faculty Fellow Chemical and Biomolecular Engineering Molecular Physiology and Biophysics Vanderbilt University j.d.young@vanderbilt.edu
2 Fluxes provide information about system bottlenecks and regulation
3 Metabolic flux changes cannot be inferred from enzyme expression Glucose Burgess et al., Cell Metabolism 5, , 2007.
4 Static metabolite abundances are not reliable indicators of flux
5 How to determine metabolic fluxes? Start by measuring external fluxes Solve for internal fluxes using mass balances
6 But external measurements usually aren t enough Glucose Glycerol Lactate
7 But external measurements usually aren t enough Glucose Glycerol Lactate
8 Isotope tags allow us to measure intracellular fluxes 13 C 12 C + + Pathway 2 Pathway 3 Pathway 1 Pathway 4 MID measured by GC- or LC-MS Abundance MID = Mass Isotopomer Distribution M0 M1 M2 M3
9 Metabolic flux analysis uses math models to decipher labeling data Wiechert Metab Eng 3: , 2001
10 Math model comprises mass balances and isotopomer balances on each intracellular metabolite Wiechert Metab Eng 3: , 2001
11 Fluxes are regressed by fitting the model to match the labeling data e a d b c Simulated Experimental Adjust fluxes
12 Fluxes are regressed by fitting the model to match the labeling data e a d b c Simulated Experimental Adjust fluxes
13 Fluxes are regressed by fitting the model to match the labeling data e a d b c Simulated Experimental Adjust fluxes
14 INCA: Isotopomer Network Compartmental Analysis mfa.vueinnovations.com Young Bioinformatics 30: , 2014 Custom MFA software Handles transient and steady-state labeling experiments Generalizable to any metabolic network of interest Recently adapted to MS/MS and NMR isotopomer measurements
15 Comparison of CHO flux maps TCA TCA TCA TCA Early Exponential Late Exponential Stationary Decline Templeton et al Biotech and Bioeng 110:
16 Treatment of airway epithelial cells with cigarette smoke condensate Rahman et al. JCI Insight 1:e88814, 2016.
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18 Pancreatic islets sense glucose and secrete insulin to control glycemia Glucose stimulated insulin secretion (GSIS) G6PC2 Levine and Leibowitz, Towards gene therapy of diabetes mellitus, Mol. Med., 1999
19 Quantifying glucose cycling in mouse pancreatic islets Novel stable isotope analyses demonstrate significant rates of glucose cycling in mouse pancreatic islets. Wall ML, Pound LD, Trenary I, O'Brien RM, Young JD. Diabetes 64: , 2015.
20 GC-MS approach for measuring positional isotope enrichment of glucose Measuring deuterium enrichment of glucose hydrogen atoms by gas chromatography/mass spectrometry. Antoniewicz MR, Kelleher JK, Stephanopoulos G. Anal Chem 83:3211-6, 2011.
21 Islets from chow fed mice incubated in 5mM D7-glucose Novel stable isotope analyses demonstrate significant rates of glucose cycling in mouse pancreatic islets. Wall ML, Pound LD, Trenary I, O'Brien RM, Young JD. Diabetes 64: , 2015.
22 Islets from chow fed mice incubated in 11mM D7-glucose Novel stable isotope analyses demonstrate significant rates of glucose cycling in mouse pancreatic islets. Wall ML, Pound LD, Trenary I, O'Brien RM, Young JD. Diabetes 64: , 2015.
23 Summary Glucose Cycling (%) [Glucose] G6pc2 Diet WT (mm) KO Chow 5 16 ± 4 2 ± 2 High fat 5 25 ± ± 2 Chow ± 6 3 ± 1 High fat ± 5 3 ± 1 Rates of glucose cycling in WT islets greater than reported by prior methods Islets from G6pc2 KO mice exhibit negligible cycling rates compared to WT islets under all conditions Glucose cycling has averaged ~10% in preliminary studies of donor human islets
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25 Stable isotope methods are needed to examine intermediary fluxes in vivo EndoRa
26 Combined 2 H and 13 C tracers have been used to assess liver CAC and GNG fluxes 2 H 2 O 2 H 2 O Glycerol Lactate Glycogen e a AA, FA 2 H 2 O [U- 13 C 3 ]-propionate d b c
27 NMR analysis of glucose positional enrichment is the gold standard but is difficult to scale down to the mouse 2 H NMR spectra 13 C NMR spectra of C-2β Jones et al. Am J Physiol Endocrinol Metab, 2001
28 GC-MS approach for measuring stable isotope enrichment of glucose GC-MS analysis Antoniewicz et al. Anal Chem 83:3211-6, 2011.
29 Dual catheter system enables continuous infusion and sampling in conscious mice Sample Erythrocytes 2 H 2 O +[6,6-2 H 2 ]Glucose [U- 13 C 3 ]Propionate Vein Artery
30 Short-term (9h) vs. long-term (19h) fasting study Overall objective: Test and validate a scaleddown, low-cost, high-throughput GC-MSbased in vivo flux analysis approach Hypothesis: GC-MS analysis of glucose 2 H/ 13 C enrichment will yield sufficient information to precisely assess GNG and CAC fluxes
31 Isotopic steady state is reached within 90 min of isotope infusion short (n=5) long (n=7) m/z 301 Hasenour et al., Am. J. Physiol. Endocrinol. Metab. 309:E191, 2015.
32 Short- and long-term fasted mice are differentially enriched at steady state Hasenour et al., Am. J. Physiol. Endocrinol. Metab. 309:E191, 2015.
33 An isotopomer model was developed to simulate the movement of tracers through liver metabolism Hasenour et al., Am. J. Physiol. Endocrinol. Metab. 309:E191, 2015.
34 Model tracks carbon and hydrogen atom transitions Lac (ABbCcde) Pyr (ABCcde) + H (b) Lactate O NADH e O a AA, FA NAD + O A Bb Ccde A B Ccde O Lactate d b Dehydrogenase OH O Lactate Pyruvate c
35 INCA Model ID GLCinf Hinf Hsink PCC SDH CS IDH OGDH PDH GPI ALDO GAPDH ENO PK PC PCK PYGL MPI GK LDH Equation Gluc.inf (AaBbCcDdEeFfg) Gluc.ext (AaBbCcDdEeFfg) H.inf (a) H (a) H Sink PropCoA (ABabCcde) + CO2 (D) SuccCoA (ACcdBabD) + H (e) SucCoA (ABabCcdD) + H (e) + H (f) 0.5*Oac (ABCefD) + 0.5*Oac (DCBefA) + H (a) + H (b) + H (c) + H (d) Oac (ABCcdD) + AcCoA (EFfgh) Cit (DCcdBFfgEA) + H (h) Cit (ABabCDcdEF) + H (e) Akg (ABCeaDcdE) + H (b) + CO2 (F) Akg (ABCabDcdE) SucCoA (BCabDcdE) + CO2 (A) Pyr (ABCabc) AcCoA (BCabc) + CO2 (A) F6P (AabBCcDdEeFfg) + H (h) G6P (AbBhCcDdEeFfg) + H (a) DHAP (CchBAab) + GAP (DdEeFfg) F6P (AabBCcDdEeFfg) + H (h) BPG (ABbCcd) + H (e) + H (f) 0.5*GAP (AfBeCcd) + 0.5*DHAP (AefBCcd) + H (b) PEP (ABCcd) + H (b) BPG (ABbCcd) PEP (ABCab) + H (c) Pyr (ABCabc) Pyr (ABCcde) + CO2 (D) + H (f) + H (g) 0.5*Oac (ABCfgD) + 0.5*Oac (DCBfgA) + H (c) + H (d) + H (e) Oac (ABCabD) PEP (ABCab) + CO2 (D) Glycogen (AaBbCcDdEeFfg) + H (h) G6P (AaBhCcDdEeFfg) + H (b) F6P (AabBCcDdEeFfg) + H (h) F6P (AahBCcDdEeFfg) + H (b) Glycerol (AaeBbCcd) + H (f) 0.5*DHAP (AfeBCcd) + 0.5*GAP (AeBfCcd) + H (a) + H (b) Lac (ABbCcde) Pyr (ABCcde) + H (b)
36 Method captures expected changes between short and long-term fasting Hasenour et al., Am. J. Physiol. Endocrinol. Metab. 309:E191, 2015.
37 Method captures expected changes between short and long-term fasting EndoRa Glucose Glycerol Lactate Glycogen e a AA, FA d b c short n=5, long n=7; V EndoRa p=0.25
38 Method captures expected changes between short and long-term fasting Glycogen Glycerol Lactate Glycogen e a AA, FA d b c short n=5, long n=7; V PYGL p=2e-04
39 Method captures expected changes between short and long-term fasting Glycerol Glycerol Lactate Glycogen e a AA, FA d b c short n=5, long n=7; V GK p=0.025
40 Method captures expected changes between short and long-term fasting CAC Glycerol Lactate Glycogen e a AA, FA d b c short n=5, long n=7; V CAC p=0.049
41 Relative fluxes have similar values and precision to NMR-based results Contribution to EndoRa This study (n=7) Satapati et al.* (n=6-8) Glycogen ± ± 0.02 Glycerol ± ± 0.02 PEP ± ± 0.02 Flux relative to CAC This study (n=7) Satapati et al.* (n=6-8) Enolase 1.59 ± ± 0.1 Pyruvate cycling 1.44 ± ± 0.1 PEPCK 3.03 ± ± 0.2 *Satapati et al. J Lipid Res, 2012
42 Future studies and applications Ongoing validation studies: different tracers, additional plasma/tissue measurements Establish a Metabolic Flux Analysis (MFA) Subcore within the Vanderbilt MMPC Will provide stable isotope analysis of tracer studies involving mice and mouse tissues Apply method to study metabolic pathophysiology in vivo L-AMPK WT vs KO comparison Effects of FFA on liver metabolism Exercise studies
43 Summary 2 H/ 13 C flux analysis can be used to dissect metabolic physiology in cells and in vivo We have developed a novel GC-MS-based 2 H/ 13 C MFA approach that can be applied to examine mouse liver metabolism in vivo Requires only 40 µl plasma Mice are conscious and unrestrained Higher throughput and lower cost than NMR INCA software enables isotopomer models to be quickly modified to test assumptions or to incorporate new tracers, measurements, pathways
44 Acknowledgements Collaborators O Brien lab G6PC2 Wasserman lab in vivo MFA Young lab Martha Wall Clint Hasenour Irina Trenary Funding NIH T32 (Martha, Clint) MMPC MICROMouse Program Vanderbilt Discovery Award Wasserman R. O Brien Clint NIH R01 DK Martha
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