Direct assessment of hepatic mitochondrial oxidative and anaplerotic fluxes in humans using dynamic 13C magnetic resonance spectroscopy

Douglas E Befroy; Rachel J Perry; Nimit Jain; Sylvie Dufour; Gary W Cline; Jeff K Trimmer; Julia Brosnan; Douglas L Rothman; Kitt Falk Petersen; Gerald I. Shulman

doi:10.1038/nm.3415

Direct assessment of hepatic mitochondrial oxidative and anaplerotic fluxes in humans using dynamic ¹³C magnetic resonance spectroscopy

Douglas E Befroy, Rachel J Perry, Nimit Jain, Sylvie Dufour, Gary W Cline, Jeff K Trimmer, Julia Brosnan, Douglas L Rothman, Kitt Falk Petersen, Gerald I. Shulman

58 Citations (Scopus)

Abstract

Despite the central role of the liver in the regulation of glucose and lipid metabolism, there are currently no methods to directly assess hepatic oxidative metabolism in humans in vivo. By using a new (13)C-labeling strategy in combination with (13)C magnetic resonance spectroscopy, we show that rates of mitochondrial oxidation and anaplerosis in human liver can be directly determined noninvasively. Using this approach, we found the mean rates of hepatic tricarboxylic acid (TCA) cycle flux (VTCA) and anaplerotic flux (VANA) to be 0.43 ± 0.04 μmol g(-1) min(-1) and 0.60 ± 0.11 μmol g(-1) min(-1), respectively, in twelve healthy, lean individuals. We also found the VANA/VTCA ratio to be 1.39 ± 0.22, which is severalfold lower than recently published estimates using an indirect approach. This method will be useful for understanding the pathogenesis of nonalcoholic fatty liver disease and type 2 diabetes, as well as for assessing the effectiveness of new therapies targeting these pathways in humans.

Original language	English
Journal	Nature Medicine
Volume	20
Issue number	1
Pages (from-to)	98-102
Number of pages	5
ISSN	1078-8956
DOIs	https://doi.org/10.1038/nm.3415
Publication status	Published - 2014

Keywords

Carbon Radioisotopes
Citric Acid Cycle
Computer Simulation
Diabetes Mellitus, Type 2
Fatty Liver
Humans
Magnetic Resonance Spectroscopy
Metabolic Networks and Pathways
Mitochondria, Liver
Monte Carlo Method
Non-alcoholic Fatty Liver Disease
Oxidation-Reduction
Staining and Labeling
Evaluation Studies
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nm.3415

Cite this

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title = "Direct assessment of hepatic mitochondrial oxidative and anaplerotic fluxes in humans using dynamic 13C magnetic resonance spectroscopy",

abstract = "Despite the central role of the liver in the regulation of glucose and lipid metabolism, there are currently no methods to directly assess hepatic oxidative metabolism in humans in vivo. By using a new (13)C-labeling strategy in combination with (13)C magnetic resonance spectroscopy, we show that rates of mitochondrial oxidation and anaplerosis in human liver can be directly determined noninvasively. Using this approach, we found the mean rates of hepatic tricarboxylic acid (TCA) cycle flux (VTCA) and anaplerotic flux (VANA) to be 0.43 ± 0.04 μmol g(-1) min(-1) and 0.60 ± 0.11 μmol g(-1) min(-1), respectively, in twelve healthy, lean individuals. We also found the VANA/VTCA ratio to be 1.39 ± 0.22, which is severalfold lower than recently published estimates using an indirect approach. This method will be useful for understanding the pathogenesis of nonalcoholic fatty liver disease and type 2 diabetes, as well as for assessing the effectiveness of new therapies targeting these pathways in humans.",

keywords = "Carbon Radioisotopes, Citric Acid Cycle, Computer Simulation, Diabetes Mellitus, Type 2, Fatty Liver, Humans, Magnetic Resonance Spectroscopy, Metabolic Networks and Pathways, Mitochondria, Liver, Monte Carlo Method, Non-alcoholic Fatty Liver Disease, Oxidation-Reduction, Staining and Labeling, Evaluation Studies, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",

author = "Befroy, {Douglas E} and Perry, {Rachel J} and Nimit Jain and Sylvie Dufour and Cline, {Gary W} and Trimmer, {Jeff K} and Julia Brosnan and Rothman, {Douglas L} and Petersen, {Kitt Falk} and Shulman, {Gerald I.}",

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AU - Befroy, Douglas E

AU - Perry, Rachel J

AU - Jain, Nimit

AU - Dufour, Sylvie

AU - Cline, Gary W

AU - Trimmer, Jeff K

AU - Brosnan, Julia

AU - Rothman, Douglas L

AU - Petersen, Kitt Falk

AU - Shulman, Gerald I.

PY - 2014

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N2 - Despite the central role of the liver in the regulation of glucose and lipid metabolism, there are currently no methods to directly assess hepatic oxidative metabolism in humans in vivo. By using a new (13)C-labeling strategy in combination with (13)C magnetic resonance spectroscopy, we show that rates of mitochondrial oxidation and anaplerosis in human liver can be directly determined noninvasively. Using this approach, we found the mean rates of hepatic tricarboxylic acid (TCA) cycle flux (VTCA) and anaplerotic flux (VANA) to be 0.43 ± 0.04 μmol g(-1) min(-1) and 0.60 ± 0.11 μmol g(-1) min(-1), respectively, in twelve healthy, lean individuals. We also found the VANA/VTCA ratio to be 1.39 ± 0.22, which is severalfold lower than recently published estimates using an indirect approach. This method will be useful for understanding the pathogenesis of nonalcoholic fatty liver disease and type 2 diabetes, as well as for assessing the effectiveness of new therapies targeting these pathways in humans.

AB - Despite the central role of the liver in the regulation of glucose and lipid metabolism, there are currently no methods to directly assess hepatic oxidative metabolism in humans in vivo. By using a new (13)C-labeling strategy in combination with (13)C magnetic resonance spectroscopy, we show that rates of mitochondrial oxidation and anaplerosis in human liver can be directly determined noninvasively. Using this approach, we found the mean rates of hepatic tricarboxylic acid (TCA) cycle flux (VTCA) and anaplerotic flux (VANA) to be 0.43 ± 0.04 μmol g(-1) min(-1) and 0.60 ± 0.11 μmol g(-1) min(-1), respectively, in twelve healthy, lean individuals. We also found the VANA/VTCA ratio to be 1.39 ± 0.22, which is severalfold lower than recently published estimates using an indirect approach. This method will be useful for understanding the pathogenesis of nonalcoholic fatty liver disease and type 2 diabetes, as well as for assessing the effectiveness of new therapies targeting these pathways in humans.

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KW - Monte Carlo Method

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KW - Evaluation Studies

KW - Journal Article

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