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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Nature Medicine
Vol/bind	20
Udgave nummer	1
Sider (fra-til)	98-102
Antal sider	5
ISSN	1078-8956
DOI	https://doi.org/10.1038/nm.3415
Status	Udgivet - 2014

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10.1038/nm.3415

Citationsformater

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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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doi = "10.1038/nm.3415",

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T1 - Direct assessment of hepatic mitochondrial oxidative and anaplerotic fluxes in humans using dynamic 13C magnetic resonance spectroscopy

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

Y1 - 2014

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.

KW - Carbon Radioisotopes

KW - Citric Acid Cycle

KW - Computer Simulation

KW - Diabetes Mellitus, Type 2

KW - Fatty Liver

KW - Humans

KW - Magnetic Resonance Spectroscopy

KW - Metabolic Networks and Pathways

KW - Mitochondria, Liver

KW - Monte Carlo Method

KW - Non-alcoholic Fatty Liver Disease

KW - Oxidation-Reduction

KW - Staining and Labeling

KW - Evaluation Studies

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/nm.3415

DO - 10.1038/nm.3415

M3 - Journal article

C2 - 24317120

SN - 1078-8956

VL - 20

SP - 98

EP - 102

JO - Nature Medicine

JF - Nature Medicine

IS - 1

ER -