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.
authors: 1] Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. [3].
authors: Douglas E
authors: DE
authors: Befroy
authors: 1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA. [3].
authors: Rachel J
authors: RJ
authors: Perry
authors: Department of Biomedical Engineering, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Nimit
authors: N
authors: Jain
authors: Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Sylvie
authors: S
authors: Dufour
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Gary W
authors: GW
authors: Cline
authors: Pfizer Pharmaceuticals, Groton, Connecticut, USA.
authors: Jeff K
authors: JK
authors: Trimmer
authors: Pfizer Pharmaceuticals, Groton, Connecticut, USA.
authors: Julia
authors: J
authors: Brosnan
authors: 1] Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Department of Biomedical Engineering, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Douglas L
authors: DL
authors: Rothman
authors: 1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Novo Nordisk Foundation Center for Basic Metabolic Research, Copenhagen, Denmark.
authors: Kitt Falk
authors: KF
authors: Petersen
authors: 1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA. [3] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA. [4] Novo Nordisk Foundation Center for Basic Metabolic Research, Copenhagen, Denmark.
authors: Gerald I
authors: GI
authors: Shulman
mesh_terms: D002250:Carbon Radioisotopes; D002952:Citric Acid Cycle / Q000502:physiology; D003198:Computer Simulation; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D005234:Fatty Liver / Q000503:physiopathology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D008930:Mitochondria, Liver / Q000378:metabolism*; D009010:Monte Carlo Method; D065626:Non-alcoholic Fatty Liver Disease; D010084:Oxidation-Reduction; D013194:Staining and Labeling / Q000379:methods
chemical_list: D002250:Carbon Radioisotopes