High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo (original) (raw)
Research Article| December 12 2008
*Department of Environmental Health Sciences, Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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*Department of Environmental Health Sciences, Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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*Department of Environmental Health Sciences, Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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*Department of Environmental Health Sciences, Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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*Department of Environmental Health Sciences, Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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†Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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*Department of Environmental Health Sciences, Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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‡Department of Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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§Department of Pathology, Molecular and Cellular Division, The University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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*Department of Environmental Health Sciences, Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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Publisher: Portland Press Ltd
Received: April 29 2008
Revision Received: August 12 2008
Accepted: August 28 2008
Accepted Manuscript online: August 28 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem J (2009) 417 (1): 183–193.
Revision Received:
August 12 2008
Accepted Manuscript online:
August 28 2008
NAFLD (non-alcoholic fatty liver disease), associated with obesity and the cardiometabolic syndrome, is an important medical problem affecting up to 20% of western populations. Evidence indicates that mitochondrial dysfunction plays a critical role in NAFLD initiation and progression to the more serious condition of NASH (non-alcoholic steatohepatitis). Herein we hypothesize that mitochondrial defects induced by exposure to a HFD (high fat diet) contribute to a hypoxic state in liver and this is associated with increased protein modification by RNS (reactive nitrogen species). To test this concept, C57BL/6 mice were pair-fed a control diet and HFD containing 35% and 71% total calories (1 cal≈4.184 J) from fat respectively, for 8 or 16 weeks and liver hypoxia, mitochondrial bioenergetics, NO (nitric oxide)-dependent control of respiration, and 3-NT (3-nitrotyrosine), a marker of protein modification by RNS, were examined. Feeding a HFD for 16 weeks induced NASH-like pathology accompanied by elevated triacylglycerols, increased CYP2E1 (cytochrome P450 2E1) and iNOS (inducible nitric oxide synthase) protein, and significantly enhanced hypoxia in the pericentral region of the liver. Mitochondria from the HFD group showed increased sensitivity to NO-dependent inhibition of respiration compared with controls. In addition, accumulation of 3-NT paralleled the hypoxia gradient in vivo and 3-NT levels were increased in mitochondrial proteins. Liver mitochondria from mice fed the HFD for 16 weeks exhibited depressed state 3 respiration, uncoupled respiration, cytochrome c oxidase activity, and mitochondrial membrane potential. These findings indicate that chronic exposure to a HFD negatively affects the bioenergetics of liver mitochondria and this probably contributes to hypoxic stress and deleterious NO-dependent modification of mitochondrial proteins.
© The Authors Journal compilation © 2009 Biochemical Society
2009
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