期刊
BIOCHEMICAL JOURNAL
卷 417, 期 -, 页码 183-193出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20080868
关键词
cytochrome c oxidase; hypoxia; liver; mitochondria; nitric oxide; non-alcoholic steatohepatitis
资金
- National Institutes of Health (NIH) [AA13395, AA15172, DK73775]
- NIH-funded University of Alabama at Birmingham Clinical Nutrition Research Center [DK56336]
- NIH Research Supplement to Promote Diversity in Health-Related Research linked to parent [AA15172]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R21DK073775, P30DK056336] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [R01AA015172, R01AA013395] Funding Source: NIH RePORTER
NAFLD (non-alcoholic fatty liver disease), associated with obesity and the cardiometabolic syndrome, is ail important medical problem affecting up to 20% of western populations. Evidence indicates that mitochondrial dysfunction plays a critical role ill 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 approximate to 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 triacyl glycerols, 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,
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