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High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo.

Mantena SK, Vaughn DP, Andringa KK, Eccleston HB, King AL, Abrams GA, Doeller JE, Kraus DW, Darley-Usmar VM, Bailey SM - Biochem. J. (2009)

Bottom Line: 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.Mitochondria from the HFD group showed increased sensitivity to NO-dependent inhibition of respiration compared with controls.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Health Sciences, Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.

ABSTRACT
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 approximately 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.

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Effect of HFD on liver hypoxia(A) Representative photomicrographs depicting patterns of pimonidazole adduct formation (brown) against a haematoxylin-nuclear counterstain (blue) in liver sections of mice fed either a control diet or HFD for 16 weeks. Increased staining for the pimonidazole adducts demonstrates increased tissue hypoxia in the HFD group as compared with control. Image analysis demonstrated increased area (B) and intensity (C) of pimonidazole adducts in liver from HFD group compared with control. Note: PP, periportal or zone 1 region of liver lobule; PC, pericentral or zone 3 region of liver lobule. Values represent the means±S.E.M. for three pairs of mice. *P<0.05, **P<0.01, compared with control.
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Figure 2: Effect of HFD on liver hypoxia(A) Representative photomicrographs depicting patterns of pimonidazole adduct formation (brown) against a haematoxylin-nuclear counterstain (blue) in liver sections of mice fed either a control diet or HFD for 16 weeks. Increased staining for the pimonidazole adducts demonstrates increased tissue hypoxia in the HFD group as compared with control. Image analysis demonstrated increased area (B) and intensity (C) of pimonidazole adducts in liver from HFD group compared with control. Note: PP, periportal or zone 1 region of liver lobule; PC, pericentral or zone 3 region of liver lobule. Values represent the means±S.E.M. for three pairs of mice. *P<0.05, **P<0.01, compared with control.

Mentions: Hypoxia has been implicated as a causative factor in alcohol-induced fatty liver disease [4,5]; however, whether hypoxia is also associated with NAFLD and NASH is not known. The hypoxia marker pimonidazole was used to determine the extent of liver hypoxia. Figure 2(A) shows the patterns of pimonidazole adduct formation (brown) against a haematoxylin nuclear counterstain (blue) in representative control and HFD livers at 16 weeks. Under normal conditions the most hypoxic region of the liver is the pericentral region or zone 3. HFD feeding for 16 weeks increased pimonidazole binding in zone 3 and extended staining into the midzonal and periportal regions when compared with control livers (Figure 2A). Liver hypoxia was also increased by feeding a HFD for 8 weeks, although to a lesser extent (results not shown). The area of pimonidazole staining in livers from HFD mice was significantly increased by 40% over that observed in controls (Figure 2B). Similarly, a HFD significantly increased the intensity of labelled cells compared with controls by approx. 60% (Figure 2C). These results are indicative of increased liver hypoxia in mice fed a HFD.


High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo.

Mantena SK, Vaughn DP, Andringa KK, Eccleston HB, King AL, Abrams GA, Doeller JE, Kraus DW, Darley-Usmar VM, Bailey SM - Biochem. J. (2009)

Effect of HFD on liver hypoxia(A) Representative photomicrographs depicting patterns of pimonidazole adduct formation (brown) against a haematoxylin-nuclear counterstain (blue) in liver sections of mice fed either a control diet or HFD for 16 weeks. Increased staining for the pimonidazole adducts demonstrates increased tissue hypoxia in the HFD group as compared with control. Image analysis demonstrated increased area (B) and intensity (C) of pimonidazole adducts in liver from HFD group compared with control. Note: PP, periportal or zone 1 region of liver lobule; PC, pericentral or zone 3 region of liver lobule. Values represent the means±S.E.M. for three pairs of mice. *P<0.05, **P<0.01, compared with control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2637578&req=5

Figure 2: Effect of HFD on liver hypoxia(A) Representative photomicrographs depicting patterns of pimonidazole adduct formation (brown) against a haematoxylin-nuclear counterstain (blue) in liver sections of mice fed either a control diet or HFD for 16 weeks. Increased staining for the pimonidazole adducts demonstrates increased tissue hypoxia in the HFD group as compared with control. Image analysis demonstrated increased area (B) and intensity (C) of pimonidazole adducts in liver from HFD group compared with control. Note: PP, periportal or zone 1 region of liver lobule; PC, pericentral or zone 3 region of liver lobule. Values represent the means±S.E.M. for three pairs of mice. *P<0.05, **P<0.01, compared with control.
Mentions: Hypoxia has been implicated as a causative factor in alcohol-induced fatty liver disease [4,5]; however, whether hypoxia is also associated with NAFLD and NASH is not known. The hypoxia marker pimonidazole was used to determine the extent of liver hypoxia. Figure 2(A) shows the patterns of pimonidazole adduct formation (brown) against a haematoxylin nuclear counterstain (blue) in representative control and HFD livers at 16 weeks. Under normal conditions the most hypoxic region of the liver is the pericentral region or zone 3. HFD feeding for 16 weeks increased pimonidazole binding in zone 3 and extended staining into the midzonal and periportal regions when compared with control livers (Figure 2A). Liver hypoxia was also increased by feeding a HFD for 8 weeks, although to a lesser extent (results not shown). The area of pimonidazole staining in livers from HFD mice was significantly increased by 40% over that observed in controls (Figure 2B). Similarly, a HFD significantly increased the intensity of labelled cells compared with controls by approx. 60% (Figure 2C). These results are indicative of increased liver hypoxia in mice fed a HFD.

Bottom Line: 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.Mitochondria from the HFD group showed increased sensitivity to NO-dependent inhibition of respiration compared with controls.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Health Sciences, Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.

ABSTRACT
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 approximately 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.

Show MeSH
Related in: MedlinePlus