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

@article{citeulike:3174461, abstract = {Nonalcoholic fatty liver disease (NAFLD) 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 nonalcoholic steatohepatitis (NASH). Herein, we hypothesize that mitochondrial defects induced by exposure to a high fat diet (HFD) contribute to a hypoxic state in liver and this is associated with increased protein modification by reactive nitrogen species (RNS). To test this concept, C57BL/6 mice were pair-fed a control diet and HFD containing 35\% and 71\% total calories from fat, respectively, for 8 or 16 weeks and liver hypoxia, mitochondrial bioenergetics, nitric oxide (NO)-dependent control of respiration, and 3-nitrotyrosine, a marker of protein modification by RNS, were examined. Feeding a HFD for 16 weeks induced NASH-like pathology accompanied by elevated triglycerides, increased CYP2E1 and iNOS 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 to controls. In addition, accumulation of 3-nitrotyrosine 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 likely contributes to hypoxic stress and deleterious NO-dependent modification of mitochondrial proteins.}, author = {Mantena, Sudheer K. and Vaughn, Denty P. and Andringa, Kelly K. and Eccleston, Heather B. and King, Adrienne L. and Abrams, Gary A. and Doeller, Jeannette E. and Kraus, David W. and Darley-Usmar, Victor and Bailey, Shannon M.}, citeulike-article-id = {3174461}, citeulike-linkout-0 = {http://www.biochemj.org/bj/imps/abs/BJ20080868.htm}, day = {28}, journal = {Biochemical Journal}, keywords = {high\_fat\_dietreactive\_species, mitochondrial\_dysfunction, ros}, month = {August}, posted-at = {2008-08-30 02:15:27}, priority = {3}, title = {High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo}, url = {http://www.biochemj.org/bj/imps/abs/BJ20080868.htm}, year = {2008} }

TY - JOUR ID - citeulike:3174461 L3 - citeulike-article-id:3174461 N2 - Nonalcoholic fatty liver disease (NAFLD) 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 nonalcoholic steatohepatitis (NASH). Herein, we hypothesize that mitochondrial defects induced by exposure to a high fat diet (HFD) contribute to a hypoxic state in liver and this is associated with increased protein modification by reactive nitrogen species (RNS). To test this concept, C57BL/6 mice were pair-fed a control diet and HFD containing 35% and 71% total calories from fat, respectively, for 8 or 16 weeks and liver hypoxia, mitochondrial bioenergetics, nitric oxide (NO)-dependent control of respiration, and 3-nitrotyrosine, a marker of protein modification by RNS, were examined. Feeding a HFD for 16 weeks induced NASH-like pathology accompanied by elevated triglycerides, increased CYP2E1 and iNOS 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 to controls. In addition, accumulation of 3-nitrotyrosine 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 likely contributes to hypoxic stress and deleterious NO-dependent modification of mitochondrial proteins. JF - Biochemical Journal TI - High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo KW - high_fat_dietreactive_species KW - mitochondrial_dysfunction KW - ros AU - Mantena, Sudheer AU - Vaughn, Denty AU - Andringa, Kelly AU - Eccleston, Heather AU - King, Adrienne AU - Abrams, Gary AU - Doeller, Jeannette AU - Kraus, David AU - Darley-Usmar, Victor AU - Bailey, Shannon PY - 2008/08/28/ UR - http://www.biochemj.org/bj/imps/abs/BJ20080868.htm ER -