Mitochondrial adaptations to steatohepatitis induced by a methionine- and choline-deficient diet.
Nonalcoholic fatty liver disease (NAFLD) has become common liver disease in Western countries. There is accumulating evidence that mitochondria play a key role in NAFLD. Nevertheless, the mitochondrial consequences of steatohepatitis are still unknown. The bioenergetic changes induced in a methionine- and choline-deficient diet (MCDD) model of steatohepatitis were studied in rats. Liver mitochondria from MCDD rats exhibited a higher rate of oxidative phosphorylation with various substrates, a rise in cytochrome oxidase (COX) activity, and an increased content in cytochrome aa3. This higher oxidative activity was associated with a low efficiency of the oxidative phosphorylation (ATP/O, i.e., number of ATP synthesized/natom O consumed). Addition of a low concentration of cyanide, a specific COX inhibitor, restored the efficiency of mitochondria from MCDD rats back to the control level. Furthermore, the relation between respiratory rate and protonmotive force (in the nonphosphorylating state) was shifted to the left in mitochondria from MCDD rats, with or without cyanide. These results indicated that, in MCDD rats, mitochondrial ATP synthesis efficiency was decreased in relation to both proton pump slipping at the COX level and increased proton leak although the relative contribution of each phenomenon could not be discriminated. MCDD mitochondria also showed a low reactive oxygen species production and a high lipid oxidation potential. We conclude that, in MCDD-fed rats, liver mitochondria exhibit an energy wastage that may contribute to limit steatosis and oxidative stress in this model of steatohepatitis.
Romestaing
Caroline
C
Laboratoire de Physiologie Intégrative, Cellulaire et Moléculaire, Unité Mixte de Recherches 5123 Centre National de la Recherche Scientifique, Université Claude Bernard Lyon 1, Villeurbanne Cedex, France. cromestaing@hotmail.com
Piquet
Marie-Astrid
MA
Letexier
Dominique
D
Rey
Benjamin
B
Mourier
Arnaud
A
Servais
Stéphane
S
Belouze
Maud
M
Rouleau
Vincent
V
Dautresme
Marianne
M
Ollivier
Isabelle
I
Favier
Roland
R
Rigoulet
Michel
M
Duchamp
Claude
C
Sibille
Brigitte
B
D000222:Adaptation, Physiological / Q000502:physiology*; D000821:Animal Feed; D000818:Animals; D002794:Choline / Q000494:pharmacology; D002796:Choline Deficiency / Q000378:metabolism* / Q000503:physiopathology; D004734:Energy Metabolism / Q000502:physiology; D005234:Fatty Liver / Q000378:metabolism* / Q000503:physiopathology; D006505:Hepatitis / Q000378:metabolism* / Q000503:physiopathology; D015850:Interleukin-6 / Q000235:genetics; D008297:Male; D044342:Malnutrition / Q000378:metabolism / Q000503:physiopathology; D008715:Methionine / Q000172:deficiency* / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D015850:Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D008715:Methionine; D002794:Choline