Alterations of hepatic ATP homeostasis and respiratory chain during development of non-alcoholic steatohepatitis in a rodent model
Article first published online: 12 MAR 2008
© 2008 The Authors
European Journal of Clinical Investigation
Volume 38, Issue 4, pages 245–252, April 2008
How to Cite
Serviddio, G., Bellanti, F., Tamborra, R., Rollo, T., Romano, A. D., Giudetti, A. M., Capitanio, N., Petrella, A., Vendemiale, G. and Altomare, E. (2008), Alterations of hepatic ATP homeostasis and respiratory chain during development of non-alcoholic steatohepatitis in a rodent model. European Journal of Clinical Investigation, 38: 245–252. doi: 10.1111/j.1365-2362.2008.01936.x
- Issue published online: 12 MAR 2008
- Article first published online: 12 MAR 2008
- Received 15 May 2007: accepted 22 January 2008
- ATP homeostasis;
- NASH development;
- oxidative phosphorylation
Background Mitochondrial dysfunction is considered a key player in non-alcoholic steatohepatitis (NASH) but no data are available on the mitochondrial function and ATP homeostasis in the liver during NASH progression. In the present paper we evaluated the hepatic mitochondrial respiratory chain activity and ATP synthesis in a rodent model of NASH development.
Materials and methods Male Wistar rats fed a High Fat/Methionine-Choline Deficient (MCD) diet to induce NASH or a control diet (SHAM), and sacrificed after 3, 7 and 11 weeks. The oxidative phosphorylation, the F0F1ATPase (ATP synthase) and the ATP content were assessed in liver mitochondria.
Results NASH mitochondria exhibited an increased rate of substrate oxidation at 3 weeks, which returned to below the normal level at 7 and 11 weeks, concomitantly with the coupling between the phosphorylation activity and the mitochondrial respiration (ADP/O). Uncoupling of NASH liver mitochondria did not allow the recovery of the maximal respiration rate at 7 and 11 weeks. The ATPase (ATP synthase) activity was similar in NASH and SHAM rats, but the mitochondrial ATP content was significantly lower in NASH livers.
Conclusions The loss of hepatic ATP stores is not dependent on the F0F1-ATPase but resides in the respiratory chain. Dysfunction of both Complex I and II of the mitochondrial respiratory chain during NASH development implies a mitochondrial adaptive mechanism occurring in the early stages of NASH.