Alterations of hepatic ATP homeostasis and respiratory chain during development of non-alcoholic steatohepatitis in a rodent model.
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.


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 F(0)F(1)ATPase (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 F(0)F(1)-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.
Serviddio
G
G
University of Foggia, Foggia, Italy. g.serviddio@unifg.it
Bellanti
F
F
Tamborra
R
R
Rollo
T
T
Romano
A D
AD
Giudetti
A M
AM
Capitanio
N
N
Petrella
A
A
Vendemiale
G
G
Altomare
E
E
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D002796:Choline Deficiency / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism*; D006505:Hepatitis / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000378:metabolism; D010085:Oxidative Phosphorylation; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar
D000255:Adenosine Triphosphate; D000410:Alanine Transaminase