Dietary steatotic liver attenuates acetaminophen hepatotoxicity in mice.
OBJECTIVE
To determine whether hepatic steatosis is susceptible to acetaminophen (APAP) hepatotoxicity.


METHODS
Male C57Bl/6 mice were fed a "Western-style" diet (high fat and high carbohydrate) for 4 months to develop severe hepatic steatosis with mild increases in alanine aminotransferase (ALT) levels. These were compared to mice fed a standard chow diet.


RESULTS
Treatment with APAP (300 mg/kg, orally) to mice fed a regular chow increased ALT levels (519-fold) and caused hepatic centrilobular injury at 6 h. APAP increased hepatic cytochrome-P (CYP)-2E1 mRNA levels (17-fold). In vivo microscopic studies showed that APAP caused a 30% decrease in sinusoidal perfusion and the infiltration of red blood cells into the space of Disse. Electron microscopy demonstrated that numerous gaps were formed in sinusoidal endothelial cells. Mice fed the "Western-style" diet were protected from APAP hepatotoxicity as evidenced by 89% decrease in ALT levels and less centrilobular injury, which was associated with 42% decrease in CYP2E1 mRNA levels. The APAP-induced liver microcirculatory dysfunction was minimized in mice fed the "Western-style" diet.


CONCLUSIONS
These results suggest that hepatic steatosis elicited by the "Western-style" diet attenuated APAP-induced hepatotoxicity by inhibiting CYP2E1 induction and by minimizing sinusoidal endothelial cell injury, leading to protection of liver microcirculation.
Ito
Yoshiya
Y
Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, Arizona 85724-5044, USA.
Abril
Edward R
ER
Bethea
Nancy W
NW
McCuskey
Margaret K
MK
McCuskey
Robert S
RS
D000082:Acetaminophen / Q000494:pharmacology / Q000633:toxicity*; D000410:Alanine Transaminase / Q000096:biosynthesis; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D004036:Diet, Atherogenic; D042783:Endothelial Cells / Q000201:enzymology / Q000648:ultrastructure; D004789:Enzyme Activation / Q000187:drug effects; D005234:Fatty Liver / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008099:Liver / Q000098:blood supply / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D051379:Mice
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1; D000410:Alanine Transaminase