Mechanism of zone-specific hepatic steatosis caused by valproate: inhibition of ketogenesis in periportal regions of the liver lobule.
Microvacuolar steatosis in periportal regions of the liver lobule was produced by injection of fasted rats with a single dose of valproate (500 mg/kg, subcutaneously). In livers perfused in the absence of exogenous fatty acids, ketone body (acetoacetate + beta-hydroxybutyrate) production was decreased by valproate (500 microM) maximally by 67%. Concomitantly, NADH fluorescence detected from the liver surface declined about 30% with a time course similar to that of the inhibition of ketogenesis. Valproate had little effect on oxygen uptake but caused an elevation of the steady state level of catalase-H2O2 corresponding to an increase in H2O2 production of about 6 mumol/g/hr. In addition, valproate decreased the rate of oxidized glutathione release into bile by 45% but had little effect on bile flow. In the presence of oleate (250 microM), valproate inhibited ketone body production by 46% and decreased NADH fluorescence by 39%. Rates of ketogenesis in periportal and pericentral regions of the liver lobule were calculated from changes in NADH fluorescence detected with micro-light guides during infusion of valproate in the presence and absence of fatty acids. In the absence of valproate, endogenous ketogenesis was about 35 mumol/g/hr in both regions of the liver lobule. In the presence of oleate, however, rates were significantly higher in pericentral regions (89 +/- 2 mumol/g/hr) than in periportal areas (71 +/- 3 mumol/g/hr). In the presence of added oleate, valproate decreased rates of ketogenesis to 34 +/- 4 mumol/g/hr in periportal regions and 51 +/- 3 mumol/g/hr in pericentral areas. We conclude, therefore, that fat accumulates in periportal areas because valproate depresses ketogenesis to a greater extent in hepatocytes localized around the portal triad.
D000818:Animals; D002374:Catalase / Q000378:metabolism; D005260:Female; D007657:Ketone Bodies / Q000096:biosynthesis; D007700:Kinetics; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D010477:Perfusion; D051381:Rats; D014635:Valproic Acid / Q000633:toxicity*
D007657:Ketone Bodies; D009243:NAD; D014635:Valproic Acid; D002374:Catalase