Olson M J, Handler J A, Thurman R G
Mol Pharmacol. 1986 Dec;30(6):520-5.
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.
通过给禁食大鼠皮下注射单剂量丙戊酸盐（500mg/kg），在肝小叶门周区域产生微泡性脂肪变性。在无外源性脂肪酸灌注的肝脏中，丙戊酸盐（500μM）使酮体（乙酰乙酸+β-羟基丁酸）生成量最大减少67%。与此同时，从肝脏表面检测到的NADH荧光下降约30%，其时间进程与酮体生成抑制相似。丙戊酸盐对氧摄取影响不大，但导致过氧化氢酶-H2O2稳态水平升高，对应H2O2生成量增加约6μmol/g/小时。此外，丙戊酸盐使氧化型谷胱甘肽释放到胆汁中的速率降低45%，但对胆汁流量影响不大。在油酸（250μM）存在的情况下，丙戊酸盐抑制酮体生成46%，并使NADH荧光降低39%。在有和没有脂肪酸存在的情况下，通过微型光导检测NADH荧光的变化，计算肝小叶门周和中央周围区域的酮体生成速率。在没有丙戊酸盐的情况下，肝小叶两个区域的内源性酮体生成约为35μmol/g/小时。然而，在油酸存在的情况下，中央周围区域的速率（89±2μmol/g/小时）显著高于门周区域（71±3μmol/g/小时）。在添加油酸的情况下，丙戊酸盐使门周区域的酮体生成速率降至34±4μmol/g/小时，中央周围区域降至51±3μmol/g/小时。因此，我们得出结论，脂肪在门周区域蓄积是因为丙戊酸盐在位于门静脉三联体周围的肝细胞中更大程度地抑制酮体生成。
