Rehnmark S, Giometti C S, Slavin B G, Doolittle M H, Reue K
Lipid Research Laboratory, West Los Angeles VA Medical Center and Department of Medicine, University of California, Los Angeles, CA 90073, USA.
J Lipid Res. 1998 Nov;39(11):2209-17.
Fatty liver dystrophy ( fld) is an autosomal recessive mutation in mice characterized by hypertriglyceridemia and fatty liver during neonatal development. The fatty liver in fld/fld mice spontaneously resolves between the age of 14-18 days, at which point the animals develop a neuropathy associated with abnormal myelin formation in peripheral nerve. We have investigated the morphological and biochemical alterations that occur in the fatty liver of neonatal fld/fld mice. Studies at the light and electron microscopic level demonstrated the accumulation of lipid droplets and hypertrophic parenchymal cells in fld neonates, with no apparent liver pathology after resolution of the fatty liver. To better characterize the biochemical basis for the development of fatty liver in fld mice, we compared protein expression patterns in the fatty liver of fld mice and in the liver of phenotypically normal (wild-type) littermates using quantitative two-dimensional gel electrophoresis. We detected 24 proteins with significantly altered expression levels (P < 0.001) in the fld fatty liver, 15 of which are proteins that are altered in abundance by peroxisome proliferating chemicals. As these compounds characteristically elicit changes in the expression of mitochondrial and peroxisomal enzymes involved in fatty acid oxidation, we quantitated rates of fatty acid oxidation in hepatocytes isolated from fld and wild-type mice. These studies revealed that hepatic fatty acid oxidation in fld neonates is reduced by 60% compared to wild-type littermates. In hepatocytes from adult fld mice that no longer exhibit a fatty liver, oxidation rates were similar to those in hepatocytes from age-matched wild-type mice. These findings indicate that altered expression of proteins involved in fatty acid oxidation is associated with triglyceride accumulation in the fld fatty liver.
脂肪肝营养不良（fld）是小鼠中的一种常染色体隐性突变，其特征为新生发育期间的高甘油三酯血症和脂肪肝。fld/fld小鼠的脂肪肝在14至18日龄之间自发消退，此时动物会出现与外周神经髓鞘形成异常相关的神经病变。我们研究了新生fld/fld小鼠脂肪肝中发生的形态学和生化改变。光镜和电镜水平的研究表明，fld新生小鼠中存在脂滴积累和实质细胞肥大，脂肪肝消退后无明显肝脏病理变化。为了更好地表征fld小鼠脂肪肝发生的生化基础，我们使用定量二维凝胶电泳比较了fld小鼠脂肪肝和表型正常（野生型）同窝小鼠肝脏中的蛋白质表达模式。我们在fld脂肪肝中检测到24种表达水平有显著改变的蛋白质（P < 0.001），其中15种蛋白质的丰度因过氧化物酶体增殖化学物质而改变。由于这些化合物通常会引起参与脂肪酸氧化的线粒体和过氧化物酶体酶表达的变化，我们对从fld和野生型小鼠分离的肝细胞中的脂肪酸氧化速率进行了定量。这些研究表明，与野生型同窝小鼠相比，fld新生小鼠的肝脏脂肪酸氧化减少了60%。在不再表现出脂肪肝的成年fld小鼠的肝细胞中，氧化速率与年龄匹配的野生型小鼠肝细胞中的氧化速率相似。这些发现表明，参与脂肪酸氧化的蛋白质表达改变与fld脂肪肝中的甘油三酯积累有关。
