Abstract
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. —Rehnmark, S., C. S. Giometti, B. G. Slavin, M. H. Doolittle, and K. Reue. The fatty liver dystrophy mutant mouse: microvesicular steatosis associated with altered expression levels of peroxisome proliferator-regulated proteins. J. Lipid Res. 1998. 39: 2209–2217.
Highlights
Fatty liver dystrophy is an autosomal recessive mutation in mice characterized by hypertriglyceridemia and fatty liver during neonatal development
We determined that isolated neonatal hepatocytes grown in culture up to 4 days continue to exhibit characteristic features of the fatty liver phenotype, including cytoplasmic lipid droplets, elevated apoA-IV mRNA levels, and reduced hepatic lipase activity
This retention of the mutant phenotype in cultured fld hepatocytes suggests that the fatty liver develops as a result of an intrinsic defect and is not caused by the hypertriglyceridemia that persists during the neonatal period
Summary
Fatty liver dystrophy ( fld) is an autosomal recessive mutation in mice characterized by hypertriglyceridemia and fatty liver during neonatal development. 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.—Rehnmark, S., C. Triglyceride levels in liver and blood of fld mice spontaneously return to normal at the suckling/weaning transition at postnatal days 13–18 [3] This reversion coincides with the change from a diet that is rich in triglycerides (mother’s milk) to one that is low in fat and high in carbohydrates (mouse chow), two lines of evidence indicate that the resolution is a genetically programmed event, and not the result of a change in diet. This reversion coincides with the change from a diet that is rich in triglycerides (mother’s milk) to one that is low in fat and high in carbohydrates (mouse chow), two lines of evidence indicate that the resolution is a genetically programmed event, and not the result of a change in diet. 1) In fld mice fed mother’s milk for a prolonged period without weaning, the fatty liver returns to normal on the same schedule as in weaned mice; and 2) after weaning, feeding fld mice a triglyceride-rich diet fails to elicit a fatty liver or hypertriglyceridemia [3]
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