THE FATTY LIVER DYSTROPHY MUTANT MOUSE - MICROVESICULAR STEATOSIS ASSOCIATED WITH ALTERED EXPRESSION LEVELS OF PEROXISOME PROLIFERATOR-REGULATED PROTEINS

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 b etween the age of 14-18 days, at which point the animals develop a neu ropathy associated with abnormal myelin formation in peripheral nerve. We have investigated the morphological and biochemical alterations th at occur in the fatty liver of neonatal fld/fld mice, Studies at the l ight and electron microscopic level demonstrated the accumulation of l ipid droplets and hypertrophic parenchymal cells in fld neonates, with no apparent liver pathology after resolution of the fatty liver. To b etter characterize the biochemical basis for the development of fatty liver in fld mice, we compared protein expression patterns in the fatt y liver of fld mice and in the liver of phenotypically normal (wild-ty pe) 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 mitoc hondrial and peroxisomal enzymes involved in fatty acid oxidation, we quantitated rates of fatty acid oxidation in hepatocytes isolated from fld and wild-type mice.jlr 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 exhibi t 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.