Thursday, November 21, 2024
11/21/2024
Mitochondrial trifunctional protein (TFP) catalyzes the last 3 steps in the beta-oxidation spiral of long chain fatty acids and consists of 4 alpha and 4 beta subunits. Long chain 3- hydroxyacyl Co-A dehydrogenase (LCHAD) resides in the alpha- subunit. Mutations in the alpha-subunit such as the prevalent G1528C mutation cause "isolated" LCHAD deficiency. Other mutations cause complete TFP deficiency (all the 3 enzymes are deficient). Recently, we have documented a fetal-maternal interaction that causes maternal liver disease in heterozygote women who carry fetuses with isolated LCHAD deficiency. This raises several questions. First, what is the mechanism of this fetal-maternal interaction? Second, what is the effect of environmental factors such as high fat diet and fasting on the development of maternal liver disease in the susceptible heterozygotes? Our hypothesis is that heterozygote women develop acute fatty liver of pregnancy (AFLP) or HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome due to accumulation of hepato-toxic fatty acid metabolites generated by either the affected fetus or the susceptible heterozygote under conditions of oxidative stress. To test this hypothesis we propose the following studies. 1) To use conventional and inducible Cre/lox P strategies to generate and characterize two knockout mice models for complete TFP deficiency (null mutation) and isolated LCHAD deficiency (G1528C mutation). Clinical, biochemical, histological, and molecular analyses will be performed. Tissue-specific and developmental stage-specific gene expression will also be characterized in these mice. Differences in the accumulated fatty acid metabolites will be correlated to the genotypes and phenotypes to elucidate the role of fatty acid metabolites in the genotype-phenotype correlations in these disorders. 2) To employ preimplantation genotyping and embryo transfer to independently study the effects of fetal and maternal genotypes on development of maternal liver disease in knockout mice. Pregnant dams will be monitored for evidence of liver disease. Fatty acid metabolites will be measured in fetal and maternal sera, fetal and maternal livers, and placentas, and will be correlated to the fetal/maternal genotypes and maternal phenotypes to identify the fatty acid metabolites that are potentially toxic to the maternal liver. 3) To conduct dietary studies in knockout mice to elucidate the effects of high fat diet and fasting on pregnant heterozygotes while carrying unaffected fetuses. Four different high fat diets will be studied to elucidate the effects of fat content, fatty acid configuration, and protein/carbohydrate contents.
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