Title

Altered lipid metabolism in vitamin A deficient liver

Date of Completion

January 2006

Keywords

Biology, Molecular|Agriculture, Animal Culture and Nutrition|Health Sciences, Nutrition

Degree

Ph.D.

Abstract

Vitamin A deficiency leads to altered lipid metabolism in the liver. The expression pattern of metabolic genes in vitamin A-sufficient (VAS) versus vitamin A-deficient (VAD) liver was compared using a Mouse Genome Oligo Set Version 3.0 (Qiagen-Operon) 70mer-oligonucleotide array. Results from microarray analysis were analyzed using the GeneSpring bioinformatics program. The microarray results were further confirmed by real-time PCR. Mice were made vitamin A deficient by placing them on the modified AIN-93G diet without vitamin A on the tenth day of gestation. Both the differential expression of metabolic genes and the metabolic outcome of this differential expression were assessed. ^ In this study, vitamin A deficiency caused a decrease in expression of genes encoding enzymes involved in mitochondrial β-oxidation, including fatty acid ligase, medium-chain acyl-CoA dehydrogenase, 3,2-trans-enoyl-CoA isomerase and carnitine o-palmitoyl transferase I in the liver. A decrease in the mitochondrial β-oxidation pathway was supported by the decreased expression of the gene encoding an enzyme of the last step of the carnitine synthesis from lysine. We also found a decrease in expression of genes encoding enzymes of peroxisomal β-oxidation, including acyl-CoA oxidase, the bifunctional enzyme, thiolase, and carnitine o-octanoyl transferase and in bile acid synthesis, 2-methyl acyl-CoA racemase and bile acid CoA:amino acid N-acyltransferase. Consistent with the changes in gene expression above, the accumulation of triglycerides and total cholesterols in the VAD liver was confirmed by Oil-Red O staining and enzymatic methods. A metabolome analysis showed that vitamin A deficiency increased PUFA levels in triglycerides in the liver. PPARα is the likely mediator of the above differential expression of genes involved in lipid oxidation. In VAD liver, PPARα was decreased at both the mRNA level and protein levels. In vitamin A deficiency, the altered lipid metabolism we observed may be mediated by a decrease in PPARα the primary regulator of the genes encoding enzymes in fatty acid oxidation in the liver.^