抄録
Dietary orotic acid is known to cause fatty liver in rodents. In order to elucidate the molecular mechanism of fatty liver induction by orotic acid, time course changes of the gene expression, clinical parameters and histopathology of the liver were investigated in rats administered sucrose-enriched diet containing 1% orotic acid for 2 weeks. The biochemical toxicity profile showed increases in aspartate aminotransferase and alanine aminotransferase, and decreases in total cholesterol, phospholipid, and triglycerides during the course of orotic acid administration. Microscopic findings of the liver showed time-dependent increase in fatty droplet and single cell necrosis of hepatocytes. The expression analysis of liver samples showed transcriptional alterations of the genes in functional classes assigned to cholesterol biosynthesis (down-regulated), fatty acid metabolism (down-regulated), and fatty acid biosynthesis (up-regulated), and secretion of cholesterol. Moreover, several genes, which were regulated by lipid-sensing nuclear receptors were also changed. These results suggested that the mechanism of fatty liver induction by orotic acid involved regulation of the nuclear receptors as well as the decreased cholesterol biosynthesis and cholesterol excretion into bile, and increased fatty acid biosynthesis.
