| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of abnormal liver dysfunction and its prevalence has markedly increased. We previously evaluated the expression of fatty acid metabolism-related genes in NAFLD and reported changes in expression that could contribute to increased fatty acid synthesis in NAFLD. In the present study, we evaluated the expression of additional fatty acid metabolism-related genes in larger groups of NAFLD (n=26) and normal liver (n=10) samples. The target genes for real-time PCR analysis were as follows: acetyl-CoA carboxylase (ACC) 1, ACC2, fatty acid synthase (FAS), sterol regulatory element-binding protein lc (SREBP1c), and adipose differentiation-related protein (ADRP) for evaluation of de novo synthesis and uptake of fatty acids; carnitine palmitoyltransferase la (CPT1a), long-chain acyl-CoA dehydrogenase (LCAD), long-chain L-3-hydroxyacyl-coenzyme A dehydrogenase α (HADHα), uncoupling protein 2 (UCP2), straight-chain acyl-CoA
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oxidase (ACOX), branched-chain acyl-CoA oxidase (BOX), cytochrome P450 2E1 (CYP2E1), CYP4A11, and peroxisome proliferator-activated receptor (PPAR) α for oxidation in the mitochondria, peroxisome and microsome; superoxide dismutase (SOD), catalase, and glutathione synthetase (GSS) for antioxidant pathways; diacylglycerol O-acyltransferase 1 (DGAT1), PPARγ, and hormone sensitive lipase (HSL) for triglyceride synthesis and catalysis. In NAFLD, although fatty acids accumulated in hepatocytes, their de novo synthesis and uptake were up-regulated in association with increased expression of ACC1, FAS, SREBP1c, and ADRP. Fatty acids oxidation-related genes, LCAD, HADHα, UCP2, ACOX, BOX, CYP2E1, and CYP4A11, were all over-expressed, indicating that oxidation was enhanced in NAFLD, whereas the expression of CTP1a and PPARα was decreased. Furthermore, SOD and catalase were also over-expressed, indicating that antioxidant pathways are activated to neutralize reactive oxygen species (ROS), which are overproduced during oxidative processes. The expression of DGAT1 was upregulated without increased PPARγ expression, whereas the expression of HSL was decreased. Our data indicated the following regarding NAFLD : 1) Increased de novo synthesis and uptake of fatty acids lead to further fatty acid accumulation in hepatocytes. 2) Mitochondrial fatty acid oxidation is decreased or fully activated. 3) In order to complement the function of mitochondria (β-oxidation), peroxisomal (β-oxidation) and microsomal (ω-oxidation) oxidation was up-regulated to decrease fatty acid accumulation. 4) Antioxidant pathways including SOD and catalase were enhanced to neutralize ROS overproduced during mitochondria, peroxisomal, and microsomal oxidation. 5) Lipid droplet formation was enhanced due to increased DGAT expression and decreased HSL expression. Further studies will be needed to clarify how fatty acid synthesis is increased by SREBP1c, which is under the control of insulin and AMP-activated protein kinase. Less
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