Evaluation of fatty acid metabolism-related gene expression in non-alcoholic fatty liver disease

非酒精性脂肪肝中脂肪酸代谢相关基因表达的评价

• 批准号: 17590658
• 负责人: NAKAMUTA Makoto
• 金额: $ 2.24万
• 依托单位: Kyushu Medical Center, National Hospital Organization (2006)Kyushu University (2005)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590658/
• 关键词: NAFLD; NASH; Fatty liver; Fatty acid metabolism; Oxidation; ROS; Insulin; AMPK; 脂肪酸合成; 脂肪酸酸化; ROS; SREBP1

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 … More 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

非酒精性脂肪性肝病（NAFLD）是肝功能异常的最常见原因之一，其患病率显着增加。我们先前评估了NAFLD中脂肪酸代谢相关基因的表达，并报道了可能导致NAFLD中脂肪酸合成增加的表达变化。在本研究中，我们评估了更多的脂肪酸代谢相关基因在NAFLD（n=26）和正常肝脏（n=10）样本中的表达。实时荧光定量PCR分析的靶基因为：乙酰辅酶A羧化酶（ACC）1、ACC 2、脂肪酸合成酶（FAS）、固醇调节元件结合蛋白1c（SREBP 1c）和脂肪分化相关蛋白（ADRP），用于评估脂肪酸的从头合成和摄取;肉毒碱棕榈酰转移酶la（CPT 1a）、长链酰基辅酶A脱氢酶（LCAD）、长链L-3-羟酰基辅酶A脱氢酶α（HADHα）、解偶联蛋白2（UCP 2）、直链酰基辅酶A ...更多信息 氧化酶（ACOX）、支链酰基辅酶A氧化酶（BOX）、细胞色素P450 2 E1（CYP 2 E1）、CYP 4A 11和过氧化物酶体增殖物激活受体（PPAR）α用于线粒体、过氧化物酶体和微粒体中的氧化;超氧化物歧化酶（SOD）、过氧化氢酶和谷胱甘肽合成酶（GSS）用于抗氧化途径;二酰基甘油O-酰基转移酶1（DGAT 1）、PPARγ和激素敏感脂肪酶（HSL）用于甘油三酯合成和催化。在NAFLD中，尽管脂肪酸在肝细胞中积累，但其从头合成和摄取与ACC 1、FAS、SREBP 1c和ADRP表达增加相关。脂肪酸氧化相关基因LCAD、HADHα、UCP 2、ACOX、BOX、CYP 2 E1和CYP 4A 11均过表达，表明NAFLD时氧化增强，而CTP 1a和PPARα表达降低。此外，SOD和过氧化氢酶也过表达，表明抗氧化途径被激活，以中和活性氧（ROS），这是在氧化过程中过度产生。DGAT 1的表达上调，而HSL的表达降低。我们的数据表明以下关于NAFLD：1）增加的从头合成和脂肪酸摄取导致肝细胞中脂肪酸的进一步积累。2)线粒体脂肪酸氧化减少或完全激活。3)为了补充线粒体（β-氧化）的功能，上调过氧化物酶体（β-氧化）和微粒体（ω-氧化）氧化以减少脂肪酸积累。4)抗氧化剂途径，包括SOD和过氧化氢酶增强，以中和在线粒体，过氧化物酶体和微粒体氧化过程中产生的ROS。5)由于DGAT表达增加和HSL表达减少，脂滴形成增强。需要进一步的研究来阐明SREBP 1c如何增加脂肪酸合成，SREBP 1c受胰岛素和AMP激活的蛋白激酶的控制。少

项目成果

NAFLDにおける脂肪酸代謝 別冊・医学のあゆみ NAFLDのすべて (西原利治 編)

NAFLD 中的脂肪酸代谢 分册：医学史 关于 NAFLD 的一切（西原俊晴主编）

• 发表时间: 2006
• 作者: 西原利治;大西三朗;中牟田 誠
• 通讯作者: 中牟田 誠

インスリン抵抗性とメタボリックシンドローム

胰岛素抵抗和代谢综合征

• 发表时间: 2008
• 作者: 窪田直人;他
• 通讯作者: 他

NAFLDにおける脂肪酸代謝 別冊・医学のあゆみ NAFLDのすべて (西原利治編)

NAFLD 中的脂肪酸代谢 分册：医学史 关于 NAFLD 的一切（西原俊晴主编）

• 发表时间: 2006
• 作者: 西原利治;大西三朗;Isse K et al.;日浅陽一;中牟田 誠
• 通讯作者: 中牟田 誠

Evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease.

• 发表时间: 2005
• 期刊: International journal of molecular medicine
• 影响因子: 5.4
• 作者: M. Nakamuta;M. Kohjima;S. Morizono;K. Kotoh;Tsuyoshi Yoshimoto;Izuru Miyagi;M. Enjoji

NAFLDのすべて

关于 NAFLD 的一切

• 发表时间: 2006
• 作者: 西原利治;大西三朗
• 通讯作者: 大西三朗