PPAR/RXR Regulation of Fatty Acid Metabolism and Fatty Acid omega-Hydroxylase (CYP4) Isozymes: Implications for Prevention of Lipotoxicity in Fatty Liver Disease.
PPAR/RXR Regulation of Fatty Acid Metabolism and Fatty Acid omega-Hydroxylase (CYP4) Isozymes: Implications for Prevention of Lipotoxicity in Fatty Liver Disease.
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DOI：
10.1155/2009/952734
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发表时间：
2009
期刊：
影响因子：
2.9
通讯作者：
Song BJ
中科院分区：
文献类型：
--
作者：
Hardwick JP;Osei-Hyiaman D;Wiland H;Abdelmegeed MA;Song BJ
脂肪肝是一种常见的脂质代谢紊乱，受个体遗传组成、药物暴露和生活方式选择的影响，这些因素通常与代谢综合征相关，包括肥胖、血脂异常、高血压、高脂血症和胰岛素抵抗性糖尿病。与肥胖相关的血脂异常常见的是肝脂肪酸的过度储存（脂肪变性），这是由于线粒体β-氧化减少，过氧化物酶体β-氧化和微粒体ω-氧化通过过氧化物酶体增殖物激活受体（PPARs）的脂肪酸增加。脂肪变性如何增加脂肪酸转运蛋白、过氧化物酶体和线粒体脂肪酸β-氧化和脂肪酸ω-氧化的PPARα激活基因表达，无论膳食脂肪酸是多不饱和（PUFA）、单不饱和（MUFA）还是饱和（SFA），都可以通过PPAR和HNF 4 α与脂肪酸转运蛋白L-FABP和ACBP的相互作用来确定。在肝脂肪变性和脂肪性肝炎中，ω-氧化细胞色素P450 CYP 4A基因表达增加，即使肝脏PPARα水平降低。尽管许多研究表明乙醇诱导的CYP 2 E1在促进氧化应激增加中的作用，但Cyp 2 e1缺失小鼠仍然发生脂肪性肝炎，CYP 4A基因表达显著增加。提示CYP 4A脂肪酸ω-羟化酶P450在脂肪性肝炎的发生发展中起重要作用。在这篇综述和教程中，我们简要描述了脂肪酸是如何通过脂肪酸转运蛋白分配到由PPARs调节的合成代谢或分解代谢途径的，我们探讨了中链脂肪酸（MCFA）CYP 4A和长链脂肪酸（LCFA）CYP 4F ω-羟化酶基因在脂肪肝中的调节。最后，我们提出一个假设，增加CYP 4A的表达，减少CYP 4F基因可能会促进脂肪变性的进展，脂肪性肝炎。
Fatty liver disease is a common lipid metabolism disorder influenced by the combination of individual genetic makeup, drug exposure, and life-style choices that are frequently associated with metabolic syndrome, which encompasses obesity, dyslipidemia, hypertension, hypertriglyceridemia, and insulin resistant diabetes. Common to obesity related dyslipidemia is the excessive storage of hepatic fatty acids (steatosis), due to a decrease in mitochondria β-oxidation with an increase in both peroxisomal β-oxidation, and microsomal ω-oxidation of fatty acids through peroxisome proliferator activated receptors (PPARs). How steatosis increases PPARα activated gene expression of fatty acid transport proteins, peroxisomal and mitochondrial fatty acid β-oxidation and ω-oxidation of fatty acids genes regardless of whether dietary fatty acids are polyunsaturated (PUFA), monounsaturated (MUFA), or saturated (SFA) may be determined by the interplay of PPARs and HNF4α with the fatty acid transport proteins L-FABP and ACBP. In hepatic steatosis and steatohepatitis, the ω-oxidation cytochrome P450 CYP4A gene expression is increased even with reduced hepatic levels of PPARα. Although numerous studies have suggested the role ethanol-inducible CYP2E1 in contributing to increased oxidative stress, Cyp2e1-null mice still develop steatohepatitis with a dramatic increase in CYP4A gene expression. This strongly implies that CYP4A fatty acid ω-hydroxylase P450s may play an important role in the development of steatohepatitis. In this review and tutorial, we briefly describe how fatty acids are partitioned by fatty acid transport proteins to either anabolic or catabolic pathways regulated by PPARs, and we explore how medium-chain fatty acid (MCFA) CYP4A and long-chain fatty acid (LCFA) CYP4F ω-hydroxylase genes are regulated in fatty liver. We finally propose a hypothesis that increased CYP4A expression with a decrease in CYP4F genes may promote the progression of steatosis to steatohepatitis.
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影响因子：
29.4
作者：
Day, CP
通讯作者：
Day, CP
影响因子：
4.8
作者：
Améen, C;Edvardsson, U;Oscarsson, J
通讯作者：
Oscarsson, J
影响因子：
4.8
作者：
Bell, LC;Guengerich, FP
通讯作者：
Guengerich, FP
影响因子：
7.4
作者：
Abdelmegeed, Mohamed A.;Moon, Kwan-Hoon;Hardwick, James P.;Gonzalez, Frank J.;Song, Byoung-Joon
通讯作者：
Song, Byoung-Joon
影响因子：
5.2
作者：
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Wijmenga, Cisca