Effect of Polyphenols on 3-Hydroxy-3-methylglutaryl-Coenzyme A Lyase Activity in Human Hepatoma HepG2 Cell Extracts
Effect of Polyphenols on 3-Hydroxy-3-methylglutaryl-Coenzyme A Lyase Activity in Human Hepatoma HepG2 Cell Extracts
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DOI：
10.1248/bpb.b13-00334
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发表时间：
2013-12-01
影响因子：
2
通讯作者：
Yamato, Susumu
中科院分区：
文献类型：
--
作者：
Nakagawa, Saori;Kojima, Yuko;Yamato, Susumu
当碳水化合物代谢受损时，脂肪酸代谢被激活。过量的乙酰辅酶A（CoA）由脂肪酸通过β-氧化产生，用于形成3-羟基-3-甲基戊二酰辅酶A（HMG-CoA），随后用于乙酰乙酸。高水平的分泌酮体（乙酰乙酸和3 β-羟基丁酸）降低血液和尿液的pH值，导致酮症酸中毒。肝细胞中的HMG-CoA裂解酶是催化HMG-CoA裂解为乙酰乙酸的限速酶，因此抑制该酶导致乙酰乙酸产生减少，换句话说，酮症酸中毒受损。抑制HMG-CoA裂解酶活性可能预防酮症酸中毒，应作为治疗靶点。多酚类化合物是一种常见的、丰富的膳食成分，对人体健康有着重要的作用。我们研究了膳食多酚对人肝癌HepG 2细胞提取物中HMG-CoA裂解酶活性的抑制作用。在所测试的9种代表性膳食多酚中，（-）-表没食子儿茶素（EGC）、（-）-表没食子儿茶素没食子酸酯（EGCG）和没食子酸（GA）有效地抑制HMG-CoA裂解酶活性。Lineweaver-Burk分析表明，EGC和EGCG可能是混合型非竞争性抑制剂。具有没食子酰基结构的连苯三酚也抑制HMG-CoA裂解酶活性，表明多酚的没食子酰基部分对于HMG-CoA裂解酶活性的抑制是重要的。
When carbohydrate metabolism is impaired, fatty acid metabolism is activated. Excess acetyl-coenzyme A (CoA) is generated from fatty acids by beta-oxidation and is used for the formation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) and subsequently for acetoacetate. High levels of secreted ketone bodies (acetoacetate and 3 beta-hydroxybutyrate) lower the pH of blood and urine, resulting in ketoacidosis. HMG-CoA lyase in hepatic cells is a rate-limiting enzyme catalyzing the cleavage of HMG-CoA to acetoacetate, and thus inhibition of this enzyme results in reduced acetoacetate production, in other words, impaired ketoacidosis. Inhibition of HMG-CoA lyase activity possibly prevents ketoacidosis and should be the therapeutic target. Polyphenols are common and abundant dietary constituents with beneficial effects on human health. We examined the inhibitory effects of dietary polyphenols on HMG-CoA lyase activity in cellular extracts of human hepatoma HepG2 cells. Of the nine representative dietary polyphenols tested, (-)-epigallocatechin (EGC), (-)-epigallocatechin gallate (EGCG), and gallic acid (GA) effectively inhibited HMG-CoA lyase activity. Lineweaver-Burk analysis revealed that EGC and EGCG are likely to be mixed-type noncompetitive inhibitors. Pyrogallol with the gallyl structure also inhibited HMG-CoA lyase activity, suggesting that the gallyl moiety of polyphenols is important for the inhibition of HMG-CoA lyase activity.