The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor α is inhibited by ethanol metabolism -: A novel mechanism for the development of ethanol-induced fatty liver
The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor α is inhibited by ethanol metabolism -: A novel mechanism for the development of ethanol-induced fatty liver
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DOI：
10.1074/jbc.m008791200
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发表时间：
2001-01-05
影响因子：
4.8
通讯作者：
Crabb, DW
中科院分区：
文献类型：
--
作者：
Galli, A;Pinaire, J;Crabb, DW
脂肪酸是过氧化物酶体增殖物激活受体 a (PPAR α) 的配体。在乙醇代谢过程中，肝脏中的脂肪酸水平会增加，并且可能会激活 PPAR α。然而，在表达酒精代谢酶的 H4IIEC3 肝癌细胞中，乙醇抑制了报告基因 PPAR α 的激活，但在缺乏这些酶的 CV-1 细胞中则不然。乙醇还降低了 PPAR α 配体 WY14,643 激活肝癌细胞或培养的大鼠肝细胞中报告构建体的能力。乙醇的这种作用被乙醇脱氢酶抑制剂 4-甲基吡唑消除，并被乙醛脱氢酶抑制剂氰胺增强，表明乙醛是乙醇作用的原因。从暴露于乙醇或乙醛的肝癌细胞中提取的 PPAR α/类视黄醇 X 受体与含有过氧化物酶体增殖物反应元件的寡核苷酸的结合较差。这种作用也被 4-甲基吡唑阻断并被氰胺增强。此外，体外翻译的 PPAR α 暴露于乙醛后无法结合 DNA。因此，乙醇代谢阻断 PPARa 的转录激活，部分原因是其结合 DNA 的能力受损。乙醇的这种作用可能会促进酒精性脂肪肝和酒精滥用的其他肝脏后果的发展。
Fatty acids are ligands for the peroxisome proliferator-activated receptor a (PPAR alpha). Fatty acid levels are increased in liver during the metabolism of ethanol and might be expected to activate PPAR alpha. However, ethanol inhibited PPAR alpha activation of a reporter gene in H4IIEC3 hepatoma cells expressing alcohol-metabolizing enzymes but not in CV-1 cells, which lack these enzymes. Ethanol also reduced the ability of the PPAR alpha ligand WY14,643 to activate reporter constructs in the hepatoma cells or cultured rat hepatocytes, This effect of ethanol was abolished by the alcohol dehydrogenase inhibitor 4-methylpyrazole and augmented by the aldehyde dehydrogenase inhibitor cyanamide, indicating that acetaldehyde was responsible for the action of ethanol. PPAR alpha /retinoid X receptor extracted from hepatoma cells exposed to ethanol or acetaldehyde bound poorly to an oligonucleotide containing peroxisome proliferator response elements. This effect was also blocked by 4-methylpyrazole and augmented by cyanamide. Furthermore, in vitro translated PPAR alpha exposed to acetaldehyde failed to bind DNA. Thus, ethanol metabolism blocks transcriptional activation by PPARa, in part due to impairment of its ability to bind DNA. This effect of ethanol may promote the development of alcoholic fatty liver and other hepatic consequences of alcohol abuse.