Molecular mechanisms of alcoholic fatty liver: role of peroxisome proliferator-activated receptor alpha
Molecular mechanisms of alcoholic fatty liver: role of peroxisome proliferator-activated receptor alpha
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DOI：
10.1016/j.alcohol.2004.07.005
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发表时间：
2004-08-01
期刊：
影响因子：
2.3
通讯作者：
You, M
中科院分区：
文献类型：
--
作者：
Crabb, DW;Galli, A;You, M
过氧化物酶体增殖物激活受体α (ppar α)的正常功能对肝脏脂肪酸代谢的调节至关重要。脂肪酸作为pparα的配体，当脂肪酸水平升高时，pparα的激活会诱导一系列脂肪酸代谢酶，使脂肪酸水平恢复正常。肝脏脂肪酸水平在乙醇消耗期间增加。然而，体外实验结果表明，乙醇代谢抑制了ppar - α结合DNA和激活报告基因的能力。这一观察结果在小鼠身上得到了进一步的研究。4周的乙醇喂养C57BL/6J小鼠也通过阻断ppar介导的反应而损害肝脏脂肪酸分解代谢。乙醇饲养降低了肝核提取物中类视黄醇X受体α (rxrα)的水平以及ppar α /RXR结合其一致序列的能力，多个ppar α调控基因的m rna水平降低[长链酰基辅酶A （acyl- coa）脱氢酶和中链酰基辅酶脱氢酶]或无法诱导[酰基辅酶A脱氢酶，肝肉碱棕榈酰辅酶A转移酶1，极长链酰基辅酶A合成酶，非常长链酰基辅酶a脱氢酶)在乙醇喂养动物的肝脏。与这一发现相一致的是，在肝脏匀浆中测定，乙醇饲养不会诱导脂肪酸β -氧化率。在饲料中加入pparα激动剂wy14643，恢复了pparα /RXR的dna结合活性，诱导了几种pparα靶基因的mRNA水平，刺激了肝脏均质液中脂肪酸β氧化的速度，并预防了乙醇喂养动物的脂肪肝。在乙醇消耗过程中阻断ppar功能有助于酒精性脂肪肝的发展，这可以通过WY14,643来克服。(C) 2005爱思唯尔公司版权所有。
Normal function of the peroxisome proliferator-activated receptor alpha (PPARalpha) is crucial for the regulation of hepatic fatty acid metabolism. Fatty acids serve as ligands for PPARalpha, and when fatty acid levels increase, activation of PPARalpha induces a battery of fatty acid-metabolizing enzymes to restore fatty acid levels to normal. Hepatic fatty acid levels are increased during ethanol consumption. However, results of in vitro work showed that ethanol metabolism inhibited the ability of PPARalpha to bind DNA and activate reporter genes. This observation has been further studied in mice. Four weeks of ethanol feeding of C57BL/6J mice also impairs fatty acid catabolism in liver by blocking PPARalpha-mediated responses. Ethanol feeding decreased the level of retinoid X receptor alpha (RXRalpha) as well as the ability of PPARalpha/RXR in liver nuclear extracts to bind its consensus sequence, and the levels of m RNAs for several PPARalpha-regulated genes were reduced [long-chain acyl coenzyme A (acyl-CoA) dehydrogenase and medium-chain acyl-CoA dehydrogenase] or failed to be induced (acyl-CoA dehydrogenase, liver carnitine palmitoyl-CoA transferase 1, very long-chain acyl-CoA synthetase, very long-chain acyl-CoA dehydrogenase) in livers of the ethanol-fed animals. Consistent with this finding, ethanol feeding did not induce the rate of fatty acid beta-oxidation, as assayed in liver homogenates. Inclusion of WY14,643, a PPARalpha agonist, in the diet restored the DNA-binding activity of PPARalpha/RXR, induced mRNA levels of several PPARalpha target genes, stimulated the rate of fatty acid beta-oxidation in liver homogenates, and prevented fatty liver in ethanol-fed animals. Blockade of PPARalpha function during ethanol consumption contributes to the development of alcoholic fatty liver, which can be overcome by WY14,643. (C) 2005 Elsevier Inc. All rights reserved.