PPARδ agonist attenuates alcohol-induced hepatic insulin resistance and improves liver injury and repair
PPARδ agonist attenuates alcohol-induced hepatic insulin resistance and improves liver injury and repair
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DOI：
10.1016/j.jhep.2009.01.021
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发表时间：
2009-06-01
影响因子：
25.7
通讯作者：
Wands, Jack R.
中科院分区：
文献类型：
--
作者：
Pang, Maoyin;de la Monte, Suzanne M.;Wands, Jack R.
背景/目的：慢性乙醇暴露通过抑制胰岛素信号和氧化损伤而损害肝脏再生。PPAR激动剂具有胰岛素增敏剂和抗炎剂的作用。我们研究了PPAR受体激动剂治疗是否可以恢复肝脏胰岛素敏感性、生存信号和相对于慢性乙醇喂养的再生反应。方法：用含0%或37%乙醇的等热量液体喂养成年大鼠，并通过腹腔注射PPAR受体激动剂。我们使用肝组织检查组织病理学、基因表达、氧化应激、胰岛素信号和2/3肝切除术后的再生反应。结果：慢性乙醇喂养可引起肝脏胰岛素抵抗、氧化应激、脂质过氧化、DNA损伤和肝细胞损伤。这些影响与胰岛素受体结合和亲和力降低、通过PI3KAkt/GSK3 β传递的存活信号受损以及介导能量代谢和组织重塑的胰岛素应答基因表达降低有关。PPAR δ受体激动剂治疗可减轻乙醇介导的肝损伤、氧化应激、脂质过氧化和胰岛素抵抗，增加PI3K/Akt/GSK3 β的信号传导，增强对部分肝切除术的再生反应。结论：即使在持续高水平乙醇消耗的情况下，施用PPAR受体激动剂也可能通过恢复胰岛素反应来减轻慢性乙醇诱导的肝损伤的严重程度和乙醇对肝脏修复的不良影响。(C) 2009年欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background/Aims: Chronic ethanol exposure impairs liver regeneration due to inhibition of insulin signaling and oxidative injury. PPAR agonists function as insulin sensitizers and anti-inflammatory agents. We investigated whether treatment with a PPAR delta agonist could restore hepatic insulin sensitivity, survival signaling, and regenerative responses vis-a-vis chronic ethanol feeding.Methods: Adult rats were fed isocaloric liquid diets containing 0% or 37% ethanol, and administered a PPAR delta agonist by i.p. injection. We used liver tissue to examine histopathology, gene expression, oxidative stress, insulin signaling, and regenerative responses to 2/3 hepatectomy.Results: Chronic ethanol feeding caused insulin resistance, increased oxidative stress, lipid peroxidation, DNA damage, and hepatocellular injury in liver. These effects were associated with reduced insulin receptor binding and affinity, impaired survival signaling through PI3KAkt/GSK3 beta, and reduced expression of insulin responsive genes mediating energy metabolism and tissue remodeling. PPAR delta agonist treatment reduced ethanol-mediated hepatic injury, oxidative stress, lipid peroxidation, and insulin resistance, increased signaling through PI3K/Akt/GSK3 beta, and enhanced the regenerative response to partial hepatectomy.Conclusions: PPAR delta agonist administration may attenuate the severity of chronic ethanol-induced liver injury and ethanol's adverse effects on the hepatic repair by restoring insulin responsiveness, even in the context of continued high-level ethanol consumption. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.