Insulin resistance, ceramide accumulation, and endoplasmic reticulum stress in human chronic alcohol-related liver disease.
Insulin resistance, ceramide accumulation, and endoplasmic reticulum stress in human chronic alcohol-related liver disease.
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人类慢性酒精相关肝病中的胰岛素抵抗，神经酰胺的积累和内质网应激。
DOI：
10.1155/2012/479348
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发表时间：
2012
影响因子：
--
通讯作者：
de la Monte SM
中科院分区：
文献类型：
--
作者：
Longato L;Ripp K;Setshedi M;Dostalek M;Akhlaghi F;Branda M;Wands JR;de la Monte SM
背景资料。慢性酒精相关性肝病(ALD)是由胰岛素抵抗、线粒体功能障碍、炎症、氧化应激和DNA损伤等因素引起的。最近的研究表明，脂代谢紊乱和神经酰胺的堆积，再加上内质网应激，加强了肝脏的胰岛素抵抗，并可能导致脂肪性肝炎的进展。目标。我们研究了晚期人类ALD患者的肝脏胰岛素抵抗与内质网应激、脂代谢紊乱和神经酰胺堆积的相关程度。方法：研究方法。我们评估了通过Akt途径的胰岛素信号的完整性，并测量了肝组织中丙酮胺和内质网应激基因的表达、内质网应激信号蛋白和神经酰胺谱。结果。与对照组相比，慢性ALD患者胰岛素、IGF-1和IGF-2受体表达增加，IGF-1R和IRS1信号转导受损，多种前胶原和内质网应激基因和蛋白表达增加，C14、C16、C18和C20神经酰胺水平升高。结论。在人类慢性ALD中，持续性的肝脏胰岛素抵抗与脂代谢紊乱、神经酰胺堆积和多个ER应激信号分子的显著上调有关。鉴于神经酰胺作为内质网应激和胰岛素抵抗的媒介，神经酰胺酶抑制剂的治疗可能有助于逆转或阻止慢性ALD的进展。
Background. Chronic alcohol-related liver disease (ALD) is mediated by insulin resistance, mitochondrial dysfunction, inflammation, oxidative stress, and DNA damage. Recent studies suggest that dysregulated lipid metabolism with accumulation of ceramides, together with ER stress potentiate hepatic insulin resistance and may cause steatohepatitis to progress. Objective. We examined the degree to which hepatic insulin resistance in advanced human ALD is correlated with ER stress, dysregulated lipid metabolism, and ceramide accumulation. Methods. We assessed the integrity of insulin signaling through the Akt pathway and measured proceramide and ER stress gene expression, ER stress signaling proteins, and ceramide profiles in liver tissue. Results. Chronic ALD was associated with increased expression of insulin, IGF-1, and IGF-2 receptors, impaired signaling through IGF-1R and IRS1, increased expression of multiple proceramide and ER stress genes and proteins, and higher levels of the C14, C16, C18, and C20 ceramide species relative to control. Conclusions. In human chronic ALD, persistent hepatic insulin resistance is associated with dysregulated lipid metabolism, ceramide accumulation, and striking upregulation of multiple ER stress signaling molecules. Given the role of ceramides as mediators of ER stress and insulin resistance, treatment with ceramide enzyme inhibitors may help reverse or halt progression of chronic ALD.
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DOI：
10.1111/j.1530-0277.2000.tb04575.x
发表时间：
2000-10-01
影响因子：
3.2
作者：
Deaciuc, IV;Nikolova-Karakashian, M;McClain, CJ
通讯作者：
McClain, CJ
影响因子：
4
作者：
de la Monte, Suzanne M.;Tong, Ming;Wands, Jack R.
通讯作者：
Wands, Jack R.
影响因子：
50.3
作者：
Carracedo, A;Lorente, M;Velasco, G
通讯作者：
Velasco, G
影响因子：
4.1
作者：
Boslem, Ebru;MacIntosh, Gemma;Biden, Trevor J.
通讯作者：
Biden, Trevor J.
DOI：
10.1111/j.1440-1746.2008.05339.x
发表时间：
2008-08-01
影响因子：
4.1
作者：
de la Monte, Suzanne M.;Yeon, Jong-Eun;Wands, Jack R.
通讯作者：
Wands, Jack R.