Restoration of Wnt/β-catenin signaling attenuates alcoholic liver disease progression in a rat model.
Restoration of Wnt/β-catenin signaling attenuates alcoholic liver disease progression in a rat model.
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DOI：
10.1016/j.jhep.2015.02.030
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发表时间：
2015-07
影响因子：
25.7
通讯作者：
Kim, Miran
中科院分区：
文献类型：
--
作者：
Huang, Chiung-Kuei;Yu, Tunan;de la Monte, Suzanne M.;Wands, Jack R.;Derdak, Zoltan;Kim, Miran
酒精性肝病（ALD）以脂肪肝、酒精性肝炎、纤维化和肝硬化为特征。然而，与进展相关的潜在机制仍然难以捉摸。由于对肝细胞的促凋亡作用，促炎性细胞因子与ALD的进展有关。Wnt/β-catenin信号通路最近已被证明可促进炎症和细胞凋亡，这表明该信号通路的激活可能调节ALD的进展。目前的研究旨在测试Wnt/β-catenin信号的药理激活是否会改变大鼠ALD模型的发生和进展。成年雄性Long Evans大鼠分别饲喂含0%或37%乙醇的等热量液体饲料8周，并在喂养方案的最后3周给予Wnt激动剂。肝脏和血液样本进行组织学检查、TUNEL分析、免疫印迹分析、实时定量PCR和丙氨酸转氨酶（ALT）检测。Wnt/β-catenin信号传导与ALD大鼠Foxo3A表达负相关，减少脂肪变性、细胞损伤和凋亡。突变实验表明，Foxo3A对调节这些效应至关重要。激活Wnt/β-catenin信号通过上调血清/糖皮质激素调节激酶1 （SGK1）抑制foxo3诱导的细胞凋亡。此外，Wnt/β-catenin信号的药理恢复可以减少ALD在体内的进展。Wnt/β-catenin信号通过拮抗foxo3a诱导的凋亡在ALD进展中发挥保护作用，激活Wnt/β-catenin信号级联可减弱ALD进展。
Alcoholic liver disease (ALD) is characterized by the development of fatty liver, alcoholic hepatitis, fibrosis and cirrhosis. However, the underlying mechanism(s) associated with progression remains elusive. Pro-inflammatory cytokines have been implicated in ALD progression due to pro-apoptotic effects on hepatocytes. Wnt/β-catenin signaling recently has been shown to promote inflammation and apoptosis, suggesting that activation of this signaling pathway may modulate ALD progression. The current study was designed to test whether pharmacological activation of Wnt/β-catenin signaling altered ALD development and progression in a rat model. Adult male Long Evans rats were fed with isocaloric liquid diets containing 0% or 37% ethanol for 8 weeks, and also treated with Wnt agonist during the last 3 weeks of the feeding regimen. Liver and blood samples were subjected to histology, TUNEL assay, immunoblot analysis, real-time quantitative PCR, and alanine transaminase (ALT) assay. Wnt/β-catenin signaling was negatively correlated with Foxo3A expression and reduced steatosis, cellular injury and apoptosis in ALD rats. Mutation experiments demonstrated that Foxo3A was critical for modulating these effects. Activation of Wnt/β-catenin signaling suppressed Foxo3Ainduced apoptosis through up-regulation of serum/glucocorticoid regulated kinase 1 (SGK1). Moreover, pharmacological restoration of Wnt/β-catenin signaling reduced ALD progression in vivo. Wnt/β-catenin signaling plays a protective role in ALD progression via antagonizing Foxo3A-induced apoptosis and activation of the Wnt/β-catenin signaling cascade attenuates ALD progression.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
25.7
作者：
Derdak Z;Lang CH;Villegas KA;Tong M;Mark NM;de la Monte SM;Wands JR
通讯作者：
Wands JR
DOI：
10.1002/hep.24517
发表时间：
2011-09-02
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Miller AM;Wang H;Bertola A;Park O;Horiguchi N;Ki SH;Yin S;Lafdil F;Gao B
通讯作者：
Gao B
影响因子：
25.7
作者：
Pang, Maoyin;de la Monte, Suzanne M.;Wands, Jack R.
通讯作者：
Wands, Jack R.
影响因子：
158.5
作者：
Keane, J;Gershon, S;Braun, MM
通讯作者：
Braun, MM