The adipokine adiponectin has potent anti-fibrotic effects mediated via adenosine monophosphate-activated protein kinase: novel target for fibrosis therapy.
The adipokine adiponectin has potent anti-fibrotic effects mediated via adenosine monophosphate-activated protein kinase: novel target for fibrosis therapy.
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DOI：
10.1186/ar4070
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发表时间：
2012-10-23
影响因子：
4.9
通讯作者：
Varga J
中科院分区：
文献类型：
--
作者：
Fang F;Liu L;Yang Y;Tamaki Z;Wei J;Marangoni RG;Bhattacharyya S;Summer RS;Ye B;Varga J
硬皮病的纤维化与胶原沉积和肌成纤维细胞积聚有关。过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体γ，过氧化物酶体增殖物激活受体脂联素是一种受PPAR-γ调节的多效性脂肪因子，其在调节成纤维细胞反应和介导PPAR-γ效应中的作用尚不清楚。在单层培养的正常成纤维细胞和三维皮肤等效物中，研究了脂联素和腺苷一磷酸蛋白激活（AMP）激酶激动剂对纤维化基因表达和TGF-β信号传导的调节。实时定量PCR检测皮肤成纤维细胞AdipoR 1/2的表达。脂联素是一种受PPAR-γ直接调节的脂肪因子，在正常和硬皮病成纤维细胞中作为一种有效的抗纤维化信号，可消除各种纤维化刺激的刺激作用，并降低硬皮病成纤维细胞中升高的胶原基因表达。脂联素反应通过AMP激酶介导，AMP激酶是一种燃料敏感细胞酶，其通过阻断经典Smad信号传导而对于下调纤维化基因是必要且充分的。此外，我们证明，内源性脂联素帐户，至少部分地，由过氧化物酶体增殖物激活受体-γ的配体发挥的抗纤维化作用。这些发现揭示了细胞能量代谢和细胞外基质稳态之间的新联系，集中在AMP激酶上。由于脂联素及其受体的水平在硬皮病患者进行性纤维化中受损，因此本研究结果表明脂联素表达或功能缺陷在硬皮病和其他慢性纤维化疾病中的进行性纤维化中具有潜在作用。因此，在成纤维细胞中恢复脂联素信号传导轴可能代表了一种新的控制纤维化的药理学方法。
Fibrosis in scleroderma is associated with collagen deposition and myofibroblast accumulation. Peroxisome proliferator activated receptor gamma (PPAR-γ), a master regulator of adipogenesis, inhibits profibrotic responses induced by transforming growth factor-ß (TGF-β), and its expression is impaired in scleroderma. The roles of adiponectin, a PPAR-γ regulated pleiotropic adipokine, in regulating the response of fibroblasts and in mediating the effects of PPAR-γ are unknown. Regulation of fibrotic gene expression and TGF-ß signaling by adiponectin and adenosine monophosphate protein-activated (AMP) kinase agonists were examined in normal fibroblasts in monolayer cultures and in three-dimensional skin equivalents. AdipoR1/2 expression on skin fibroblasts was determined by real-time quantitative PCR. Adiponectin, an adipokine directly regulated by PPAR-γ, acts as a potent anti-fibrotic signal in normal and scleroderma fibroblasts that abrogates the stimulatory effects of diverse fibrotic stimuli and reduces elevated collagen gene expression in scleroderma fibroblasts. Adiponectin responses are mediated via AMP kinase, a fuel-sensing cellular enzyme that is necessary and sufficient for down-regulation of fibrotic genes by blocking canonical Smad signaling. Moreover, we demonstrate that endogenous adiponectin accounts, at least in part, for the anti-fibrotic effects exerted by ligands of PPAR-γ. These findings reveal a novel link between cellular energy metabolism and extracellular matrix homeostasis converging on AMP kinase. Since the levels of adiponectin as well as its receptor are impaired in scleroderma patients with progressive fibrosis, the present results suggest a potential role for defective adiponectin expression or function in progressive fibrogenesis in scleroderma and other chronic fibrosing conditions. Restoring the adiponectin signaling axis in fibroblasts might, therefore, represent a novel pharmacological approach to controlling fibrosis.
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影响因子：
7.7
作者：
Iwaki, M;Matsuda, M;Shimomura, I
通讯作者：
Shimomura, I
影响因子：
--
作者：
Ghosh, AK;Bhattacharyya, S;Varga, J
通讯作者：
Varga, J
影响因子：
3.6
作者：
Arakawa, Hiroki;Jinnin, Masatoshi;Ihn, Hironobu
通讯作者：
Ihn, Hironobu
硬皮病皮肤的基因表达特征中的分子亚群。
影响因子：
3.7
作者：
Milano A;Pendergrass SA;Sargent JL;George LK;McCalmont TH;Connolly MK;Whitfield ML
通讯作者：
Whitfield ML
影响因子：
5.1
作者：
Nakanishi-Minami, Tomoko;Kishida, Ken;Shimomura, Iichiro
通讯作者：
Shimomura, Iichiro