Hedgehog controls hepatic stellate cell fate by regulating metabolism.
Hedgehog controls hepatic stellate cell fate by regulating metabolism.
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DOI：
10.1053/j.gastro.2012.07.115
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发表时间：
2012-11
期刊：
影响因子：
29.4
通讯作者：
Diehl AM
中科院分区：
文献类型：
--
作者：
Chen Y;Choi SS;Michelotti GA;Chan IS;Swiderska-Syn M;Karaca GF;Xie G;Moylan CA;Garibaldi F;Premont R;Suliman HB;Piantadosi CA;Diehl AM
肝硬化是肝脏修复缺陷的致残性结果，其发病机制涉及来自静止肝星状细胞（HSC）的肌成纤维细胞的不受调节的积累，但控制HSC转分化的机制尚不清楚。我们研究了Hedgehog （Hh）通路是否通过调节代谢来控制HSC的命运。微阵列、定量PCR和免疫印迹分析用于鉴定静止与肌成纤维细胞HSC中代谢基因的差异表达。糖酵解和乳酸生成在HSC中被破坏，以确定代谢是否影响转分化。通过改变Hh信号和缺氧诱导因子（HIF）1α活性来确定改变糖酵解活性的因素。在肝硬化患者的活检样本和给药CCl4或胆管结扎后的小鼠肝脏样本中，对调节糖酵解的基因表达的变化进行了量化和定位。小鼠给予全身Hh抑制剂，以确定它们是否影响肝基质的糖酵解活性；在肌成纤维细胞中，Hh信号也被有条件地破坏，以确定糖酵解活性的影响。静息培养的HSC向肌成纤维细胞的转分化诱导糖酵解并引起乳酸积累。调节糖酵解的基因表达增加需要Hh信号传导并参与HIF1α的诱导。Hh信号、HIF1α、糖酵解或乳酸积累抑制剂可将肌成纤维细胞转化为静止的HSC。在患病动物和患者的肝脏中，糖酵解基质细胞的数量与纤维化的严重程度相关。条件性地破坏肌成纤维细胞中的Hh信号可减少小鼠糖酵解性肌成纤维细胞的数量和肝纤维化；在给予Hh药物抑制剂后观察到类似的效果。Hedgehog信号通过调节代谢来控制HSC的命运。这些结果可用于肝硬化的诊断和治疗。
Pathogenesis of cirrhosis, a disabling outcome of defective liver repair, involves deregulated accumulation of myofibroblasts derived from quiescent hepatic stellate cells (HSC), but the mechanisms that control HSC transdifferentiation are poorly understood. We investigated whether the Hedgehog (Hh) pathway controls HSC fate by regulating metabolism. Microarray, quantitative PCR, and immunoblot analyses were used to identify metabolic genes that were differentially expressed in quiescent vs myofibroblast HSC. Glycolysis and lactate production were disrupted in HSC to determine if metabolism influenced transdifferentiation. Hh signaling and hypoxia-inducible factor (HIF)1α activity were altered to identify factors that alter glycolytic activity. Changes in expression of genes that regulate glycolysis were quantified and localized in biopsy samples from patients with cirrhosis, and liver samples from mice following administration of CCl4 or bile-duct ligation. Mice were given systemic inhibitors of Hh to determine if they affect glycolytic activity of the hepatic stroma; Hh signaling was also conditionally disrupted in myofibroblasts to determine the effects of glycolytic activity. Transdifferentiation of cultured, quiescent HSC into myofibroblasts induced glycolysis and caused lactate accumulation. Increased expression of genes that regulate glycolysis required Hh signaling and involved induction of HIF1α. Inhibitors of Hh signaling, HIF1α, glycolysis, or lactate accumulation converted myofibroblasts to quiescent HSC. In diseased livers of animals and patients, numbers of glycolytic stromal cells were associated with the severity of fibrosis. Conditional disruption of Hh signaling in myofibroblasts reduced numbers of glycolytic myofibroblasts and liver fibrosis in mice; similar effects were observed following administration of pharmacologic inhibitors of Hh. Hedgehog signaling controls HSC fate by regulating metabolism. These findings might be applied to diagnosis and treatment of cirrhosis.
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影响因子：
5.6
作者：
Lee, Ting Fang;Mak, Ki M.;Rackovsky, Ori;Lin, Yun-Lian;Kwong, Allison J.;Loke, Johnny C.;Friedman, Scott L.
通讯作者：
Friedman, Scott L.
影响因子：
24.5
作者：
Kluwe, Johannes;Wongsiriroj, Nuttaporn;Schwabe, Robert F.
通讯作者：
Schwabe, Robert F.
DOI：
10.1152/ajpgi.00292.2009
发表时间：
2009-12-01
影响因子：
4.5
作者：
Choi, Steve S.;Omenetti, Alessia;Diehl, Anna Mae
通讯作者：
Diehl, Anna Mae
DOI：
10.1073/pnas.96.26.15143
发表时间：
1999-12-21
影响因子：
11.1
作者：
Bezerra, JA;Bugge, TH;Degen, JL
通讯作者：
Degen, JL
DOI：
10.1073/pnas.0909353106
发表时间：
2009-10-20
影响因子：
11.1
作者：
Lee, KangAe;Zhang, Huafeng;Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.