Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase Mediates Fibrotic and Inflammatory Effects of Leptin on Hepatic Stellate Cells
Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase Mediates Fibrotic and Inflammatory Effects of Leptin on Hepatic Stellate Cells
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DOI：
10.1002/hep.22560
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发表时间：
2008-12-01
期刊：
影响因子：
13.5
通讯作者：
Brenner, David A.
中科院分区：
文献类型：
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作者：
De Minicis, Samuele;Seki, Ekjhiro;Brenner, David A.
虽然瘦素可诱导肝星状细胞（hsc）的纤维化活性，但其机制尚不完全清楚。为了研究还原性烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NADPH）和活性氧（ROS）在造血干细胞中瘦素信号传导中的潜在作用，我们分析了原生野生型（WT）、p47（phox-/-）和转录蛋白3 （STAT3）缺失的造血干细胞中瘦素诱导的细胞内信号传导途径。NADPH氧化酶抑制剂二苯碘（DPI）和缺乏NADPH成分p47（phox）的造血干细胞中，瘦素刺激的ROS生成在人和小鼠造血干细胞中被减弱。NADPH氧化酶抑制可阻断瘦素诱导的细胞外信号调节激酶（ERK）和AKT的磷酸化，而非STAT3的磷酸化。此外，瘦素诱导的ROS生成被Janus激酶（JAK）抑制剂AG490抑制，但在stat3缺失的hsc中观察到正常的ROS生成。在HSC中抑制NADPH不仅导致瘦素介导的HSC增殖减少，而且还降低了瘦素介导的纤维化标志物胶原α 1(1)和α -平滑肌肌动蛋白以及炎症介质单核细胞趋化蛋白-1 （MCP-1）、巨噬细胞炎症蛋白1 （MIP-1）和巨噬细胞炎症蛋白2 （MIP-2）的上调。在体内，瘦素增强了WT小鼠中趋化因子（C-C基序）配体4 （CCl4）诱导的趋化因子表达，但在p47（phox-/-）小鼠中观察到钝化反应。总之，NADPH氧化酶是瘦素增殖、纤维化和炎症作用的关键介质。瘦素诱导的NADPH氧化酶作用于JAK激活的下游，但不依赖于STAT3。我们的研究结果，结合先前对血管紧张素II和血小板衍生生长因子（PDGF）的研究，将NADPH置于造血干细胞纤维化信号反应的中心，并证明其作为抗纤维化治疗的药理学靶点的潜在作用。(肝脏病学48:2016 2008;2026)。
Although leptin induces fibrotic activity in hepatic stellate cells (HSCs), the mechanisms are not entirely understood. To investigate the potential role of reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH) and reactive oxygen species (ROS) in leptin signaling in HSCs, we analyzed leptin-induced intracellular signaling pathways in primary wild-type (WT), p47(phox-/-), and signal transducer and activator of transcription protein 3 (STAT3)-deleted HSCs. Leptin-stimulated ROS production was attenuated in human and mouse HSCs by the NADPH oxidase inhibitor diphenylene-iodonium (DPI) and in HSCs lacking the NADPH component p47(phox). Leptin-induced phosphorylation of extracellular signal-regulated kinase (ERK) and AKT, but not of STAT3, was blocked by NADPH oxidase inhibition. Moreover, leptin-induced ROS production was inhibited by the Janus kinase (JAK) inhibitor, AG490, but normal ROS production was observed in STAT3-deleted HSCs. Pharmacologic or genetic inhibition of NADPH in HSCs not only resulted in a reduction of leptin-mediated HSC proliferation but also reduced the leptin-mediated up-regulation of the fibrogenic markers collagen alpha 1 (1) and alpha-smooth muscle actin and of the inflammatory mediators monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein 1 (MIP-1), and macrophage inflammatory protein 2 (MIP-2). In vivo, leptin enhanced chemokine expression induced by chemokine (C-C motif) ligand 4 (CCl4) in WT mice, but a blunted response was observed in p47(phox-/-) mice. In conclusion, NADPH oxidase is a crucial mediator of proliferative, fibrogenic, and inflammatory actions of leptin. Leptin-induced NADPH oxidase acts downstream of JAK activation but is independent of STAT3. Our results, in conjunction with previous studies on angiotensin II and platelet-derived growth factor (PDGF), place NADPH in the center of the fibrogenic signaling response in HSCs and demonstrate its potential role as a pharmacological target for antifibrotic therapies. (HEPATOLOGY 2008;48:2016-2026.)