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Reduced nicotinamide adenine dinucleotide phosphate oxidase mediates fibrotic and inflammatory effects of leptin on hepatic stellate cells
Author(s) -
De Minicis Samuele,
Seki Ekihiro,
Oesterreicher Christoph,
Schnabl Bernd,
Schwabe Robert F.,
Brenner David A.
Publication year - 2008
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22560
Subject(s) - nadph oxidase , nicotinamide adenine dinucleotide phosphate , leptin , chemistry , janus kinase 2 , stat3 , leptin receptor , reactive oxygen species , chemokine , microbiology and biotechnology , stat protein , janus kinase , signal transduction , biology , medicine , endocrinology , oxidase test , biochemistry , receptor , enzyme , obesity
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 α1(I) and α‐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 (CCl 4 ) 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. (H EPATOLOGY 2008;48:2016–2026.)