Leptin facilitates proliferation of hepatic stellate cells through up-regulation of platelet-derived growth factor receptor

Lang, Tie; Ikejima, Kenichi; Yoshikawa, Mutsuko; Enomoto, Nobuyuki; Iijima, Katsuyori; Kitamura, Tsuneo; Takei, Yoshiyuki; Sato, Nobuhiro

doi:10.1016/j.bbrc.2004.08.192

Cited by 36 publications

(23 citation statements)

References 20 publications

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“…These cells have been considered to be quiescent (Saile et al, 1997(Saile et al, , 1999Paik et al, 2003). The quiescent state of the cells was also confirmed, before and after stimulation with LPS (see below), by the absence of the expression of a-smooth muscle actin (Western analysis; Chi et al, 2003) and PDGFRb (PCR analysis; Lang et al, 2004), the two markers of stellate cell activation (Ramadori, 1991;Wong et al, 1994;Geerts et al, 1994;Pinzani and Gentilini, 1999) (results not shown).…”

mentioning

confidence: 71%

“…The efficiency of cDNA synthesis and reverse transcription was ensured by determining b-actin mRNA from the same amount of cDNA. For PDGFRb mRNA expression, after a 10 min denaturation period at 958C, 30 cycles of PCR was carried out at 958C for 45 sec, 588C for 45 sec, and 728C for 1 min, followed by final extension at 728C for 7 min (Lang et al, 2004). For LBP, TLR-2, TLR-4, and CD-14, PCR was carried out as follows: initial denaturation at 948C for 5 min, followed by 30 cycles (CD-14 and b-actin) or 28 cycles (LBP) of denaturation at 948C for 1 min, annealing [608C for 1 min (CD-14); 588C for 2 min (LBP); and 558C for 1 min (b-actin)], and extension at 728C for 1 min (b-actin) or 2 min (CD-14 and LBP), and finally 10 min of final extension at 728C.…”

Section: Determination Of Dna Synthesismentioning

confidence: 99%

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Normal rat hepatic stellate cells respond to endotoxin in LBP‐independent manner to produce inhibitor(s) of DNA synthesis in hepatocytes

Thirunavukkarasu

Uemura

Wang

et al. 2005

Journal Cellular Physiology

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Endotoxin is implicated in the pathology of acute liver failure. The mechanisms of its actions on quiescent hepatic stellate cells (qHSCs) and their implications in hepatocyte injury are incompletely understood. We investigated effects of endotoxin (bacterial lipopolysaccharide; LPS) on qHSCs and subsequently on hepatocytes. After overnight culture following their isolation, qHSCs were incubated with or without endotoxin for 24 h. The cells and the culture supernatant were analyzed for cytokines and nitric oxide (NO) synthesis. The effects of qHSC-conditioned media on hepatocytes were then determined. LPS increased inducible NO synthase expression, stimulated NO synthesis, and inhibited DNA synthesis in qHSCs. qHSC-conditioned medium inhibited DNA synthesis in hepatocytes without affecting NO synthesis, while LPS (1-1,000 ng/ml)-conditioned qHSC medium stimulated NO synthesis and caused further inhibition of DNA synthesis and apoptosis. These effects of LPS were more pronounced when qHSCs were incubated with serum, but not with LPS-binding protein (LBP) although CD14 (a receptor for LPS-LBP complex) was found in qHSCs. LPS stimulated the synthesis of TNF-alpha, interleukin (IL)-6, and IL-1beta but not of TGF-beta in qHSCs. Individually or together, L-N(G)-monomethylarginine and antibodies to IL-1beta, IL-6, and TNF-alpha only partly reversed qHSC + LPS-conditioned medium-induced inhibition of DNA synthesis in hepatocytes. These results suggest that the effects of LPS on qHSCs are novel, occurring without the aid of LBP/CD14. They also indicate that other factors, in addition to NO, TGF-beta, TNF-alpha, IL-1beta, and IL-6 are involved in the mechanisms of the growth inhibitory effects of qHSCs on hepatocytes.

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mentioning

confidence: 71%

Section: Determination Of Dna Synthesismentioning

confidence: 99%

Normal rat hepatic stellate cells respond to endotoxin in LBP‐independent manner to produce inhibitor(s) of DNA synthesis in hepatocytes

Thirunavukkarasu

Uemura

Wang

et al. 2005

Journal Cellular Physiology

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“…Those studies also showed that Hh pathway activity was required for PDGF-related mitogenicity (6). Interestingly, other researchers demonstrated that leptin up-regulates HSC expression of PDGF receptors and showed that this plays an important role in leptin-related HSC growth and fibrogenesis (37). Thus, the new data advance understanding about this process by demonstrating that HSC-derived Shh acts in an autocrine fashion to initiate signaling that culminates in the activation of Gli transcription factors with resultant induction of Hh-regulated target genes, including snail.…”

Section: Discussionmentioning

confidence: 96%

Leptin Promotes the Myofibroblastic Phenotype in Hepatic Stellate Cells by Activating the Hedgehog Pathway

Choi

Syn

Karaca

et al. 2010

Journal of Biological Chemistry

156

146

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Trans-differentiation of quiescent hepatic stellate cells (Q-HSCsLeptin-ObRb interactions were not necessary for HSC transdifferentiation to occur in vitro or in vivo but are important because liver fibrogenesis was attenuated in db/db mice. These findings reveal that leptin activates Hh signaling to alter gene expression programs that control cell fate and have important implications for liver fibrosis and other leptin-regulated processes involving EMTs, including development, obesity, and cancer metastasis.

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“…Finally, to explain the possible relationship of leptin and NGAL levels with imatinib therapy, we have to bear in mind that imatinib modulates several signal pathways such as Kit, PDGFRs, MEK/MAPK and others [28,29,30,31], while NGAL and leptin regulate these pathways, and their expression could be regulated by the same pathways [32,33,34,35]. …”

Section: Discussionmentioning

confidence: 99%

Imatinib Mesylate Therapy Induces Reduction in Neutrophil Gelatinase-Associated Lipocalin Serum Levels and Increase in Leptin Concentrations in Chronic Myeloid Leukemia Patients in Molecular Remission

Alonci

Allegra²,

Russo³

et al. 2011

Acta Haematol

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The aim of the present study was to determine serum levels of neutrophil gelatinase-associated lipocalin (NGAL) and leptin in patients with chronic myeloid leukemia (CML) at diagnosis and after imatinib therapy when patients achieved a complete molecular remission. The study was conducted on 22 patients with CML in the chronic phase and 10 healthy subjects. The median serum NGAL levels in CML patients at diagnosis were significantly higher compared to age-matched controls. After imatinib therapy, all patients achieved complete molecular remission and NGAL levels decreased and were found significantly lower with respect to the baseline. No significant correlations were found between NGAL levels and other disease parameters. Before imatinib therapy, the median blood leptin levels were not significantly different from those of controls. After therapy with imatinib, all patients in molecular remission presented an increase in leptin levels. Future research is eagerly awaited as it may demonstrate the real role of NGAL and leptin in the onset and progression of CML.

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Leptin facilitates proliferation of hepatic stellate cells through up-regulation of platelet-derived growth factor receptor

Cited by 36 publications

References 20 publications

Normal rat hepatic stellate cells respond to endotoxin in LBP‐independent manner to produce inhibitor(s) of DNA synthesis in hepatocytes

Normal rat hepatic stellate cells respond to endotoxin in LBP‐independent manner to produce inhibitor(s) of DNA synthesis in hepatocytes

Leptin Promotes the Myofibroblastic Phenotype in Hepatic Stellate Cells by Activating the Hedgehog Pathway

Imatinib Mesylate Therapy Induces Reduction in Neutrophil Gelatinase-Associated Lipocalin Serum Levels and Increase in Leptin Concentrations in Chronic Myeloid Leukemia Patients in Molecular Remission

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