Kupffer Cells Mediate Leptin-Induced Liver Fibrosis

Wang, Jianhua; Leclercq, Isabelle; Brymora, Joanne; Xu, Ning; Ramezani-Moghadam, Mehdi; London, Roslyn M.; Brigstock, David R.; George, Jacob

doi:10.1053/j.gastro.2009.04.011

Cited by 173 publications

(129 citation statements)

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“…Notably, a previous study confirmed that galanin inhibits leptin expression and secretion in rat adipose tissue and 3T3-L1 adipocytes (5). Leptin has been shown to possess direct profibrogenic activity in the liver, and the absence of leptin is associated with a marked attenuation of the hepatic response to a diverse range of fibrotic stimuli (6). It has been hypothesized that leptin acts directly on hepatic stellate cells (HSCs) to trigger downstream response pathways that ultimately lead to the deposition of extracellular matrix (ECM) (7).…”

Section: Introductionmentioning

confidence: 62%

Galanin receptor 2 mediates antifibrogenic effects of galanin on hepatic stellate cells

Zhou

et al. 2016

Experimental and Therapeutic Medicine

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Abstract.Galanin is an endogenous factor involved in the negative regulation of the biological effects of leptin in bioenergetic metabolism. Leptin promotes fibrogenic effects in hepatic stellate cells (HSCs), however, little is known about the effects of galanin on HSCs. In the present study, the biological functions of galanin and its receptors (GalRs) in HSCs were investigated using cell culture in vitro. It was found that galanin and GalR3 mRNA are expressed in quiescent and activated HSCs. GalR2 expression was undetectable in quiescent HSCs but was markedly induced in activated HSCs. In the HSC-T6 cell line, which is an activated rat HSC cell line, treatment with 100 nmol/l galanin significantly inhibited cell proliferation. It also inhibited transforming growth factor (TGF)-β1 and α-smooth muscle actin (SMA) expression and upregulated peroxisome proliferator-activated receptor (PPAR)-γ expression. Following the knockdown of GalR2 by specific small interfering RNA, the activation of GalR3 by galanin does not influence these effects of galanin on HSCs. However, activation of GalR2 alone by galanin following the knockdown of GalR3 inhibits HSC proliferation and TGF-β1 and α-SMA expression, in addition to inducing PPAR-γ expression. These data suggest that galanin inhibits HSC activation and suppresses the profibrogenic features of these cells, and these effects might be mediated by GalR2. Thus, galanin is a potential endogenous factor in the inhibition of liver fibrosis. IntroductionGalanin is a 29-amino acid peptide naturally present in the tissues and fluids of humans and animals (1). To date three galanin receptors (GalR1, GalR2 and GalR3) have been discovered to be widely distributed in the mammalian central and peripheral nervous system (2). It is acknowledged that galanin has a critical role in the regulation of energy homeostasis (3). Leptin, another adipocyte-derived hormone, is also a key factor in the regulation of body weight and energy expenditure and acts in rodents via hypothalamus receptors to inhibit feeding and increase thermogenesis (4). Notably, a previous study confirmed that galanin inhibits leptin expression and secretion in rat adipose tissue and 3T3-L1 adipocytes (5). Leptin has been shown to possess direct profibrogenic activity in the liver, and the absence of leptin is associated with a marked attenuation of the hepatic response to a diverse range of fibrotic stimuli (6). It has been hypothesized that leptin acts directly on hepatic stellate cells (HSCs) to trigger downstream response pathways that ultimately lead to the deposition of extracellular matrix (ECM) (7). However, little is known about the effects of galanin on HSCs. Since the activation and proliferation of HSCs are the key factors in the progress of liver fibrosis, in view of the counteracting effect of galanin on leptin in food intake and energy metabolism, the effect of galanin on the proliferation of HSCs becomes an interesting research topic.It may be hypothesized that galanin is able to inhibit the activation and p...

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Section: Introductionmentioning

confidence: 62%

Galanin receptor 2 mediates antifibrogenic effects of galanin on hepatic stellate cells

Zhou

et al. 2016

Experimental and Therapeutic Medicine

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“…In Kupffer cells, the transient activation of STAT3 by IL-6 is proinflammatory, promoting HSC survival and proliferation (10). The activation of STAT3 in HSCs by IL-6 or leptin stimulates HSC survival, proliferation, and activation (8,16,17). Nevertheless, the exact mechanisms of IL-6/STAT3 in HSC during liver fibrogenesis remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

Shiau²,

Jao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Signal transducer and activator of transcription 3 (STAT3) had been involved in liver fibrogenesis. We aimed to explore the antifibrotic activities of sorafenib and its derivative SC-1 (devoid of Raf kinase inhibition activity) both in vivo and in vitro with special focus on the STAT3 pathway in hepatic stellate cells (HSCs). The clinical role of STAT3 in chronic hepatitis B (CHB) was also investigated. Experimental fibrosis mouse models were established by thioacetamide injection and bile duct ligation in Balb/C mice and treated with sorafenib and SC-1. Rat and human HSCs were used for mechanistic investigations. Forty CHB patients were enrolled to quantify the hepatic phospho-STAT3 (p-STAT3) levels and correlated with liver fibrosis. Both sorafenib and SC-1 ameliorated liver fibrosis in vivo and promoted HSC apoptosis in vitro. p-STAT3 and downstream signals were down-regulated after sorafenib and SC-1 treatment in HSC. STAT3 overexpression in HSC enhanced cell proliferation and undermined the apoptotic effects of sorafenib and SC-1, whereas STAT3-specific inhibition promoted HSC apoptosis. Sorafenib and SC-1 activated Src-homology protein tyrosine phosphatase-1 (SHP-1) and STAT3 inhibition followed. Of particular interest, in CHB patients with advanced liver fibrosis, p-STAT3 in HSC was significantly overexpressed and positively correlated with the severity of liver fibrosis and plasma IL-6 levels. In conclusion, sorafenib and SC-1 ameliorate liver fibrosis through STAT3 inhibition in HSC and STAT3 may potentially serve as a promising fibrotic biomarker and target in liver fibrosis. SHP-1 phosphatase-directed STAT3 inhibition may represent a previously unidentified strategy for antifibrotic drug discovery.hepatic stellate cell | STAT3 | SHP-1 | hepatitis B | liver fibrosis

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“…This is relevant because of the emerging evidence indicating that angiogenesis is not only a critical component of chronic wound healing but can indeed favor liver fibrogenesis. Finally, it has also been reported that leptin, in addition to stimulate increased phagocytic activity and cytokine secretion by Kupffer cells and macrophages [58], may act indirectly on HSC by stimulating Kupffer cells to up-regulate their expression of TGFβ1 [59].…”

Section: Adipokinesmentioning

confidence: 99%

Cellular and molecular mechanisms in liver fibrogenesis

Novo

Cannito

Paternostro

et al. 2014

Archives of Biochemistry and Biophysics

178

194

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Kupffer Cells Mediate Leptin-Induced Liver Fibrosis

Abstract: Background & Aims-Leptin has pro-fibrogenic effects in liver, although the mechanisms of this process are unclear. We sought to elucidate the direct and indirect effects of leptin on hepatic stellate cells (HSCs).

Cited by 173 publications

References 50 publications

Galanin receptor 2 mediates antifibrogenic effects of galanin on hepatic stellate cells

Galanin receptor 2 mediates antifibrogenic effects of galanin on hepatic stellate cells

Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

Cellular and molecular mechanisms in liver fibrogenesis

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