DLPC and SAMe combined prevent leptin‐stimulated TIMP‐1 production in LX‐2 human hepatic stellate cells by inhibiting H<sub>2</sub>O<sub>2</sub>‐mediated signal transduction

Cao, Qi; Mak, Ki M.; Lieber, Charles S.

doi:10.1111/j.1478-3231.2005.01204.x

Cited by 19 publications

(10 citation statements)

References 48 publications

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“…Specifically, leptin inhibits MMP-1 expression in both rat HSCs and the human HSC line, LX-2, via Jak/Stat signaling [Cao et al, 2007; Lin et al, 2006]. Leptin also induces TIMP-1 expression in rat HSCs and LX-2 cells [Cao et al, 2006a; Lin et al, 2006], enhancing collagen deposition. Adiponectin suppresses Il-1β–induced MMP 13 expression and [Chen et al, 2006; Lee et al, 2008], and regulates TIMP-1 expression in macrophages [Kumada et al, 2004], but these effects were observed in the context of inflammatory responses.…”

Section: Resultsmentioning

confidence: 99%

Adiponectin activation of AMPK disrupts leptin‐mediated hepatic fibrosis via suppressors of cytokine signaling (SOCS‐3)

Handy

Saxena

Pingping

et al. 2010

J of Cellular Biochemistry

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Adiponectin is an adipocytokine that was recently shown to be anti-fibrogenic in hepatic fibrosis. Leptin, on the other hand, promotes hepatic fibrosis. The purpose of the present study was to elucidate a mechanism (or mechanisms) whereby adiponectin dampens leptin signaling in activated hepatic stellate cells (HSCs), and prevents excess extracellular matrix production. Activated HSCs, between passages 2 and 5, were cultured and exposed to recombinant human adiponectin and recombinant leptin. Immunoblot analysis for SOCS-3, TIMP-1, and the phosphorylated species of Stat3 and adenosine monophosphate-activated protein kinase (AMPK) were conducted. We also examined MMP-1 activity by immunosorbant fluorimetric analysis. In HSCs, adiponectin-induced phosphorylation of AMPK, and subsequently suppressed leptin-mediated Stat3 phosphorylation and SOCS-3 induction. Adiponectin also blocked leptin-stimulated secretion of TIMP-1, and significantly increased MMP-1 activity, in vitro. To extend this study, we treated adiponectin knockout mice (Ad-/-) daily with 5 mg/kg recombinant leptin and/or carbon tetrachloride (2 ml/kg) for 6 weeks. Post-necropsy analysis was performed to examine for inflammation, and histological changes in the Ad-/- and wild-type mice. There was no significant difference in inflammation, or aminotransferases, between mice receiving carbon tetrachloride and leptin versus carbon tetrachloride alone. As anticipated, the combination of leptin and CCl(4) enhanced hepatic fibrosis in both wild-type and Ad-/- mice, as estimated by amount of collagen in injured livers, but wild-type mice had significantly higher levels of SOCS-3 and significantly lower levels of TIMP-1 mRNA and protein than did adiponectin KO mice exposed to both CCl(4) and leptin. We therefore conclude that the protective effects of adiponectin against liver fibrosis require AMPK activation, and may occur through inhibition of the Jak-Stat signal transduction pathway.

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Section: Resultsmentioning

confidence: 99%

Adiponectin activation of AMPK disrupts leptin‐mediated hepatic fibrosis via suppressors of cytokine signaling (SOCS‐3)

Handy

Saxena

Pingping

et al. 2010

J of Cellular Biochemistry

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“…In addition, it was demonstrated on cultured HSC that DLPC reduces the activation of HSC by down-regulating ␣-SMA and ␣1(I) procollagen gene expression (Poniachik et al, 1999;Cao et al, 2002c) and that it inhibits HSC proliferation (Brady et al, 1998). Recently, it was reported that DLPC prevents production of tissue inhibitor of matrix metalloproteinase I in a human hepatic stellate cell line (Cao et al, 2006). Moreover, DLPC decreases TNF-␣ production in KC isolated from ethanol-fed rats (Cao et al, 2002a,b).…”

Section: Discussionmentioning

confidence: 99%

Effects of a New Bioactive Lipid-Based Drug Carrier on Cultured Hepatic Stellate Cells and Liver Fibrosis in Bile Duct-Ligated Rats

Adrian¹,

Poelstra²,

Scherphof³

et al. 2007

J Pharmacol Exp Ther

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“…These differential responses are associated with impaired LPS activation of NF-κB counteracted by enhanced activation of ERK1/2 and early-immediate gene-1 (Egr-1) (111). Dilinoleoylphosphatidylcholine (DLPC) decreases lipopolysaccharide-induced TNF-α generation by Kupffer cells of ethanol-fed rats by blocking p38, ERK1/2, and NF-κB activation (112). DLPC also decreases TNF-α induction by acetaldehyde, a toxic metabolite released by ethanol oxidation (57).…”

Section: Role Of Cytokines and Nuclear Factor-kappa B (Nf-κb)mentioning

confidence: 99%

Kupffer cells and alcoholic liver disease

Cubero

Nieto

2006

Rev. esp. enferm. dig.

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Liver disease is a major cause of illness and death worldwide. A central component in the complex network leading to the development of alcoholic liver disease is the activation of Kupffer cells by endotoxin and other soluble mediators. Alcohol consumption induces a state of 'leaky gut' increasing plasma and liver endotoxin levels. When Kupffer cells become activated, they interact with a complex of proteins located on the extracellular membrane signaling to produce a wide array of soluble factors, including cytokines, chemokines, growth factors, cyclooxygenase and lipoxygenase metabolites, and reactive oxygen species such as superoxide anion, hydrogen peroxide, and nitric oxide, all of which provide physiologically diverse and pivotal paracrine effects on all other liver cell types and, ultimately, liver injury. Kupffer cells are also central to the liver homeostatic response to injury as upon cellular degenerative changes, they immediately respond to the insult and release mediators to orchestrate inflammatory and reparative responses. Thus, the homeostatic responses are initiated by Kupffer cell-derived mediators at the cellular level and underlie the liver's defense and reparative mechanisms against injury. In order to understand better the role of Kupffer cells in the onset of liver injury, animal models in which Kupffer cells are inactivated, and cell culture settings (e.g. co-cultures) are being used with promising results that advance our understanding of alcoholic liver disease.

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DLPC and SAMe combined prevent leptin‐stimulated TIMP‐1 production in LX‐2 human hepatic stellate cells by inhibiting H₂O₂‐mediated signal transduction

Abstract: As decreased TIMP-1 production may enhance collagen deposition, the combined administration of DLPC+SAMe should be considered for the prevention of H2O2-mediated signaling and the resulting fibrosis.

Cited by 19 publications

References 48 publications

Adiponectin activation of AMPK disrupts leptin‐mediated hepatic fibrosis via suppressors of cytokine signaling (SOCS‐3)

Adiponectin activation of AMPK disrupts leptin‐mediated hepatic fibrosis via suppressors of cytokine signaling (SOCS‐3)

Effects of a New Bioactive Lipid-Based Drug Carrier on Cultured Hepatic Stellate Cells and Liver Fibrosis in Bile Duct-Ligated Rats

Kupffer cells and alcoholic liver disease

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DLPC and SAMe combined prevent leptin‐stimulated TIMP‐1 production in LX‐2 human hepatic stellate cells by inhibiting H2O2‐mediated signal transduction

Abstract: As decreased TIMP-1 production may enhance collagen deposition, the combined administration of DLPC+SAMe should be considered for the prevention of H2O2-mediated signaling and the resulting fibrosis.

Cited by 19 publications

References 48 publications

Adiponectin activation of AMPK disrupts leptin‐mediated hepatic fibrosis via suppressors of cytokine signaling (SOCS‐3)

Adiponectin activation of AMPK disrupts leptin‐mediated hepatic fibrosis via suppressors of cytokine signaling (SOCS‐3)

Effects of a New Bioactive Lipid-Based Drug Carrier on Cultured Hepatic Stellate Cells and Liver Fibrosis in Bile Duct-Ligated Rats

Kupffer cells and alcoholic liver disease

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DLPC and SAMe combined prevent leptin‐stimulated TIMP‐1 production in LX‐2 human hepatic stellate cells by inhibiting H₂O₂‐mediated signal transduction