Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells.
Leptin upregulates collagen expression in hepatic stellate cells (HSCs), but the possible modulation of other actions has not been elucidated. The aim of this study was to investigate the expression and function of leptin receptors (ObR) in human HSCs and the biological actions regulated by leptin. Exposure of HSCs to leptin resulted in upregulation of monocyte chemoattractant protein 1 (MCP-1) expression. Leptin also increased gene expression of the proangiogenic cytokines vascular endothelial growth factor (VEGF) and angiopoietin-1, and VEGF was also upregulated at the protein level. Activated HSCs express ObRb and possibly other ObR isoforms. Exposure to leptin increased the tyrosine kinase activity of ObR immunoprecipitates and resulted in activation of signal transducer and activator of transcription 3. Several signaling pathways were activated by leptin in HSCs, including extracellular-signal-regulated kinase, Akt, and nuclear factor kappaB, the latter being relevant for chemokine expression. Leptin also increased the abundance of hypoxia-inducible factor 1alpha, which regulates angiogenic gene expression, in an extracellular-signal-regulated kinase- and phoshatidylinositol 3-kinase-dependent fashion. In vivo, leptin administration induced higher MCP-1 expression and more severe inflammation in mice after acute liver injury. Conversely, in leptin-deficient mice, the increase in MCP-1 messenger RNA and mononuclear infiltration was less marked than in wild-type littermates. Finally, ObR expression colocalized with VEGF and alpha-smooth muscle actin after induction of fibrosis in rats. In conclusion, ObR activation in HSCs leads to increased expression of proinflammatory and proangiogenic cytokines, indicating a complex role for leptin in the regulation of the liver wound-healing response.
Aleffi
Sara
S
Dipartimento di Medicina Interna, University of Florence, Italy.
Petrai
Ilaria
I
Bertolani
Cristiana
C
Parola
Maurizio
M
Colombatto
Sebastiano
S
Novo
Erica
E
Vizzutti
Francesco
F
Anania
Frank A
FA
Milani
Stefano
S
Rombouts
Krista
K
Laffi
Giacomo
G
Pinzani
Massimo
M
Marra
Fabio
F
D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000209:etiology*; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000502:physiology*; D054411:Receptors, Leptin; D015398:Signal Transduction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D014945:Wound Healing
C111835:CCL2 protein, human; D018932:Chemokine CCL2; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C515448:LEPR protein, human; D020738:Leptin; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases