Expression of leptin receptors in hepatic sinusoidal cells

Abstract

Emerging evidence has suggested a critical role of leptin in hepatic inflammation and fibrogenesis, however, the precise mechanisms underlying the profibrogenic action of leptin in the liver has not been well elucidated. Therefore, the present study was designed to investigate the expression and functions of leptin receptors (Ob-R) in hepatic sinusoidal cells. Hepatic stellate cells (HSCs), Kupffer cells and sinusoidal endothelial cells (SECs) were isolated from rat livers by in situ collagenase perfusion followed by differential centrifugation technique, and expression of Ob-Ra and Ob-Rb, short and long Ob-R isoforms, respectively, were analyzed by RT-PCR. Ob-Ra mRNA was detected ubiquitously in HSCs and SECs. In contrast, Ob-Rb was detected clearly only in SECs and Kupffer cells, but not in 7-day cultured HSCs. Indeed, tyrosine-phosphorylation of STAT-3, a downstream event of Ob-Rb signaling, was observed in SECs, but not in HSCs, 1 hr after incubation with leptin. Further, leptin increased AP-1 DNA binding activity and TGF-beta 1 mRNA levels in Kupffer cells and SECs, whereas leptin failed to increase TGF-beta 1 mRNA in HSCs. These findings indicated that SECs and Kupffer cells, but not HSCs, express functional leptin receptors, through which leptin elicits production of TGF-beta 1. It is hypothesized therefore that leptin, produced systemically from adipocytes and locally from HSCs, up-regulates TGF-beta 1 thereby facilitate tissue repairing and fibrogenesis in the sinusoidal microenvironment.

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

“…1). These findings are consistent with findings that have been reported by other groups (8,26,27) and suggest that leptin signaling activity might increase during HSC transdifferentiation, despite associated repression of leptin receptor mRNAs. To further evaluate leptin receptor function in MF-HSCs, day 7 cultures of MF-HSCs were treated with exogenous leptin, and effects on HSC gene expression were assessed by qRT-PCR.…”

“…Evidence that treating HSCs with siRNA to knock down expression of leptin significantly inhibited the myofibroblastic phenotype of cultured HSCs (34) supported this concept. Other reports, however, failed to demonstrate such leptin-dependent effects when HSCs were cultured in serumenriched medium (27,35), prompting speculation that leptin was neither necessary nor sufficient for HSC activation and leaving lingering questions about the ultimate significance of leptin-HSC interactions.…”

Pleiotrophin Regulates the Retention and Self-Renewal of Hematopoietic Stem Cells in the Bone Marrow Vascular Niche

“…We then performed gene expression analysis of FACS-sorted VE-cadherin + PTN + cells, which revealed enrichment for VEGFR2 and VEGFR3, which are markers of BM sinusoidal endothelium (Hooper et al, 2009)(Table 1). Interestingly, VE-cadherin + PTN + cells were also enriched for expression of CXCL12 and the leptin receptor (lepR), proteins which have been shown to be expressed by both perivascular stromal cells and sinusoidal ECs (Dar et al, 2005; Ding et al, 2012; Ikejima et al, 2004; Sugiyama et al, 2006). VEcadherin + PTN + cells lacked expression of Nestin, a marker of BM mesenchymal stromal cells (MSCs) (Mendez-Ferrer et al, 2010).…”

“…Here, we demonstrate via immunohistochemical and FACS analysis that PTN is expressed uniquely by VE-cadherin + ECs that co-express VEGFR2 and VEGFR3 + , consistent with BM sinusoidal ECs (Hooper et al, 2009). Interestingly, PTN + ECs also express CXCL12 and lepR, which can be expressed by both sinusoidal ECs and perivascular reticular cells (Dar et al, 2005; Ding et al, 2012; Ikejima et al, 2004; Sugiyama et al, 2006). Of note, a prior study suggested that calvarial bone osteoblasts expressed PTN (Tezuka et al, 1990), but we found little evidence that osterix + bone lineage cells expressed PTN in the BM.…”

Hepatobiliary Diseases and Insulin Resistance

“…Leptin levels are elevated in obese adults [80], indicating a resistance to the effects of leptin in these individuals [81]. Recent reports have suggested that leptin is involved in wound repair and fibrosis [82][83][84][85]. Irrespective of the organ, wound repair involves integrated and balanced cell proliferation, angiogenesis, and extracellular matrix production.…”