Abstract
Background and AimsLysophosphatidic acid (LPA) is a multi-function glycerophospholipid. LPA affects the proliferation of hepatocytes and stellate cells in vitro, and in a partial hepatectomy induced liver regeneration model, the circulating LPA levels and LPA receptor (LPAR) expression levels in liver tissue are significantly changed. Liver sinusoidal endothelial cells (Lsecs) play an important role during liver regeneration. However, the effects of LPA on Lsecs are not well known. Thus, we investigated the effects of LPA on the expression profiles of angiogenic factors, cytokines, and chemokines in Lsecs.MethodsMouse Lsecs were isolated using CD31-coated magnetic beads. The mRNA expression levels of LPAR’s and other target genes were determined by quantitative RT-PCR. The protein levels of angiogenesis factors, cytokines, and chemokines were determined using protein arrays and enzyme immunoassay (EIA). Critical LPAR related signal transduction was verified by using an appropriate chemical inhibitor.ResultsLPAR1 and LPAR3 mRNA’s were expressed in mouse LPA-treated Lsecs. Treating Lsecs with a physiological level of LPA significantly enhanced the protein levels of angiogenesis related proteins (cyr61 and TIMP-1), cytokines (C5/C5a, M-CSF, and SDF-1), and chemokines (MCP-5, gp130, CCL28, and CXCL16). The LPAR1 and LPAR3 antagonist ki16425 significantly inhibited the LPA-enhanced expression of cyr61, TIMP-1, SDF-1, MCP-5, gp130, CCL28, and CXCL16, but not that of C5/C5a or M-CSF. LPA-induced C5/C5a and M-CSF expression may have been through an indirect regulation mechanism.ConclusionLPA regulated the expression profiles of angiogenic factors, cytokines, and chemokines in Lsecs that was mediated via LPAR1 and LPAR3 signaling. Most of the factors that were enhanced by LPA have been found to play critical roles during liver regeneration. Thus, these results may prove useful for manipulating LPA effects on liver regeneration.
Highlights
Lysophosphatidic acid (LPA) is a potent signaling lipid molecule that is involved in numerous phenomena, such as cell migration, preventing cellular apoptosis, angiogenesis, and others
The LPAR1 and LPAR3 antagonist ki16425 significantly inhibited the LPA-enhanced expression of cyr61, TIMP-1, SDF-1, MCP-5, gp130, CCL28, and CXCL16, but not that of C5/C5a or M-CSF
LPA regulated the expression profiles of angiogenic factors, cytokines, and chemokines in Liver sinusoidal endothelial cells (Lsecs) that was mediated via LPAR1 and LPAR3 signaling
Summary
LPA is a potent signaling lipid molecule that is involved in numerous phenomena, such as cell migration, preventing cellular apoptosis, angiogenesis, and others. By using a partial hepatectomy mouse model, Simo et al found that liver regeneration after partial hepatectomy was associated with significant changes in circulating LPA levels (LPA increased significantly at 72 hours post- partial hepatectomy to 6.30 ± 0.67 μM as compared to 3.58 ± 0.37 μM in sham-operated mice) and that hepatic mRNA levels of LPAR1, LPAR3, and LPAR6 were expressed in a time- and cell-dependent manner [9]. Their immunohistochemical staining results revealed that LPAR1 protein was expressed in non-parenchyma cells, and that LPAR3 and LPAR6 proteins were widely distributed in regenerating liver tissue [9]. We investigated the effects of LPA on the expression profiles of angiogenic factors, cytokines, and chemokines in Lsecs
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