Altered lysophosphatidic acid (LPA) receptor expression during hepatic regeneration in a mouse model of partial hepatectomy

Simo, Kerri A.; Niemeyer, David J.; Hanna, Erin M.; Swet, Jacob H.; Thompson, Kyle J.; Sindram, David; Iannitti, David A.; Eheim, Ashley; Sokolov, Eugene P.; Zuckerman, Valentina; McKillop, Iain H.

doi:10.1111/hpb.12176

Cited by 17 publications

(19 citation statements)

References 39 publications

(120 reference statements)

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“…Moreover, LPAR6 was more widely stained than LPAR1 and LPAR3. These results suggest that LPA receptors (LPAR1, LPAR3, LPAR6) can promote liver regeneration after hepatectomy [128].…”

Section: Lpar and Liver Regenerationmentioning

confidence: 72%

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Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases

Xiang¹,

Lü²,

Shao³

et al. 2020

J. Cancer

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Lysophosphatidic acid (LPA, 1-acyl-2-hemolytic-sn-glycerol-3-phosphate) extracted from membrane phospholipid is a kind of simple bioactive glycophospholipid, which has many biological functions such as stimulating cell multiplication, cytoskeleton recombination, cell survival, drug-fast, synthesis of DNA and ion transport. Current studies have shown that six G-coupled protein receptors (LPAR1-6) can be activated by LPA. They stimulate a variety of signal transduction pathways through heterotrimeric G-proteins (such as Gα12/13, Gαq/11, Gαi/o and GαS). LPA and its receptors play vital roles in cancers, nervous system diseases, cardiovascular diseases, liver diseases, metabolic diseases, etc. In this article, we discussed the structure of LPA receptors and elucidated their functions in various diseases, in order to better understand them and point out new therapeutic schemes for them.

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“…Moreover, LPAR6 was more widely stained than LPAR1 and LPAR3. These results suggest that LPA receptors (LPAR1, LPAR3, LPAR6) can promote liver regeneration after hepatectomy [128].…”

Section: Lpar and Liver Regenerationmentioning

confidence: 72%

“…Furthermore, blocking the production of inflammatory cytokines (TNF-α and IL-1β) protects against APAP-induced acute liver injury. But this process was independent of LPA receptors [128]. Hepatitis was a key factor in the development of liver fibrosis.…”

Section: Lpar and Liver Fibrosismentioning

confidence: 99%

Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases

Xiang¹,

Lü²,

Shao³

et al. 2020

J. Cancer

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“…Indeed, the relative absence of well-characterized LPAR subtypes (LPARs1–5) within the liver presents somewhat of a paradox in understanding how LPA affects liver function and hepatic pathogenesis. For example, in animal models, correlations between circulating LPA and degree of underlying liver injury are reported [ 41 ] yet LPARs 1–5 are barely detectable (if at all) in rodent hepatocytes/liver tissue [ 28 ]. Similarly, cirrhotic and HCC patients exhibit elevated serum LPA levels, while the relative expression of LPA species in patients at risk for developing HCC suggest serum LPA profiles may be beneficial in identifying those patients with HCC [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…Studies by our group and others now report LPAR6, the most recently characterized LPAR subtype [ 24 , 25 ], is expressed in normal liver/hepatocytes, and is significantly elevated in human HCC [ 26 , 27 ] and regenerating rodent liver [ 28 ]. During the course of these studies we reported LPAR1 and LPAR3 expression was increased in a subset of human HCC and cirrhotic non-tumor liver (NTL) compared to liver from non-tumor burdened patients [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

Expression and function of lysophosphatidic acid receptors (LPARs) 1 and 3 in human hepatic cancer progenitor cells

et al. 2015

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Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and is characterized by rapid tumor expansion and metastasis. Lysophosphatidic acid (LPA) signaling, via LPA receptors 1–6 (LPARs1–6), regulates diverse cell functions including motility, migration, and proliferation, yet the role of LPARs in hepatic tumor pathology is poorly understood. We sought to determine the expression and function of endothelial differentiation gene (EDG) LPARs (LPAR1–3) in human HCC and complimentary in vitro models. Human HCC were characterized by significantly elevated LPAR1/LPAR3 expression in the microenvironment between the tumor and non-tumor liver (NTL), a finding mirrored in human SKHep1 cells. Analysis of human tissue and human hepatic tumor cells in vitro revealed cells that express LPAR3 (HCC-NTL margin in vivo and SKHep1 in vitro) also express cancer stem cell markers in the absence of hepatocyte markers. Treatment of SKHep1 cells with exogenous LPA led to significantly increased cell motility but not proliferation. Using pharmacological agents and cells transfected to knock-down LPAR1 or LPAR3 demonstrated LPA-dependent cell migration occurs via an LPAR3-Gi-ERK-pathway independent of LPAR1. These data suggest cells that stain positive for both LPAR3 and cancer stem cell markers are distinct from the tumor mass per se, and may mediate tumor invasiveness/expansion via LPA-LPAR3 signaling.

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“…Ikeda et al first demonstrated that LPA might affect the proliferation of hepatocytes and stellate cells in those liver diseases that disrupted platelet activation [ 8 ]. Recently, 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 ]. Additionally, 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 ].…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidic Acid Alters the Expression Profiles of Angiogenic Factors, Cytokines, and Chemokines in Mouse Liver Sinusoidal Endothelial Cells

Chou

Lai

et al. 2015

PLoS ONE

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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.

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Altered lysophosphatidic acid (LPA) receptor expression during hepatic regeneration in a mouse model of partial hepatectomy

Abstract: Liver regeneration following PHx is associated with significant changes in circulating LPA and hepatic LPAR1, LPAR3 and LPAR6 expression in a time- and cell-dependent manner. Furthermore, changes in LPA-LPAR post-PHx occur after the first round of hepatocyte division is complete.

Cited by 17 publications

References 39 publications

Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases

Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases

Expression and function of lysophosphatidic acid receptors (LPARs) 1 and 3 in human hepatic cancer progenitor cells

Lysophosphatidic Acid Alters the Expression Profiles of Angiogenic Factors, Cytokines, and Chemokines in Mouse Liver Sinusoidal Endothelial Cells

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