PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-9 (9)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
Document Types
1.  The Lysophosphatidic Acid Receptor LPA1 Promotes Epithelial Cell Apoptosis after Lung Injury 
Increased epithelial cell apoptosis in response to lung injury has been implicated in the development of idiopathic pulmonary fibrosis (IPF), but the molecular pathways promoting epithelial cell apoptosis in this disease have yet to be fully identified. Lysophosphatidic acid (LPA), which we have previously demonstrated to mediate bleomycin lung injury–induced fibroblast recruitment and vascular leak in mice and fibroblast recruitment in patients with IPF, is an important regulator of survival and apoptosis in many cell types. We now show that LPA signaling through its receptor LPA1 promotes epithelial cell apoptosis induced by bleomycin injury. The number of apoptotic cells present in the alveolar and bronchial epithelia of LPA1–deficient mice was significantly reduced compared with wild-type mice at Day 3 after bleomycin challenge, as was lung caspase-3 activity. Consistent with these in vivo results, we found that LPA signaling through LPA1 induced apoptosis in normal human bronchial epithelial cells in culture. LPA-LPA1 signaling appeared to specifically mediate anoikis, the apoptosis of anchorage-dependent cells induced by their detachment. Similarly, LPA negatively regulated attachment of R3/1 rat alveolar epithelial cell line cells. In contrast, LPA signaling through LPA1 promoted the resistance of lung fibroblasts to apoptosis, which has also been implicated in IPF. The ability of LPA-LPA1 signaling to promote epithelial cell apoptosis and fibroblast resistance to apoptosis may therefore contribute to the capacity of this signaling pathway to regulate the development of pulmonary fibrosis after lung injury.
doi:10.1165/rcmb.2010-0155OC
PMCID: PMC3326436  PMID: 22021336
pulmonary fibrosis; apoptosis; epithelial cells, lysophosphatidic acid; LPA1
2.  Autotaxin expression from synovial fibroblasts is essential for the pathogenesis of modeled arthritis 
Synovial fibroblasts from patients and mice with arthritis express autotaxin, and ablation of autotaxin in fibroblasts ameliorates disease.
Rheumatoid arthritis is a destructive arthropathy characterized by chronic synovial inflammation that imposes a substantial socioeconomic burden. Under the influence of the proinflammatory milieu, synovial fibroblasts (SFs), the main effector cells in disease pathogenesis, become activated and hyperplastic, releasing proinflammatory factors and tissue-remodeling enzymes. This study shows that activated arthritic SFs from human patients and animal models express significant quantities of autotaxin (ATX; ENPP2), a lysophospholipase D that catalyzes the conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA). ATX expression from SFs was induced by TNF, and LPA induced SF activation and effector functions in synergy with TNF. Conditional genetic ablation of ATX in mesenchymal cells, including SFs, resulted in disease attenuation in animal models of arthritis, establishing the ATX/LPA axis as a novel player in chronic inflammation and the pathogenesis of arthritis and a promising therapeutic target.
doi:10.1084/jem.20112012
PMCID: PMC3348105  PMID: 22493518
3.  Expression of the Splicing Factor Gene SFRS10 is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis 
Cell metabolism  2011;14(2):208-218.
SUMMARY
Alternative mRNA splicing provides transcript diversity and may contribute to human disease. We demonstrate that expression of several genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. We evaluated a representative splicing factor, SFRS10, down-regulated in both obese human liver and muscle and in high fat-fed mice, and determined metabolic impact of reduced expression. SFRS10-specific siRNA induces lipogenesis and lipid accumulation in hepatocytes. Moreover, Sfrs10 heterozygous mice have increased hepatic lipogenic gene expression, VLDL secretion, and plasma triglycerides. We demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10; reduced SFRS10 favors the lipogenic β isoform of LPIN1. Importantly, LPIN1β-specific siRNA abolished lipogenic effects of decreased SFRS10 expression. Together, our results indicate that reduced expression of SFRS10, as observed in tissues from obese humans, alters LPIN1 splicing, induces lipogenesis, and therefore contributes to metabolic phenotypes associated with obesity.
doi:10.1016/j.cmet.2011.06.007
PMCID: PMC3167228  PMID: 21803291
4.  Ethanol-Induced Alterations in Fatty Acid-Related Lipids in Serum and Tissues in Mice 
Background
Chronic alcohol consumption is a major factor for several human diseases and alcoholism is associated with a host of societal problems. One of the major alcohol- induced metabolic changes is the increased NADH levels, which reduces glucose synthesis and increases fatty acid (FA) synthesis. Probably more important is the induction of FA synthesizing enzymes under the control of sterol regulatory element binding proteins (SREBP), plus increased malonyl-CoA which blocks FA entry to the mitochondria for oxidation. The changes in FA-related lipids, particularly lysophospholipids (LPLs) and ceramides (Cers), in different tissues in ethanol-fed have not been reported.
Methods
We systematically determined the levels of FA-related lipids, including FAs, phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), lysophosphatidylinositol (LPI), sphingomyelins (SMs), and ceramides (Cers) in the serum and different tissues by high-performance-liquid-chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). The study was performed in C57BL/6J mice fed with Lieber DeCarli diet; in which ethanol was added to account for 27.5% of total calories. The serum and tissues were collected at the time of sacrifice in these mice and the results were compared to pair-fed controls.
Results
The important observation was that ethanol induced tissue-specific changes, which were related to different FA chains. Several 22:6 FA, 18:0 FA, 18:0 to 18:3 FA-containing lipids were significantly increased in the serum, liver, and skeletal muscle, respectively. In the kidney, all 22:6 FA-containing lipids detected were increased. In addition, alterations of other lipids in tissues, except adipose tissue, were also observed.
Conclusions
We found tissue-specific alterations in the levels of FA-related lipids after ethanol administration. The implications of these findings pertinent to human physiology/pathology warrant further investigation. More studies are needed to explore the mechanisms on the different effects of ethanol on certain lipids in different tissues.
doi:10.1111/j.1530-0277.2010.01338.x
PMCID: PMC3058922  PMID: 21058963
Ethanol; fatty acid-related lipids; phospholipids; HPLC-ESI-MS/MS
5.  Omega-3 and omega-6 fatty acids suppress ER- and oxidative-stress in cultured neurons and neuronal progenitor cells from mice lacking PPT1 
Neuroscience letters  2010;479(3):292-296.
Reactive oxygen species (ROS) damage to brain lipids, carbohydrates, proteins, and DNA may contribute to neurodegeneration. We previously reported that ER- and oxidative stress cause neuronal apoptosis in infantile neuronal ceroid lipofuscinosis (INCL), a lethal neurodegenerative storage disease, caused by palmitoyl-protein thioesterase-1(PPT1)-deficiency. Polyunsaturated fatty acids (PUFA) are essential components of cell membrane phospholipids in the brain and excessive ROS may cause oxidative damage PUFA leading to neuronal death. Using cultured neurons and neuroprogenitor cells from mice lacking Ppt1, which mimic INCL, we demonstrate that Ppt1-deficient neurons and neuroprogenitor cells contain high levels of ROS, which may cause perxidation of PUFA and render them incapable of providing protection against oxidative stress. We tested whether treatment of these cells with omega-3 or omega-6 PUFA protects the neurons and neuroprogenitor cells from oxidative stress and suppress apoptosis. We report here that both omega-3 and omega-6 fatty acids protect the Ppt1-deficient cells from ER- as well as oxidative stress and suppress apoptosis. Our results suggest that PUFA supplementation may have neuroprotective effects in INCL.
doi:10.1016/j.neulet.2010.05.083
PMCID: PMC2904481  PMID: 20561933
INCL; palmitoyl-protein thioesterase-1; Batten disease; Neurodegenaration; ER-stress; Oxidative stress; Apoptosis; PUFA
6.  Measurement of endogenous lysophosphatidic acid by ESI-MS/MS in plasma samples requires pre-separation of lysophosphatidylcholine 
The levels of lysophosphatidic acid (LPA) or lysophosphatidylcholine (LPC) in plasma have been shown to be markers for several human diseases, including cancers. Here we show that the presence of LPC or other lysophospholipids (LPLs) in lipids extracted from biological samples affects accurate measurement of endogenous LPA in biological samples. We report for the first time the artificial conversion of LPC and lysophosphatidylserine (LPS) to LPA at the ion source of electrospray ionization tandem mass spectrometry (ESI-MS/MS). To avoid the interference of LPC with the quantification of LPA, a method based on high-performance-liquid-chromatography (HPLC) separation of LPA from LPC has been developed.
doi:10.1016/j.jchromb.2009.08.032
PMCID: PMC2760648  PMID: 19734112
High-performance-liquid-chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS); lysophosphatidic acid (LPA); lysophosphatidylcholine (LPC)
7.  Autotaxin expression and its connection with the TNF-alpha-NF-κB axis in human hepatocellular carcinoma 
Molecular Cancer  2010;9:71.
Background
Autotaxin (ATX) is an extracellular lysophospholipase D that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Both ATX and LPA have been shown to be involved in many cancers. However, the functional role of ATX and the regulation of ATX expression in human hepatocellular carcinoma (HCC) remain elusive.
Results
In this study, ATX expression was evaluated in tissues from 38 human HCC and 10 normal control subjects. ATX was detected mainly in tumor cells within tissue sections and its over-expression in HCC was specifically correlated with inflammation and liver cirrhosis. In addition, ATX expression was examined in normal human hepatocytes and liver cancer cell lines. Hepatoma Hep3B and Huh7 cells displayed stronger ATX expression than hepatoblastoma HepG2 cells and normal hepatocytes did. Proinflammtory cytokine tumor necrosis factor alpha (TNF-α) promoted ATX expression and secretion selectively in Hep3B and Huh7 cells, which led to a corresponding increase in lysophospholipase-D activity. Moreover, we explored the mechanism governing the expression of ATX in hepatoma cells and established a critical role of nuclear factor-kappa B (NF-κB) in basal and TNF-α induced ATX expression. Further study showed that secreted enzymatically active ATX stimulated Hep3B cell invasion.
Conclusions
This report highlights for the first time the clinical and biological evidence for the involvement of ATX in human HCC. Our observation that links the TNF-α/NF-κB axis and the ATX-LPA signaling pathway suggests that ATX is likely playing an important role in inflammation related liver tumorigenesis.
doi:10.1186/1476-4598-9-71
PMCID: PMC2867819  PMID: 20356387
8.  S1P differentially regulates migration of human ovarian cancer and human ovarian surface epithelial cells 
Molecular cancer therapeutics  2008;7(7):1993-2002.
Epithelial ovarian cancer (EOC) arises from the epithelial layer covering the surface of ovaries and intra-peritoneal metastasis is commonly observed at diagnosis. Sphingosine-1-phosphate (S1P), a bioactive lipid signaling molecule, is potentially involved in EOC tumorigenesis. We have found that S1P is elevated in human EOC ascites. We show that physiologically relevant concentrations of S1P stimulate migration and invasion of EOC cells, but inhibit migration of human ovarian surface epithelial (HOSE) cells. In addition, S1P inhibits lysophosphatidic acid (LPA)-induced cell migration in HOSE, but not in EOC cells. We have provided the first line of evidence that the expression levels of S1P receptor subtypes are not the only determinants for how cells respond to S1P. Even though S1P1 is expressed and functional in HOSE cells, the inhibitory effect mediated by S1P2 is dominant in those cells. The cellular pre-existing stress fibers are also important determinants for the migratory response to S1P. Differential S1P-induced morphology changes are noted in EOC and HOSE cells. Pre-existing stress fibers in HOSE cells are further enhanced by S1P treatment, resulting in the negative migratory response to S1P. By contrast, EOC cells lost stress fibers and S1P treatment induces filopodium-like structures at cell edges, which correlates with increased cell motility. In addition, inhibition of the protein kinase C pathway is likely to be involved in the inhibitory effect of S1P on LPA-induced cell migration in HOSE cells. These findings are important for the development of new therapeutics targeting S1P and LPA in EOC.
doi:10.1158/1535-7163.MCT-08-0088
PMCID: PMC2649755  PMID: 18645009
Sphingosine-1-phosphate (S1P); Epithelial Ovarian Cancer (EOC); Human Ovarian Surface Epithelial (HOSE); Migration; Stress Fibers
9.  Abnormalities in Osteoclastogenesis and Decreased Tumorigenesis in Mice Deficient for Ovarian Cancer G Protein-Coupled Receptor 1 
PLoS ONE  2009;4(5):e5705.
Ovarian cancer G protein-coupled receptor 1 (OGR1) has been shown to be a proton sensing receptor in vitro. We have shown that OGR1 functions as a tumor metastasis suppressor gene when it is over-expressed in human prostate cancer cells in vivo. To examine the physiological functions of OGR1, we generated conditional OGR1 deficient mice by homologous recombination. OGR1 deficient mice were viable and upon gross-inspection appeared normal. Consistent with in vitro studies showing that OGR1 is involved in osteoclastogenesis, reduced osteoclasts were detected in OGR1 deficient mice. A pH-dependent osteoclasts survival effect was also observed. However, overall abnormality in the bones of these animals was not observed. In addition, melanoma cell tumorigenesis was significantly inhibited in OGR1 deficient mice. OGR1 deficient mice in the mixed background produced significantly less peritoneal macrophages when stimulated with thioglycolate. These macrophages also showed altered extracellular signal-regulated kinases (ERK) activation and nitric oxide (NO) production in response to lipopolysaccharide. OGR1-dependent pH responses assessed by cAMP production and cell survival in macrophages or brown fat cells were not observed, presumably due to the presence of other proton sensing receptors in these cells. Our results indicate that OGR1's role in osteoclastogenesis is not strong enough to affect overall bone development and its role in tumorigenesis warrants further investigation. The mice generated can be potentially used for several disease models, including cancers or osteoclast-related diseases.
doi:10.1371/journal.pone.0005705
PMCID: PMC2684630  PMID: 19479052

Results 1-9 (9)