• cancer
• gastrointestinal
• inflammation
• lysophosphatidic acid

• Lysophospholipids/metabolism
• Humans
• Signal Transduction
• Animals
• Gastrointestinal Tract/metabolism
• Gastrointestinal Tract/immunology
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/immunology
• Receptors, Lysophosphatidic Acid/metabolism

• I01 BX004459 BLRD VA
• I01 BX006369 BLRD VA
• R01 DK116799 NIDDK NIH HHS

• ALD
• G protein coupled receptors
• HCC
• NAFLD
• Poly-unsaturated fatty acid lipid mediators
• eicosanoids
• liver cancer
• liver fibrosis
• lyso-phospholipids
• steatohepatitis
• viral hepatitis

• Humans
• Non-alcoholic Fatty Liver Disease/complications
• Liver Diseases, Alcoholic/metabolism
• Carcinoma, Hepatocellular/pathology
• Phospholipids/metabolism
• Liver Neoplasms/pathology
• Liver/pathology

• U01 AA026962 NIAAA NIH HHS
• R21 AA029206 NIAAA NIH HHS

• Alzheimer’s disease
• eicosanoids
• lipidomics
• lysophospholipids
• sphingolipids

• Autotaxin
• COVID-19
• inflammation
• lysophosphatidic acids
• severity

The KAI1/CD82 gene inhibits the metastasis of most tumors and is remarkably correlated with tumor invasion and prognosis. Cell metabolism dysregulation is an important cause of tumor occurrence, development, and metastasis. As one of the important characteristics of tumors, cell metabolism dysregulation is attracting increasing research attention. Phospholipids are an indispensable substance in the metabolism in various tumor cells. Phospholipid metabolites have become important cell signaling molecules. The pathological role of lysophosphatidic acid (LPA) in tumors was identified in the early 1990s. Currently, LPA inhibitors have entered clinical trials but are not yet used in clinical treatment. Autotaxin (ATX) has lysophospholipase D (lysoPLD) activity and can regulate LPA levels in vivo. The LPA receptor family and ATX/lysoPLD are abnormally expressed in various gastrointestinal tumors. According to our recent pre-experimental results, KAI1/CD82 might inhibit the migration and metastasis of cancer cells by regulating the ATX-LPA axis. However, no relevant research has been reported. Clarifying the mechanism of ATX-LPA in the inhibition of cancer metastasis by KAI1/CD82 will provide an important theoretical basis for targeted cancer therapy. In this paper, the molecular compositions of the KAI1/CD82 gene and the ATX-LPA axis, their physiological functions in tumors, and their roles in gastrointestinal cancers and target therapy are reviewed.

• KAI1/CD82
• Autotaxin
• Lysophosphatidic acid
• Pancreatic cancer
• Liver cancer

• Bioinformatics
• Cytokine network
• In vivo tumorigenicity
• Lysophosphatidic acid receptor 2
• Renal cell carcinoma

Gastric cancer (GC) is regarded as the most prevalent malignancy with the high mortality rate, worldwide. However, gastroscopy, a biopsy of suspected sample, and detecting CEA, CA19-9, and CA72-4 are presently used, but these diagnostic approaches have several limitations. Recently, microRNAs as the most important member of noncoding RNAs (ncRNAs) have received attention; recent evidence demonstrates that they can be used as the promising candidate biomarkers for GC diagnosis. We aimed to investigate the association between the microRNA-29a, -101, and -103 expression and autotaxin (ATX) and lysophosphatidic acid receptor 2 (LPA2) expression in GC patients. Material and Methods. The present study was conducted on 40 paired samples of primary GC tissue and adjacent noncancerous tissue. The gene expression levels of miR-101, -103, -29, ATX, and LPA2 were analyzed by quantitative reverse-transcription PCR (qRT-PCR). Besides, the protein levels of ATX and LPA2 were evaluated using western blot.

The expression levels of miR-29 and miR-101 were significantly lower (p value < 0.0001), but the miR-103 and LPA2 were significantly higher in gastric tumor samples compared to the corresponding nontumor tissues (p value < 0.0001). Moreover, the diagnostic accuracy of miRs to discrimine the GC patients from noncancerous controls was reliable (miR-101, sensitivity: 82.5% and specificity: 85%; miR-103, sensitivity: 72.5% and specificity: 90%; miR-29, sensitivity: 77.5% and specificity: 70%).

It seems that determining the expression level of miR-101, -103, and -29, as the novel diagnostic biomarkers, has diagnostic value to distinguish GC patients from healthy individuals.

Numerous studies have investigated the possible involvement of eicosanoids, lysophospholipids, and sphingolipids in cancer. We considered that comprehensive measurement of these lipid mediators might provide a better understanding of their involvement in the pathogenesis of cancer. In the present study, we attempted to elucidate the modulations of sphingolipids, lysophospholipids, diacyl‐phospholipids, eicosanoids, and related mediators in cancer by measuring their levels simultaneously by a liquid chromatography‐mass spectrometry method in a mouse model of carcinomatous peritonitis.

We investigated the modulations of these lipids in both ascitic fluid and plasma specimens obtained from Balb/c mice injected intraperitoneally with Colon‐26 cells, as well as the modulations of the lipid contents in the cancer cells obtained from the tumor xenografts.

The results were as follows: the levels of sphingosine 1‐phosphate were increased, while those of lysophosphatidic acid (LysoPA), especially unsaturated long‐chain LysoPA, tended to be increased, in the ascitic fluid. Our findings suggested that ceramides, sphingomyelin, and phosphatidylcholine, their precursors, were supplied by both de novo synthesis and from elsewhere in the body. The levels of lysophosphatidylserine (LysoPS), lysophosphatidylinositol, lysophosphatidylglycerol, and lysophosphatidylethanolamine were also increased in the ascitic fluid, while those of phosphatidylserine (PS), a precursor of LysoPS, were markedly decreased. The levels of arachidonic acid derivatives, especially PGE2‐related metabolites, were increased, while the plasma levels of eicosanoids and related mediators were decreased. Comprehensive statistical analyses mainly identified PS in the ascitic fluid and eicosanoids in the plasma as having highly negative predictive values for cancer.

The results proposed many unknown associations of lipid mediators with cancer, underscoring the need for further studies. In particular, the PS/LysoPS pathway could be a novel therapeutic target, and plasma eicosanoids could be useful biomarkers for cancer.

• cancer
• eicosanoids
• liquid chromatography-mass spectrometry
• lysophospholipids
• sphingolipids

• autotaxin
• liver cancer
• lysophosphatidic acid
• metastasis
• tumorigenesis

• National Natural Science Foundation of China

Background: Hepatitis B virus (HBV) infection is a major risk factor causing hepatocellular carcinoma (HCC) development, but the molecular mechanisms are not fully elucidated. It has been reported that virus infection induces ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2) expression, the latter participates in tumor progression. Therefore, the aim of the present study was to investigate whether HBV induced HCC malignancy via ENPP2.

Methods: HCC patient clinical data were collected and prognosis was analyzed. Transient transfection and stable ectopic expression of the HBV genome were established in hepatoma cell lines. Immunohistochemical staining, RT-qPCR, western blot, and ELISA assays were used to detect the expression and secretion of ENPP2. Finally, CCK-8, colony formation, and migration assays as well as a subcutaneous xenograft mouse model were used to investigate the influence of HBV infection, ENPP2 expression, and activated hepatic stellate cells (aHSCs) on HCC progression in vitro and in vivo.

Results: The data from cancer databases indicated that the level of ENPP2 was significant higher in HCC compared within normal liver tissues. Clinical relevance analysis using 158 HCC patients displayed that ENPP2 expression was positively correlated with poor overall survival and disease-free survival. Statistical analysis revealed that compared to HBV-negative HCC tissues, HBV-positive tissues expressed a higher level of ENPP2. In vitro, HBV upregulated ENPP2 expression and secretion in hepatoma cells and promoted hepatoma cell proliferation, colony formation, and migration via enhancement of ENPP2; downregulation of ENPP2 expression or inhibition of its function suppressed HCC progression. In addition, aHSCs strengthened hepatoma cell proliferation, migration in vitro, and promoted tumorigenesis synergistically with HBV in vivo; a loss-function assay further verified that ENPP2 is essential for HBV/aHSC-induced HCC progression.

Conclusion: HBV enhanced the expression and secretion of ENPP2 in hepatoma cells, combined with aHSCs to promote HCC progression via ENPP2.

• ectonucleotide pyrophosphatase-phosphodiesterase 2
• hepatic stellate cells
• hepatitis B virus-related hepatocellular carcinoma
• prognosis
• progression

Gastric cancer (GC) is a malignant tumor derived from gastric mucosal epithelial cells. In recent years, it has been found that the Hhip and Lpar2 genes play an important role in the development of GC. The Hhip gene can inhibit the proliferation and invasion of GC cells by participating in the Hedgehog signaling pathway, while the Lpar2 gene promotes the development of GC by activating the ATX-LPA signaling pathway. In this paper, we will review the changes of expression levels, molecular mechanism, and clinical application of Hhip and Lpar2 genes in GC patients.

• Gastric cancer
• Hhip
• Lpar2
• GIN
• Correlation

Lysophosphatidic acid (LPA) refers to a family of simple phospholipids that act as ligands for G protein-coupled receptors. While LPA exerts effects throughout the body in normal physiological circumstances, its pathological role in cancer is of great interest from a therapeutic viewpoint. The numerous LPA receptors (LPARs) are coupled to a variety of G proteins, and more than one LPAR is typically expressed on any given cell. While the individual receptors signal through conventional GPCR pathways, LPA is particularly efficacious in stimulating cancer cell proliferation and migration. This review addresses the mechanistic aspects underlying these pro-tumorigenic effects. We provide examples of LPA signaling responses in various types of cancers, with an emphasis on those where roles have been identified for specific LPARs. While providing an overview of LPAR signaling, these examples also reveal gaps in our knowledge regarding the mechanisms of LPA action at the receptor level. The current understanding of the LPAR structure and the roles of LPAR interactions with other receptors are discussed. Overall, LPARs provide insight into the potential molecular mechanisms that underlie the ability of individual GPCRs (or combinations of GPCRs) to elicit a unique spectrum of responses from their agonist ligands. Further knowledge of these mechanisms will inform drug discovery, since GPCRs are promising therapeutic targets for cancer.

• G protein-coupled receptors
• cancers
• lysophosphatidic acid

Lysophosphatidic acid (LPA) is a bioactive lipid mediator primarily derived from membrane phospholipids. LPA initiates cellular effects upon binding to a family of G protein-coupled receptors, termed LPA receptors (LPAR1 to LPAR6). LPA signaling drives cell migration and proliferation, cytokine production, thrombosis, fibrosis, angiogenesis, and lymphangiogenesis. Since the expression and function of LPA receptors are critical for cellular effects, selective antagonists may represent a potential treatment for a broad range of illnesses, such as cardiovascular diseases, idiopathic pulmonary fibrosis, voiding dysfunctions, and various types of cancers. More new LPA receptor antagonists have shown their therapeutic potentials, although most are still in the preclinical trial stage. This review provided integrative information and summarized preclinical findings and recent clinical trials of different LPA receptor antagonists in cancer progression and resistance. Targeting LPA receptors can have potential applications in clinical patients with various diseases, including cancer.

• antagonist
• cancer
• clinical trial
• lysophosphatidic acid
• lysophosphatidic receptor
• therapy

• Endothelial differentiating gene
• G-protein coupled receptors
• Invasion
• LPA modulators
• Lysophosphatidic acid
• Lysophospholipase D
• Migration
• Proliferation

• bioluminescence resonance energy transfer technique
• cAMP
• crosstalk
• hypoxia-inducible factor 1α

Lipid phosphate phosphatases (LPPs) are a group of three enzymes (LPP1–3) that belong to a phospholipid phosphatase (PLPP) family. The LPPs dephosphorylate a wide spectrum of bioactive lipid phosphates, among which lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) are two important extracellular signaling molecules. The LPPs are integral membrane proteins, which are localized on plasma membranes and intracellular membranes, including the endoplasmic reticulum and Golgi network. LPPs regulate signaling transduction in cancer cells and demonstrate different effects in cancer progression through the breakdown of extracellular LPA and S1P and other intracellular substrates. This review is intended to summarize an up-to-date understanding about the functions of LPPs in cancers.

• G protein-coupled receptor
• PAP-2
• autotaxin
• lysophosphatidate

• Animals
• Cell Membrane/chemistry
• Cell Membrane/metabolism
• Humans
• Lysophospholipids/genetics
• Lysophospholipids/metabolism
• Neoplasms/enzymology
• Neoplasms/genetics
• Phosphatidate Phosphatase/chemistry
• Phosphatidate Phosphatase/genetics
• Phosphatidate Phosphatase/metabolism
• Signal Transduction
• Sphingosine/analogs & derivatives
• Sphingosine/genetics
• Sphingosine/metabolism
• Up-Regulation

• 703926 Canadian Cancer Society Research Institute
• 300034 Canadian Breast Cancer Foundation
• 7/17 Women and Children's Health Research Institute, University of Alberta
• PJT-169140 CIHR

The tumor microenvironment (TME) may be best conceptualized as an ecosystem comprised of cancer cells interacting with a multitude of stromal components such as the extracellular matrix (ECM), blood and lymphatic networks, fibroblasts, adipocytes, and cells of the immune system. At the center of this crosstalk between cancer cells and their TME is the bioactive lipid lysophosphatidic acid (LPA). High levels of LPA and the enzyme generating it, termed autotaxin (ATX), are present in many cancers. It is also well documented that LPA drives tumor progression by promoting angiogenesis, proliferation, survival, invasion and metastasis. One of the hallmarks of cancer is the ability to modulate and escape immune detection and eradication. Despite the profound role of LPA in regulating immune functions and inflammation, its role in the context of tumor immunity has not received much attention until recently where emerging studies highlight that this signaling axis may be a means that cancer cells adopt to evade immune detection and eradication. The present review aims to look at the immunomodulatory actions of LPA in baseline immunity to provide a broad understanding of the subject with a special emphasis on LPA and cancer immunity, highlighting the latest progress in this area of research.

• LPA
• LPAR5
• autotaxin
• cytotoxic T cells
• immune cells
• immune checkpoint
• immunoediting
• immunosuppression
• immunosurveillance
• lysophosphatidic acid
• tumor microenvironment
• tumor-associated macrophages

• Chemotherapy
• Inflammation
• Nrf2
• Oxidative stress
• Radiotherapy
• Tumor microenvironment

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.

• LPAR
• cancer
• lysophosphatidic acid
• physiology and pathology
• structure

Lysophosphatidylserine (LysoPS) is a lysophospholipid, its generating enzyme, phosphatidylserine-specific phospholipase A1 (PS-PLA1), reportedly plays roles in stomach and colon cancers. Here, we examined the potential roles of LysoPS in hepatocellular carcinoma (HCC). The ninety-seven HCC patients who underwent surgical treatment were enrolled in this study and approved by the institutional review board. Among LysoPS-related enzymes and receptors, increased PS-PLA1 or LysoPS receptor 1 (LPS1) mRNA was observed in HCC tissues compared to non-HCC tissues. PS-PLA1 mRNA in HCC was associated with no clinical parameters, while LPS1 mRNA in HCC was correlated inversely with tumor differentiation. Furthermore, higher serum PS-PLA1 was observed in HCC patients compared to healthy control and correlated with PS-PLA1 mRNA in non-HCC tissues and with serum AST or ALT. Additionally, serum levels of PS-PLA1 were higher in HCC patients with HCV-related liver injury than in those with HBV or non-HBV-, non-HCV-related liver diseases. In conclusion, among LysoPS-related enzymes and receptors, PS-PLA1 and LPS1 mRNA were increased in HCC. Based on the correlation between the serum PS-PLA1 and the mRNA level of PS-PLA1 in non-HCC tissues, the liver may be the main source of serum PS-PLA1, and serum PS-PLA1 levels may be a useful marker for liver injury.

• Drug discovery and design
• Drug therapy
• Hepatocellular carcinoma (HCC)
• Lysophosphatidic acid receptor 6 (LPAR6)
• Lysophosphatidic acid receptor 6 antagonists

Circulating autotaxin (ATX) is elevated in persons with liver disease, particularly in the setting of chronic hepatitis C virus (HCV) and HCV/HIV infection. It is thought that plasma ATX levels are, in part, attributable to impaired liver clearance that is secondary to fibrotic liver disease. In a discovery data set, we identified plasma ATX to be associated with parameters of systemic immune activation during chronic HCV and HCV/HIV infection. We and others have observed a partial normalization of ATX levels within months of starting interferon-free direct-acting antiviral (DAA) HCV therapy, consistent with a non-fibrotic liver disease contribution to elevated ATX levels, or HCV-mediated hepatocyte activation. Relationships between ATX, lysophosphatidic acid (LPA) and parameters of systemic immune activation will be discussed in the context of HCV infection, age, immune health, liver health, and hepatocellular carcinoma (HCC).

• Aging
• Autotaxin
• Hepatitis
• Hepatocellular Carcinoma
• Immune Activation
• Immunity
• Inflammation
• Liver
• Lysophosphatidic Acid

Liver cancer is one of the leading causes of death worldwide due to late diagnosis and scarcity of treatment options. The major risk factor for liver cancer is cirrhosis with the underlying causes of cirrhosis being viral infection (hepatitis B or C), metabolic deregulation (Non-alcoholic fatty liver disease (NAFLD) in the presence of obesity and diabetes), alcohol or cholestatic disorders. Lysophosphatidic acid (LPA) is a bioactive phospholipid with numerous effects, most of them compatible with the hallmarks of cancer (proliferation, migration, invasion, survival, evasion of apoptosis, deregulated metabolism, neoangiogenesis, etc.). Autotaxin (ATX) is the enzyme responsible for the bulk of extracellular LPA production, and together with LPA signaling is involved in chronic inflammatory diseases, fibrosis and cancer. This review discusses the most important findings and the mechanisms related to ATX/LPA/LPAR involvement on metabolic, viral and cholestatic liver disorders and their progression to liver cancer in the context of human patients and mouse models. It focuses on the role of ATX/LPA in NAFLD development and its progression to liver cancer as NAFLD has an increasing incidence which is associated with the increasing incidence of liver cancer. Bearing in mind that adipose tissue accounts for the largest amount of LPA production, many studies have implicated LPA in adipose tissue metabolism and inflammation, liver steatosis, insulin resistance, glucose intolerance and lipogenesis. At the same time, LPA and ATX play crucial roles in fibrotic diseases. Given that hepatocellular carcinoma (HCC) is usually developed on the background of liver fibrosis, therapies that both delay the progression of fibrosis and prevent its development to malignancy would be very promising. Therefore, ATX/LPA signaling appears as an attractive therapeutic target as evidenced by the fact that it is involved in both liver fibrosis progression and liver cancer development.

• ENPP2)
• LPA receptors (LPARs)
• Liver fibrosis
• Lysophosphatidic acid (LPA), Autotaxin (ATX
• cholangiocarcinoma
• cirrhosis
• hepatocellular carcinoma (HCC)

The intestinal epithelium interacts dynamically with the immune system to maintain its barrier function to protect the host, while performing the physiological roles in absorption of nutrients, electrolytes, water and minerals. The importance of lysophosphatidic acid (LPA) and its receptors in the gut has been progressively appreciated. LPA signaling modulates cell proliferation, invasion, adhesion, angiogenesis, and survival that can promote cancer growth and metastasis. These effects are equally important for the maintenance of the epithelial barrier in the gut, which forms the first line of defense against the milieu of potentially pathogenic stimuli. This review focuses on the LPA-mediated signaling that potentially contributes to inflammation and tumor formation in the gastrointestinal tract.

• colorectal cancer
• inflammation
• intestine
• lysophosphatidic acid

Lysophosphatidic acid (LPA), a glycerophospholipid, consists of a glycerol backbone connected to a phosphate head group and an acyl chain linked to sn-1 or sn-2 position. In the circulation, LPA is in sub-millimolar range and mainly derived from hydrolysis of lysophosphatidylcholine, a process mediated by lysophospholipase D activity in proteins such as autotaxin (ATX). Intracellular and extracellular LPAs act as bioactive lipid mediators with diverse functions in almost every mammalian cell type. The binding of LPA to its receptors LPA_1-6 activates multiple cellular processes such as migration, proliferation and survival. The production of LPA and activation of LPA receptor signaling pathways in the events of physiology and pathophysiology have attracted the interest of researchers. Results from studies using transgenic and gene knockout animals with alterations of ATX and LPA receptors genes, have revealed the roles of LPA signaling pathways in metabolic active tissues and organs. The present review was aimed to summarize recent progresses in the studies of extracellular and intracellular LPA production pathways. This includes the functional, structural and biochemical properties of ATX and LPA receptors. The potential roles of LPA production and LPA receptor signaling pathways in obesity, insulin resistance and liver fibrosis are also discussed.

• Autotaxin
• Lysophosphatidic acid receptors
• Obesity
• Lysophosphatidic acid
• Insulin resistance
• Liver fibrosis

• Adipocytes/physiology
• Animals
• Humans
• Insulin Resistance/physiology
• Liver Cirrhosis/blood
• Liver Cirrhosis/pathology
• Lysophosphatidylcholines/metabolism
• Lysophospholipids/blood
• Lysophospholipids/metabolism
• Models, Animal
• Obesity/blood
• Obesity/pathology
• Phosphoric Diester Hydrolases/metabolism
• Receptors, Lysophosphatidic Acid/metabolism
• Signal Transduction/physiology

The purpose of this study was to determine whether serum autotaxin concentrations reflect liver stiffness in patients with chronic hepatitis C virus (HCV) treated with direct‐acting antiviral agents. Adult patients with chronic HCV were enrolled from January 2016 to August 2017. Autotaxin concentrations in these patients were compared with those of a control group consisting of healthy individuals. Liver stiffness was determined by transient elastography. The relationship between fibrosis markers and fibrosis scores was evaluated before and after treatment. Data from 155 HCV patients and 56 control subjects were analyzed. Autotaxin concentrations were significantly higher in HCV patients with liver stiffness scores less than or equal to 7.4 kPa versus controls. Autotaxin concentrations at the end of treatment and beyond were significantly lower than those prior to treatment. Pretreatment and posttreatment autotaxin concentrations in male and female patients with liver stiffness scores greater than 14.9 kPa changed significantly (P < 0.01 and P < 0.01, respectively). From the start of treatment to 6 months following treatment, the fibrosis marker/liver stiffness score ratios changed as follows: autotaxin: 0.189 (95% confidence interval [CI]: 0.169‐0.209) to 0.191 (95% CI: 0.166‐0.216; P= 0.88); Wisteria floribundaagglutinin‐positive Mac‐2‐binding protein: 0.294 (95% CI: 0.256‐0.332) to 0.223 (95% CI: 0.191‐0.255; P< 0.001); hyaluronic acid: 19.05 (95% CI: 14.29‐23.81) to 13.92 (95% CI: 11.16‐16.70; P = 0.044); and type IV collagen 7S: 0.560 (95% CI: 0.515‐0.604) to 0.546 (95% CI: 0.497‐0.895; P = 0.052). Conclusion: Autotaxin concentrations reflect liver stiffness before and after antiviral treatment in patients with chronic HCV infection.

A quarter-century after the discovery of autotaxin in cell culture, the autotaxin-lysophosphatidate (LPA)-lipid phosphate phosphatase axis is now a promising clinical target for treating chronic inflammatory conditions, mitigating fibrosis progression, and improving the efficacy of existing cancer chemotherapies and radiotherapy. Nearly half of the literature on this axis has been published during the last five years. In cancer biology, LPA signaling is increasingly being recognized as a central mediator of the progression of chronic inflammation in the establishment of a tumor microenvironment which promotes cancer growth, immune evasion, metastasis, and treatment resistance. In this review, we will summarize recent advances made in understanding LPA signaling with respect to chronic inflammation and cancer. We will also provide perspectives on the applications of inhibitors of LPA signaling in preventing cancer initiation, as adjuncts extending the efficacy of current cancer treatments by blocking inflammation caused by either the cancer or the cancer therapy itself, and by disruption of the tumor microenvironment. Overall, LPA, a simple molecule that mediates a plethora of biological effects, can be targeted at its levels of production by autotaxin, LPA receptors or through LPA degradation by lipid phosphate phosphatases. Drugs for these applications will soon be entering clinical practice.

• adjuvant therapy
• chemoresistance
• chronic inflammation
• fibrosis
• hallmarks of cancer
• lipid phosphate phosphatases
• lysophosphatidic acid
• metastasis
• radiotherapy

• apolipoprotein M
• autotaxin
• lysophosphatidic acid
• lysophosphatidylserine
• lysophospholipids
• sphingosine 1-phosphate

• Animals
• Body Fluids/metabolism
• Humans
• Laboratories
• Lysophospholipids/blood
• Lysophospholipids/metabolism

Lysophosphatidic acid (LPA) receptor signaling has been implicated in cardiovascular and obesity-related metabolic disease. However, the distribution and regulation of LPA receptors in the myocardium and adipose tissue remain unclear.

This study aimed to characterize the mRNA expression of LPA receptors (LPA1-6) in the murine and human myocardium and adipose tissue, and its regulation in response to obesity.

LPA receptor mRNA levels were determined by qPCR in i) heart ventricles, isolated cardiomyocytes, and perigonadal adipose tissue from chow or high fat-high sucrose (HFHS)-fed male C57BL/6 mice, ii) 3T3-L1 adipocytes and HL-1 cardiomyocytes under conditions mimicking gluco/lipotoxicity, and iii) human atrial and subcutaneous adipose tissue from non-obese, pre-obese, and obese cardiac surgery patients.

LPA1-6 were expressed in myocardium and white adipose tissue from mice and humans, except for LPA3, which was undetectable in murine adipocytes and human adipose tissue. Obesity was associated with increased LPA4, LPA5 and/or LPA6 levels in mice ventricles and cardiomyocytes, HL-1 cells exposed to high palmitate, and human atrial tissue. LPA4 and LPA5 mRNA levels in human atrial tissue correlated with measures of obesity. LPA5 mRNA levels were increased in HFHS-fed mice and insulin resistant adipocytes, yet were reduced in adipose tissue from obese patients. LPA4, LPA5, and LPA6 mRNA levels in human adipose tissue were negatively associated with measures of obesity and cardiac surgery outcomes. This study suggests that obesity leads to marked changes in LPA receptor expression in the murine and human heart and white adipose tissue that may alter LPA receptor signaling during obesity.

• 3T3-L1 Cells
• Adipose Tissue, White/metabolism
• Adult
• Aged
• Animals
• Female
• Gene Expression Profiling
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Myocardium/metabolism
• Obesity/etiology
• Obesity/genetics
• Obesity/metabolism
• RNA, Messenger/metabolism
• Receptors, Lysophosphatidic Acid/genetics

• Natural Sciences and Engineering Research Council of Canada
• Banting Research Foundation
• New Brunswick Health Research Foundation
• New Brunswick Innovation Foundation
• Chesley Research Fund
• Canadian Diabetes Association
• Canada Foundation for Innovation

• Autotaxin
• hyaluronic acid
• liver fibrosis
• lysophosphatidic acid
• type IV collagen

• hepatocellular carcinoma
• laparoscopic hepatectomy
• recurrence
• strategy
• survival

• Blood Loss, Surgical
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/surgery
• China/epidemiology
• Disease-Free Survival
• Female
• Hepatectomy
• Humans
• Laparoscopy
• Liver Neoplasms/mortality
• Liver Neoplasms/surgery
• Male
• Middle Aged
• Neoplasm Recurrence, Local/mortality
• Neoplasm Recurrence, Local/surgery
• Postoperative Complications
• Risk Factors