Autotaxin Concentrations Research Articles

Autotaxin concentrations in peritoneal dialysis effluent reflect peritoneal function.

Peritoneal equilibration test (PET) has been used to monitor peritoneal function. A more convenient marker would be useful in clinical situations including home medical care. Autotaxin is known to leak into the interstitium as vascular permeability increases during the progression of tissue fibrosis. Therefore, we hypothesized that autotaxin concentrations in peritoneal dialysis (PD) effluent might reflect peritoneal function. This study enrolled 45 patients undergoing PD from 2016 to 2021. Autotaxin concentrations measured in PD effluent were evaluated for their associations with markers obtained from PET. Mean age was 69 years, and 33 patients were men. Univariate and multivariate analyses revealed that autotaxin concentrations are associated with dialysate/plasma creatinine ratio, end/start dialysate glucose ratio, and the dip in the dialysate sodium concentration, a marker of ultrafiltration capacity, at baseline (all p < 0.05). Autotaxin concentrations in PD effluent might be an adjunct marker that reflects peritoneal function.

ISABELA Studies: Plasma Exposure and Target Engagement Do Not Explain the Lack of Efficacy of Ziritaxestat in Patients with Idiopathic Pulmonary Fibrosis.

Autotaxin (ATX) contributes to the production of lysophosphatidic acid (LPA), which is associated with fibrosis development in idiopathic pulmonary fibrosis (IPF). The ATX inhibitor ziritaxestat failed to reduce decline in forced vital capacity (FVC) in patients with IPF in ISABELA 1 and 2 (NCT03711162 and NCT03733444), two identically designed phase III studies. In the current analysis, we evaluated pharmacokinetic and pharmacodynamic data from the pooled ISABELA studies to determine whether the lack of efficacy could be attributed to insufficient exposure and/or target engagement. Nonlinear mixed effect modeling was performed to predict ziritaxestat exposure in individual patients and describe its effect on LPA C18:2 levels. We assessed whether there was a correlation between ziritaxestat and ATX concentration and evaluated the relationship between LPA C18:2 reduction and change from baseline in FVC. Ziritaxestat exposure in patients with IPF was numerically lower in those who received ziritaxestat on top of pirfenidone than in those who received ziritaxestat on top of nintedanib or ziritaxestat alone. In most patients, LPA C18:2 reduction was comparable to that reported in healthy volunteers. ATX concentrations increased over time and correlated weakly with ziritaxestat exposure and LPA C18:2 reduction. No correlation between reduction in LPA C18:2 and change from baseline in FVC was apparent. Based on these evaluations, exposure and target engagement are not thought to have contributed to the lack of efficacy observed. We hypothesize that the lack of efficacy of ziritaxestat in the ISABELA program, despite adequate LPA reduction, could be due to the involvement of an alternative pro-fibrotic pathway.

Upregulation of autotaxin by oxidative stress via Nrf2 activation: A novel insight into the compensation mechanism in preeclamptic placenta

The response of autotaxin (ATX)–lysophosphatidic acid (LPA) signaling system to placental oxidative stress (OS) and its significance to preeclampsia were investigated. For this purpose, oxidative stress index (OSI) and ATX levels were measured in the serum of pregnant women with preeclampsia. The expression levels of ATX and LPA receptors were assessed in trophoblast cells under high OS and glucose deprivation/re-oxygenation (OGD/R) conditions, with particular emphasis on the antioxidative nuclear factor erythroid 2-related factor 2 (NRF2) pathway. The influence of ATX–LPA signaling on cell migration was also evaluated using the wound healing assay. ATX concentrations and OSI in the serum were found to be elevated in preeclamptic women. The serum ATX levels were also positively correlated with OSI. Trophoblast cells responded to OS by increasing ATX mRNA expression concomitantly with intranuclear translocation of Nrf2, whereas inhibition of Nrf2 activation reverted this effect. The ATX–LPA signaling pathway facilitated trophoblast cell motility after Nrf2 activation. In conclusion, OS accumulation in preeclamptic placenta may activate the ATX–LPA system in trophoblasts via the Nrf2 pathway to sustain trophoblast functionality.

Lipoprotein(a) As a Potential Predictive Factor for Earlier Aortic Valve Replacement in Patients with Bicuspid Aortic Valve.

Bicuspid aortic valve (BAV) affects 0.5-2% of the general population and constitutes the major cause of severe aortic valve stenosis (AVS) in individuals ≤70 years. The aim of the present study was to evaluate the parameters that may provide information about the risk of AVS developing in BAV patients, with particular emphasis on lipoprotein(a) (Lp(a)), which is a well-recognized risk factor for stenosis in the general population. We also analyzed the impact of autotaxin (ATX) and interleukin-6 (IL-6) as parameters potentially related to the pathomechanism of Lp(a) action. We found that high Lp(a) levels (>50 mg/dL) occurred significantly more frequently in patients with AVS than in patients without AVS, both in the group below and above 45 years of age (p = 0.036 and p = 0.033, respectively). Elevated Lp(a) levels were also strictly associated with the need for aortic valve replacement (AVR) at a younger age (p = 0.016). However, the Lp(a) concentration did not differ significantly between patients with and without AVS. Similarly, we observed no differences in ATX between the analyzed patient groups, and both ATX activity and concentration correlated significantly with Lp(a) level (R = 0.465, p < 0.001 and R = 0.599, p < 0.001, respectively). We revealed a significantly higher concentration of IL-6 in young patients with AVS. However, this observation was not confirmed in the group of patients over 45 years of age. We also did not observe a significant correlation between IL-6 and Lp(a) or between CRP and Lp(a) in any of the analyzed groups of BAV patients. Our results demonstrate that a high level of Lp(a), greater than 50 mg/dL, may be a significant predictive factor for earlier AVR. Lp(a)-related parameters, such as ATX and IL-6, may be valuable in providing information about the additional cardiovascular risks associated with developing AVS.

Endothelial Specific Deletion of Autotaxin Improves Stroke Outcomes

Autotaxin (ATX) is an extracellular secretory enzyme (lysophospholipase D) that catalyzes the hydrolysis of lysophosphatidyl choline to lysophosphatidic acid (LPA). The ATX-LPA axis is a well-known pathological mediator of liver fibrosis, metastasis in cancer, pulmonary fibrosis, atherosclerosis, and neurodegenerative diseases. Also, it is believed that LPA may cause vascular permeability. In ischemic stroke, vascular permeability leading to hemorrhagic transformation is a major limitation for therapies and an obstacle to stroke management. So, in this study, we generated an endothelial-specific ATX deletion in mice (ERT2 ATX-/-) to observe stroke outcomes in a mouse stroke model to analyze the role of endothelial ATX. The AR2 probe and Evans Blue staining were used to perform the ATX activity and vascular permeability assays, respectively. Laser speckle imaging was used to observe the cerebral blood flow following stroke. In this study, we observed that stroke outcomes were alleviated with endothelial deletion of ATX. Permeability and infarct volume was reduced in ERT2 ATX-/- mice compared to ischemia-reperfusion (I/R) only mice. In addition, cerebral blood flow was retained in ERT2 ATX-/- compared to I/R mice. The outcomes in the stroke model are alleviated due to limited LPA concentration, reduced ATX concentration, and ATX activity in ERT2 ATX-/- mice. In this study, we observed that ATX produced by the endothelium could be a major factor responsible for increases in permeability and infarcts, and adverse effects on the cerebral blood flow during cerebral ischemic reperfusion. LPA produced specifically by endothelial cells in the vasculature can disrupt the BBB leading ultimately to neuronal loss and glial activation. With the deletion of ATX from the endothelium, the microvasculature might be more resilient due to reduced LPA. We found evidence that the functional outcomes of ischemic stroke were alleviated with ATX deletion. Therefore, endothelial ATX can be targeted to make better and more effective therapies for stroke management. his research was supported by Louisiana State University Health Sciences-Shreveport Intramural Grant 110101074A to SM; National Institutes of Health grants HL141998 and HL141998-01S1 to SM; grants AA025744, AA026708, and AA025744-02S1 to MP; grants HL122354 and HL145753 to MSB; P20GM12130 to Dr. Christopher Kevil. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Endothelial Specific Deletion of Autotaxin Improves Stroke Outcomes.

Autotaxin (ATX) is an extracellular secretory enzyme (lysophospholipase D) that catalyzes the hydrolysis of lysophosphatidyl choline to lysophosphatidic acid (LPA). The ATX-LPA axis is a well-known pathological mediator of liver fibrosis, metastasis in cancer, pulmonary fibrosis, atherosclerosis, and neurodegenerative diseases. Additionally, it is believed that LPA may cause vascular permeability. In ischemic stroke, vascular permeability leading to hemorrhagic transformation is a major limitation for therapies and an obstacle to stroke management. Therefore, in this study, we generated an endothelial-specific ATX deletion in mice (ERT2 ATX-/-) to observe stroke outcomes in a mouse stroke model to analyze the role of endothelial ATX. The AR2 probe and Evans Blue staining were used to perform the ATX activity and vascular permeability assays, respectively. Laser speckle imaging was used to observe the cerebral blood flow following stroke. In this study, we observed that stroke outcomes were alleviated with the endothelial deletion of ATX. Permeability and infarct volume were reduced in ERT2 ATX-/- mice compared to ischemia-reperfusion (I/R)-only mice. In addition, the cerebral blood flow was retained in ERT2 ATX-/- compared to I/R mice. The outcomes in the stroke model are alleviated due to the limited LPA concentration, reduced ATX concentration, and ATX activity in ERT2 ATX-/- mice. This study suggests that endothelial-specific ATX leads to increased LPA in the brain vasculature following ischemic-reperfusion and ultimately disrupts vascular permeability, resulting in adverse stroke outcomes.

Utility of serum autotaxin levels for predicting post hepatectomy liver failure in hepatocellular carcinoma.

This study aimed to evaluate the usefulness of serum autotaxin, a novel liver fibrosis marker, for predicting post hepatectomy liver failure (PHLF) in patients undergoing hepatectomy for hepatocellular carcinoma (HCC). Autotaxin was measured in sera from 269 patients undergoing hepatectomy for HCC. Correlations between autotaxin level, liver fibrosis stage (METAVIR F0-F4), and PHLF, as assessed by the International Study Group of Liver Surgery criteria, were analyzed. Median autotaxin concentrations correlated significantly with fibrosis stage (F0, 0.93; F1, 0.96; F2, 1.18; F3, 1.40; and F4, 1.47 mg/l; P < .0001). Autotaxin levels were significantly higher in female patients and hepatitis C virus antibody-positive patients compared with male or antibody-negative patients (P < .0001). PHLF grade ≥ B occurred in 25 patients (9.3%). A PHLF prediction model was constructed from four variables (autotaxin, resection rate, sex, and hepatitis C virus antibody positivity) and gave an area under the receiver operating characteristic curve of 0.8 (95% confidence interval [CI]: 0.69-0.87), which was superior to models based on ALPlat and resection rate (0.75, 95% CI: 0.64-0.83) or indocyanine green retention test and resection rate (0.72, 95% CI: 0.61-0.81). Serum autotaxin has utility for predicting liver fibrosis and PHLF in patients with HCC.

Serum autotaxin levels correlate with the severity of pruritus in intrahepatic cholestasis of pregnancy.

This study aimed to examine autotaxin (ATX) concentrations in the serum of pregnant women complicated with intrahepatic cholestasis of pregnancy (ICP) and compare them with individuals with uncomplicated healthy pregnancies. This prospective case-control study took place with 83 pregnant women. The study group included 43 pregnant women presenting with a singleton pregnancy diagnosed with ICP in their third trimester of pregnancy. The diagnostic power of the ATX variable was examined by receiver operating characteristic analysis, and the cut-off value calculated according to the Youden index was summarized with the related sensitivity and specificity points. The mean serum concentration of maternal ATX was significantly higher in the ICP cases (8.91 ± 2.69 pg/mL) compared to the pregnant women in the control group (3.59 ± 1.39 ng/mL, p < 0.001). According to the Youden index, a 5.80 ng/mL cut-off value of serum ATX concentrations can be used to diagnose ICP with 97.7% sensitivity and 97.5% specificity. A significant highly positive correlation was found between maternal serum ATX levels and maternal serum total bile acid levels (r=0.633 and p < 0.001) and itch intensity, which was objectified by the visual analog scale score (r=0.951 and p < 0.001). Maternal serum ATX levels were significantly increased in ICP patients as compared with healthy pregnant women. Also, serum ATX activity was highly correlated with the itch intensity. We consider that ATX might represent a robust, accurate, and reliable circulating biomarker to diagnose ICP.

Autotaxin is a potential link between genetic risk factors and immunological disturbances of plasmacytoid dendritic cells in systematic lupus erythematosus.

The importance of autotaxin, an enzyme that catalyzes lysophospholipid production, has recently been recognized in various diseases, including cancer and autoimmune diseases. Herein, we examined the role of autotaxin in systemic lupus erythematosus (SLE), utilizing data from ImmuNexUT, a comprehensive database consisting of transcriptome data and expression quantitative trait locus (eQTL) data of immune cells from patients with immune-mediated disorders. Serum autotaxin concentrations in patients with SLE and healthy controls (HCs) were compared. The transcriptome data of patients with SLE and age- and sex-matched HCs were obtained from ImmuNexUT. The expression of ENPP2, the gene encoding autotaxin, was examined in peripheral blood immune cells. Next, weighted gene correlation network analysis (WGCNA) was performed to identify genes with expression patterns similar to ENPP2. The ImmuNexUT eQTL database and public epigenomic databases were used to infer the relationship between autotaxin and pathogenesis of SLE. Autotaxin levels were elevated in the serum of patients with SLE compared to HCs. Furthermore, the expression of ENPP2 was higher in plasmacytoid dendritic cells (pDCs) than in other immune cell subsets, and its expression was elevated in pDCs of patients with SLE compared to HCs. In WGCNA, ENPP2 belonged to a module that correlated with disease activity. This module was enriched in interferon-associated genes and included genes whose expression was influenced by single-nucleotide polymorphisms associated with SLE, suggesting that it is a key module connecting genetic risk factors of SLE with disease pathogenesis. Analysis utilizing the ImmuNexUT eQTL database and public epigenomic databases suggested that the increased expression of ENPP2 in pDCs from patients with SLE may be caused by increased expression of interferon-associated genes and increased binding of STAT3 complexes to the regulatory region of ENPP2. Autotaxin may play a critical role in connecting genetic risk factors of SLE to disease pathogenesis in pDCs.

Inhibition of the enzyme autotaxin reduces cortical excitability and ameliorates the outcome in stroke.

Stroke penumbra injury caused by excess glutamate is an important factor in determining stroke outcome; however, several therapeutic approaches aiming to rescue the penumbra have failed, likely due to unspecific targeting and persistent excitotoxicity, which continued far beyond the primary stroke event. Synaptic lipid signaling can modulate glutamatergic transmission via presynaptic lysophosphatidic acid (LPA) 2 receptors modulated by the LPA-synthesizing molecule autotaxin (ATX) present in astrocytic perisynaptic processes. Here, we detected long-lasting increases in brain ATX concentrations after experimental stroke. In humans, cerebrospinal fluid ATX concentration was increased up to 14 days after stroke. Using astrocyte-specific deletion and pharmacological inhibition of ATX at different time points after experimental stroke, we showed that inhibition of LPA-related cortical excitability improved stroke outcome. In transgenic mice and in individuals expressing a single-nucleotide polymorphism that increased LPA-related glutamatergic transmission, we found dysregulated synaptic LPA signaling and subsequent negative stroke outcome. Moreover, ATX inhibition in the animal model ameliorated stroke outcome, suggesting that this approach might have translational potential for improving the outcome after stroke.

Plasma Concentrations of Lysophosphatidic Acid and Autotaxin in Abstinent Patients with Alcohol Use Disorder and Comorbid Liver Disease.

Lysophosphatidic acid (LPA) is an endogenous lysophospholipid and a bioactive lipid that is synthesized by the enzyme autotaxin (ATX). The ATX–LPA axis has been associated with cognitive dysfunction and inflammatory diseases, mainly in a range of nonalcoholic liver diseases. Recently, preclinical and clinical evidence has suggested a role of LPA signaling in alcohol use disorder (AUD) and AUD-related cognitive function. However, the ATX–LPA axis has not been sufficiently investigated in alcoholic liver diseases. An exploratory study was conducted in 136 participants, 66 abstinent patients with AUD seeking treatment for alcohol (alcohol group), and 70 healthy control subjects (control group). The alcohol group was divided according to the presence of comorbid liver diseases (i.e., fatty liver/steatosis, alcoholic steatohepatitis, or cirrhosis). All participants were clinically evaluated, and plasma concentrations of total LPA and ATX were measured using enzyme-linked immunosorbent assays. Data were primarily analyzed using analysis of covariance (ANCOVA) while controlling for age, body mass index, and sex. Logistic regression models were created to assess the association of the ATX–LPA axis and AUD or liver disease. LPA and ATX were log10-transformed to fit the assumptions of parametric testing.The main results were as follows: total LPA and ATX concentrations were dysregulated in the alcohol group, and patients with AUD had significantly lower LPA (F(1,131) = 10.677, p = 0.001) and higher ATX (F(1,131) = 8.327, p = 0.005) concentrations than control subjects; patients with AUD and liver disease had significantly higher ATX concentrations (post hoc test, p < 0.05) than patients with AUD but not liver disease; significant correlations between AUD-related variables and concentrations of LPA and ATX were only found in the non-liver disease subgroup (the duration of alcohol abstinence with LPA and ATX (r = +0.33, p < 0.05); and the severity of AUD with ATX (rho = −0.33, p < 0.05)); and a logistic regression model with LPA, ATX, and AUD-related variables showed an excellent discriminative power (area under the curve (AUC) = 0.915, p < 0.001) for distinguishing patients with AUD and comorbid liver disease. In conclusion, our data show that the ATX–LPA axis is dysregulated in AUD and suggest this lipid signaling, in combination with relevant AUD-related variables, as a reliable biomarker of alcoholic liver diseases.

Dysregulation of the Lysophosphatidylcholine/Autotaxin/Lysophosphatidic Acid Axis in Acute-on-Chronic Liver Failure Is Associated With Mortality and Systemic Inflammation by Lysophosphatidic Acid-Dependent Monocyte Activation.

Acute-on-chronic liver failure (ACLF) is characterized by systemic inflammation, monocyte dysfunction, and susceptibility to infection. Lysophosphatidylcholines (LPCs) are immune-active lipids whose metabolic regulation and effect on monocyte function in ACLF is open for study. Three hundred forty-two subjects were recruited and characterized for blood lipid, cytokines, phospholipase (PLA), and autotaxin (ATX) concentration. Peripheral blood mononuclear cells and CD14+ monocytes were cultured with LPC, or its autotaxin (ATX)-derived product, lysophosphatidic acid (LPA), with or without lipopolysaccharide stimulation and assessed for surface marker phenotype, cytokines production, ATX and LPA-receptor expression, and phagocytosis. Hepatic ATX expression was determined by immunohistochemistry. Healthy volunteers and patients with sepsis or acute liver failure served as controls. ACLF serum was depleted in LPCs with up-regulated LPA levels. Patients who died had lower LPC levels than survivors (area under the receiver operating characteristic curve, 0.94; P<0.001). Patients with high-grade ACLF had the lowest LPC concentrations and these rose over the first 3days of admission. ATX concentrations were higher in patients with AD and ACLF and correlated with Model for End-Stage Liver Disease, Consortium on Chronic Liver Failure-Sequential Organ Failure Assessment, and LPC/LPA concentrations. Reduction in LPC correlated with higher monocyte Mer-tyrosine-kinase (MerTK) and CD163 expression. Plasma ATX concentrations rose dynamically during ACLF evolution, correlating with IL-6 and TNF-α, and were associated with increased hepatocyte ATX expression. ACLF patients had lower human leukocyte antigen-DR isotype and higher CD163/MerTK monocyte expression than controls; both CD163/MerTK expression levels were reduced in ACLF ex vivo following LPA, but not LPC, treatment. LPA induced up-regulation of proinflammatory cytokines by CD14+ cells without increasing phagocytic capacity. ATX up-regulation in ACLF promotes LPA production from LPC. LPA suppresses MerTK/CD163 expression and increases monocyte proinflammatory cytokine production. This metabolic pathway could be investigated to therapeutically reprogram monocytes in ACLF.

The impact of achieving a sustained virological response with direct-acting antivirals on serum autotaxin levels in chronic hepatitis C patients

BackgroundAutotaxin (ATX) is an emerging biomarker for liver fibrosis. Achievement of sustained virological response (SVR) by direct-acting antivirals (DAAs) results in hepatic fibrosis regression in chronic hepatitis C (CHC) patients. In this context, the clinical implications of ATX have not yet been well-defined. In this study, we aimed to assess the impact of achieving SVR with DAA therapy on serum ATX levels and whether these levels can reflect the regression of hepatic fibrosis in CHC patients. We evaluated serum ATX levels at baseline and 12 weeks post-DAA therapy in 48 CHC patients. We compared ATX with FIB4 score and AST-to-Platelet Ratio Index (APRI) as regards the detection of grade F3–4 fibrosis.ResultsSerum ATX levels were significantly declined in 47 patients after the achievement of SVR12 (p < 0.001). The diagnostic ability of ATX for the detection of grade F3–4 fibrosis was inferior to FIB4 and APRI scores at baseline and SVR12.ConclusionAchievement of SVR with DAA therapy causes a significant decline in serum autotaxin concentrations, suggesting early regression of hepatic fibrosis in CHC patients. However, its diagnostic capability for routine patient monitoring and follow-up is still under debate.

NSun2 regulates aneurysm formation by promoting autotaxin expression and T cell recruitment.

Abdominal aortic aneurysm (AAA) is characterized by inflammatory cell infiltration and aggravated by hyperhomocysteinemia (HHcy). It is unknown whether the homocysteine (Hcy)-activated RNA methyltransferase NOP2/Sun domain family member 2 (NSun2) is associated with AAA. Here, we found that NSun2 deficiency significantly attenuated elastase-induced and HHcy-aggravated murine AAA with decreased T cell infiltration in the vessel walls. T cell labeling and adoptive transfer experiments confirmed that NSun2 deficiency inhibited the chemotaxis of vessels to T cells. RNA sequencing of endothelial cells showed that Hcy induced the accumulation of various metabolic enzymes of the phospholipid PC-LPC-LPA metabolic pathway, especially autotaxin (ATX). In the elastase-induced mouse model of AAA, ATX was specifically expressed in the endothelium and the plasma ATX concentration was upregulated and even higher in the HHcy group, which were decreased dramatically by NSun2 knockdown. In vitro Transwell experiments showed that ATX dose-dependently promoted T cell migration. HHcy may upregulate endothelial ATX expression and secretion and in turn recruit T cells into the vessel walls to induce vascular inflammation and consequently accelerate the pathogenesis of AAA. Mechanistically, secreted ATX interacted with T cells by binding to integrin α4, which subsequently activated downstream FAK/Src-RhoA signaling pathways and then induced T cell chemokinesis and adhesion. ATX overexpression in the vessel walls reversed the inhibited development of AAA in the NSun2-deficient mice. Therefore, NSun2 mediates the development of HHcy-aggravated AAA primarily by increasing endothelial ATX expression, secretion and T cell migration, which is a novel mechanism for HHcy-aggravated vascular inflammation and pathogenesis of AAA.

Urinary autotaxin concentrations are associated with kidney injury

BackgroundWhile basic researches have shown the involvement of the autotaxin-lysophosphatidic acid (ATX-LPA) axis in the pathogenesis of kidney diseases, no clinical studies have revealed the association between urinary ATX concentrations and kidney disease yet. We investigate the clinical characteristics in relation to the urinary ATX concentrations and the potential association between urinary ATX concentrations and various kidney diseases. MethodsWe measured the urinary ATX concentrations in residual urine samples after routine clinical testing from a total of 326 subjects with various kidney diseases and healthy subjects. We compared the urinary ATX concentrations in relation to clinical parameters and urinary biomarkers, and investigated their association with various kidney diseases. ResultsThe urinary ATX concentrations were associated with the gender, eGFR, presence/absence of hematuria, serum ATX, urinary concentrations of total protein (TP), microalbumin, N-acetyl-β-D-glucosaminidase (NAG), α1-microglobulin (α1-MG), and transforming growth factor-β. Multiple regression analyses identified urinary α1-MG, age, urinary TP, NAG, and hematuria as being significantly associated with the urinary ATX concentrations. Urinary ATX concentrations were higher in subjects with membranous nephropathy and systemic lupus erythematosus than in the control subjects. ConclusionsUrinary ATX might be associated with pathological conditions of the kidney associated with kidney injury.

Is there a Correlation between Monocyte Chemoattractant Protein-1 with Autotaxin, Azurocidin-1, Apolipoprotein C-III and Elastase-2 in Male Iraqi Acute Myocardial Infraction Patients?

Acute Myocardial infarction (AMI) is one of the important reasons of loss of life and bodily incapacity global prompt via cardiovascular diseases (CVD). AMI stimulates the innate immune system that is required to employee leukocytes to remove necrotic cells and recruit myocardial healing. To evaluate serum concentrations of Monocyte Chemoattractant Protein-1 (MCP-1), Autotaxin (ATX), Azurocidin-1 (AZU-1), Apolipoprotein C-III (APOC3) and Elastase-2 (ELA-2) in male Iraqi AMI patients and healthy controls (HCs), and explain the association of MCP-1with ATX, AZU-1, APOC3 and ELA-2 in male Iraqi AMI patients, also explore the best parameter which can use to differentiate between AMI patients. This case-control study included 84 men aged 40–68 years. Waist circumference (WC), hip circumference (HC), thoracic circumference (TC), neck circumference (NC), height, weight, age, and further covariates were obtained via an inquiry form. They were separated into two equivalent groups: the patients group and the healthy group, serum concentrations of MCP-1, ATX, AZU-1, APOC3 and ELA-2 were estimated via ELISA. Serum of MCP-1, ATX, AZU-1, APOC3 and ELA-2 concentrations were importantly greater in patients with AMI than in HCs (p&lt; 0.001). MCP-1 concentrations were importantly linked with ATX, AZU-1, APOC3 and ELA-2 in AMI cases (p&lt; 0.001). The greater value of MPC-1 association was with ELA-2 (r=0.592). MCP-1 exhibited the maximum value for área under curve (AUC=1) in comparison to other studied biomarkers. The present data explained the role of MCP-1, ATX, AZU-1, APOC3 and ELA-2 in AMI disease; we found they have central functions in this disease, mainly obese patients. Attention must be taken to avoid confusion among risk markers and risk factors. Great serum concentrations of MCP-1 offered important correlations between risk markers and risk factors of AMI disease.

P5292Obesity paradox, hyperlipoproteinemia(a), autotaxin concentration and stenotic atherosclerosis of different vascular territories

Abstract Background Controversial data have recently emerged about the role of obesity in the development of cardiovascular diseases, otherwise known as “Obesity paradox”. Autotaxin (ATX) hydrolyzes lysophosphatidylcholine to lysophosphatidic acid, a lipid mediator involved in pathological processes, including obesity. Purpose To investigate the association between obesity and stenotic atherosclerosis of different vascular territories. Methods The study included 1225 patients with results of instrumental examination of coronary, carotid and lower limbs arteries. Stenotic atherosclerosis (≥50%) in any vascular bed was diagnosed in 889 patients. Results The patients were divided into two groups depending on body mass index (BMI) (table). The groups were comparable on age, lipids and frequency of CHD. The obesity negatively associated with lower extremity artery disease (LEAD) (odds ratio (OR) 0.51; 95% CI 0.36–0.72, p&lt;0.01) adjusted for gender, age, smoking, type 2 diabetes, lipids and Lp(a). Multifocal atherosclerosis was also negatively associated with obesity (OR 0.44; 95% CI 0.28–0.71, p&lt;0.01). ATX level was lower in patients with LEAD (median [25; 75%]: 492 [418; 573] ng/ml) vs. patients without LEAD (520 [424; 618] ng/ml, p&lt;0.05). The similar results for ATX concentration were shown for patients with multifocal atherosclerosis vs. without stenotic atherosclerosis: 478 [414; 571] ng/ml vs. 551 [412; 678] ng/ml, p&lt;0.05. The corresponding trend was observed in patients with and without coronary heart disease (CHD) (502 [421; 594] vs. 545 [425; 638] ng/ml, p=0.05). ATX level was associated with BMI (r=0.34, p&lt;0.01) and negatively correlated with LEAD and multifocal atherosclerosis in obesity patients (r=−0.2, p&lt;0.05 in both cases). Characteristics of study groups Parameters Control, BMI &lt;30 kg/m2, n=846 Obesity, BMI ≥30 kg/m2, n=379 Hypertension 585 (69%) 316 (83%)*** Type 2 diabetes 133 (16%) 115 (30%)*** Lipoprotein(a), mg/dl 23.9 [9.0; 54.7] 18.0 [6.6; 49.2]* Lipoprotein(a) ≥30 mg/dl 372 (44%) 137 (36%)* Autotaxin, ng/ml 513.5±137.3 528.4±140.1 Carotid atherosclerosis 293 (35%) 127 (33%) CHD 539 (64%) 206 (54%)** LEAD 224 (26%) 66 (17%)*** *p&lt;0.05, **p&lt;0.005, ***p&lt;0.0005 compare with control group. Conclusion “Obesity paradox” was observed in the patients with LEAD, CHD and multifocal atherosclerosis and it could be associated with lysophosphatidic acid pathway.

Autotaxin is a valuable biomarker for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease.

We investigated the characteristics of serum autotaxin (ATX) and its diagnostic performance for liver fibrosis in a large cohort of patients with non-alcoholic fatty liver disease (NAFLD). We compared the usefulness of ATX and other fibrosis markers in 307 biopsy-confirmed NAFLD patients. In addition, in 145 participants with NAFLD, we compared the diagnostic performance of ATX with that of non-invasive imaging methods (vibration-controlled transient elastography and magnetic resonance elastography [MRE]). Serum ATX concentration was significantly correlated with fibrosis stage in male and female NAFLD patients. In male patients, the area under the receiver operating characteristic (AUROC) curve values of ATX for the diagnosis of ≥stage 1, ≥stage 2, ≥stage 3, and ≥stage 4 fibrosis were 0.65, 0.75, 0.81, and 0.95, respectively. In female NAFLD participants, the AUROC values were all >0.81. The sensitivity of ATX was highest for the diagnosis of ≥stage 2 and ≥stage 3 fibrosis in both men and women with NAFLD. In the comparison between ATX and non-invasive imaging methods, the AUROC for MRE was the highest at every stage of fibrosis. Serum ATX concentration is significantly correlated with fibrosis stage in NAFLD patients. The diagnostic accuracy of ATX for liver fibrosis is lower than that of MRE, but the sensitivities of ATX for the diagnosis of ≥stage 2 and ≥stage 3 were highest. We conclude that ATX is useful for the selection of patients requiring further evaluation for liver fibrosis.

Acute and chronic effect of bariatric surgery on circulating autotaxin levels.

Autotaxin (ATX), an adipose tissue‐derived lysophospholipase, has been involved in the pathophysiology of cardiometabolic diseases. The impact of bariatric surgery on circulating ATX levels is unknown. We examined the short‐ (24 h, 5 days) and longer‐term (6 and 12 months) impact of bariatric surgery; as well as the short‐term effect of caloric restriction (CR) on plasma ATX levels in patients with severe obesity. We measured ATX levels in 69 men and women (mean age: 41 ± 11 years, body mass index: 49.8 ± 7.1 kg/m2), before and after biliopancreatic diversion with duodenal switch surgery (BPD‐DS) as well as in a control group (patients with severe obesity without surgery; n = 34). We also measured ATX levels in seven patients with severe obesity and type 2 diabetes who underwent a 3‐day CR protocol before their BPD‐DS. At baseline, ATX levels were positively associated with body mass index, fat mass, insulin resistance (HOMA‐IR) as well as insulin and leptin levels and negatively with fat‐free mass. ATX concentrations decreased 26.2% at 24 h after BPD‐DS (342.9 ± 152.3 pg/mL to 253.2 ± 68.9 pg/mL, P < 0.0001) and by 16.4% at 12 months after BPD‐DS (342.9 ± 152.3 pg/mL to 286.8 ± 182.6 pg/mL, P = 0.04). ATX concentrations were unchanged during follow‐up in the control group (P = 0.4), and not influenced by short‐term CR. In patients with severe obesity, bariatric surgery induced a rapid and sustained decrease in plasma ATX levels. Acute changes in ATX may not be explained by bariatric surgery‐induced CR.

Autotaxin and soluble IL-2 receptor concentrations in cerebrospinal fluids are useful for the diagnosis of central nervous system invasion caused by haematological malignancies.

Invasion of the central nervous system by haematological malignancies is diagnosed by cytological analyses of cerebrospinal fluid or diagnostic imaging, while quantitative biomarkers for central nervous system invasion are not available and needed to be developed. In this study, we measured the concentrations of autotaxin and soluble IL-2 receptor in cerebrospinal fluid and evaluated their usefulness as biomarkers for central nervous system invasion. We observed that both the autotaxin and soluble IL-2 receptor concentrations in cerebrospinal fluid were higher in subjects with central nervous system invasion than in those without, and the cerebrospinal fluid concentrations were independent from the serum concentrations of these biomarkers. ROC analyses revealed that the soluble IL-2 receptor concentration in cerebrospinal fluid was a strong discriminator of central nervous system invasion in subjects with haematological malignancies, while the autotaxin concentration in cerebrospinal fluid also had a strong ability to discriminate central nervous system invasion when the subjects were limited to those with lymphoma. The combined measurement of autotaxin and soluble IL-2 receptor in cerebrospinal fluid improved the sensitivity without notably reducing the specificity for central nervous system invasion in subjects with lymphoma when central nervous system invasion was diagnosed in cases where either value was beyond the respective cut-off value. These results suggest the possible usefulness of soluble IL-2 receptor and autotaxin concentrations in cerebrospinal fluid for the diagnosis of central nervous system invasion.