Autotaxin Concentrations Research Articles

Serum Autotaxin Concentrations Reflect Changes in Liver Stiffness and Fibrosis After Antiviral Therapy in Patients with Chronic Hepatitis C.

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.

Autotaxin exacerbates tumor progression by enhancing MEK1 and overriding the function of miR-489-3p

Upregulated expression of autotaxin, a secreted phospholipase and phosphodiesterase enzyme, appears in malignant disease. The identification of a circulating miRNA signature should distinguish autotaxin-mediated disease and also elucidate unknown molecular mechanisms that rationalize its malignant potential. Using female transgenic ‘AT-ATX’ mice, whereby human wild-type autotaxin is expressed in liver under the control of the alpha-1 antitrypsin promoter, transgenic animals express augmented autotaxin in circulation and a percentage develop tumors. Serum collected at necropsy had circulating miRNAs analyzed for statistical significance. The ensuing autotaxin-mediated miRNome differentiated between groups: healthy FVB/N mice versus AT-ATX mice with and without tumors. Intriguingly, miR-489-3p was sharply increased in AT-ATX tumor-bearing mice. Tissue analysis showed a correlation between miR-489-3p expression in tumors and surrounding milieu with autotaxin concentration in circulation. Sequence alignment suggested miR-489-3p targets MEK1, which was confirmed through in vitro studies. Exogenously added miR-489-3p, which decreases MEK1 in normal cells, dramatically increased MEK1 expression in cells stably expressing autotaxin. Taken together, this suggests that autotaxin overrides the normal regulatory function of miR-489-3p to inhibit MEK1 via coordinately increased miR-489-3p appearing in serum.

Serum Autotaxin Is a Useful Disease Progression Marker in Patients with Primary Biliary Cholangitis

Autotaxin (ATX) is a secreted enzyme metabolized by liver sinusoidal endothelial cells that has been associated with liver fibrosis. We evaluated serum ATX values in 128 treatment-naïve, histologically assessed primary biliary cholangitis (PBC) patients and 80 healthy controls for comparisons of clinical parameters in a case-control study. The median ATX concentrations in controls and PBC patients of Nakanuma’s stage I, II, III, and IV were 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which increased significantly with disease stage (r = 0.53, P < 0.0001) as confirmed by Scheuer’s classification (r = 0.43, P < 0.0001). ATX correlated with Wisteria floribunda agglutinin-positive Mac-2 binding protein (M2BPGi) (r = 0.51, P < 0.0001) and fibrosis index based on four factors (FIB-4) index (r = 0.51, P < 0.0001). While ALP and M2BPGi levels had decreased significantly (both P < 0.001) by 12 months of ursodeoxycholic acid treatment, ATX had not (0.95 to 0.96 mg/L) (P = 0.07). We observed in a longitudinal study that ATX increased significantly (P < 0.00001) over 18 years in an independent group of 29 patients. Patients succumbing to disease-related death showed a significantly higher ATX increase rate (0.05 mg/L/year) than did survivors (0.02 mg/L/year) (P < 0.01). ATX therefore appears useful for assessing disease stage and prognosis in PBC.

Autotaxin-Lysophosphatidic Acid Pathway in Intraocular Pressure Regulation and Glaucoma Subtypes.

To compare the levels of autotaxin (ATX), lysophosphatidic acid (LPA), and lysophosphatidylcholine (LPC) in the aqueous humor (AH) of healthy control subjects with those of patients with different subtypes of glaucoma, and also to investigate the relationship of the ATX-LPA pathway with IOP and subtype of glaucoma. This study included 164 eyes of 164 consecutive cases of cataract and glaucoma surgery (37 healthy, 31 normal tension glaucoma, 49 primary open angle glaucoma, 28 secondary open angle glaucoma, and 19 exfoliation glaucoma). Aqueous levels of LPA, LPC, and ATX were quantified using liquid chromatography-tandem mass spectrometry and a two-site immunoenzymetric assay. The association between aqueous levels of ATX/LPA/LPC and IOP elevation in different glaucoma subtypes was investigated. The diagnostic values of indices of the ATX-LPA pathway were compared using receiver operating characteristic curve analysis. Notable increases in ATX/LPA/LPC levels in glaucoma patients were observed. The ATX-LPA pathway was significantly related to IOP elevation and the subtype of glaucoma, especially in SOAG and XFG patients, and the area under the curve was significant for discriminating glaucoma eyes from healthy eyes. Bioactive ATX/LPA/LPC concentrations were present in aqueous humor, and higher ATX and LPA concentrations were significantly correlated with IOP in all study subjects. Furthermore, the ATX-LPA pathway was significantly related to glaucoma subtype. These results reveal the potentially important role of the ATX-LPA pathway for IOP regulation in healthy subjects and glaucoma patients.

Serum autotaxin is a useful liver fibrosis marker in patients with chronic hepatitis B virus infection.

Autotaxin (ATX) is a secreted enzyme that is considered to be associated with liver damage as well as fibrosis. This study assessed the ability of ATX to diagnose liver fibrosis in patients with chronic hepatitis B virus (HBV) infection. Serum ATX levels were retrospectively evaluated in 101 treatment-naïve patients with HBV-related chronic hepatitis or cirrhosis, all of whom had undergone liver biopsy at our hospital. Serum ATX concentration increased significantly according to liver fibrosis stage in overall (r = 0.46, P < 0.0001), male (r = 0.55, P < 0.0001), and female (r = 0.52, P = 0.0006) patient groups. When analyzed by gender, serum ATX was one of the most reliable markers for all fibrosis stages compared with other tested non-invasive markers, which included hyaluronic acid, type IV collagen 7S, aspartate aminotransferase-to-platelet ratio index, and fibrosis index based on four factors, according to receiver operating characteristic curve analysis. Based on this histologically proven data, ATX represents a novel non-invasive biomarker for liver fibrosis in HBV-infected patients.

Performance of autotaxin as a serum marker for liver fibrosis.

Background Because autotaxin reportedly has a better performance than hyaluronic acid as a marker for liver fibrosis for the prediction of cirrhosis caused by hepatitis C, we aimed to further evaluate the role of autotaxin in liver fibrosis of other aetiologies. Methods Autotaxin antigen was measured in serum samples from 108 patients with chronic hepatitis B and 128 patients with non-alcoholic fatty liver disease who had undergone a liver biopsy as well as healthy subjects and patients with chronic kidney disease, diabetes mellitus, rheumatoid arthritis and cardiac dysfunction. Results When evaluated using receiver operator characteristics curves, the performance of autotaxin for the prediction of significant fibrosis (F2-F4) in chronic hepatitis B patients was better than that of hyaluronic acid or type IV collagen 7S. In non-alcoholic fatty liver disease patients, however, the performance of autotaxin for the prediction of significant fibrosis was poorer than that of hyaluronic acid or type IV collagen 7S. The increase in the serum autotaxin concentrations was less notable than that of hyaluronic acid or type IV collagen in patients with chronic kidney disease, diabetes mellitus, rheumatoid arthritis or cardiac dysfunction. Food intake did not affect the serum autotaxin concentrations. Conclusions Autotaxin is useful as a serum marker for liver fibrosis caused by not only chronic viral hepatitis C but also by hepatitis B, although it was less useful in patients with non-alcoholic fatty liver disease. The increase in serum autotaxin concentrations is fairly specific for liver fibrosis, and the serum autotaxin concentrations can be analysed without consideration of food intake before blood collection.

Association of Serum Autotaxin Levels with Liver Fibrosis in Patients with Chronic Hepatitis C

Metabolized by liver sinusoidal endothelial cells, autotaxin (ATX) is a secreted enzyme considered to be associated with liver damage. We sought to clarify the diagnostic ability of ATX for liver fibrosis in 593 biopsy-confirmed hepatitis C virus (HCV)-infected patients. The diagnostic accuracy of ATX was compared with clinical parameters and the established fibrosis biomarkers Wisteria floribunda agglutinin-positive Mac-2-binding protein, FIB-4 index, AST-to-platelet ratio, and Forn’s index. Median ATX levels were consistently higher in female controls and patients than in their male counterparts (P < 0.01). Serum ATX concentration increased significantly according to liver fibrosis stage in overall and both genders (P < 0.001). The cutoff values of ATX for prediction of fibrosis stages ≥F1, ≥F2, ≥F3, and F4 were 0.8, 1.1, 1.3, and 1.7 mg/L, respectively, in male patients and 0.9, 1.7, 1.8, and 2.0 mg/L, respectively, in female patients. The area under the receiver operating characteristic curve for ATX to diagnose fibrosis of ≥F2 (0.861) in male patients was superior to those of FIB-4 index and Forn’s index (P < 0.001), while that in female patients (0.801) was comparable with those of the other markers. ATX therefore represents a novel non-invasive biomarker for liver fibrosis in HCV-infected patients.

Validation of an autotaxin enzyme immunoassay in human serum samples and its application to hypoalbuminemia differentiation

Background Autotaxin (ATX), a tumor cell motility-stimulating factor, regulates the blood concentrations of lysophosphatidic acid (LPA), an important and multi-functional bioactive lipid, through its lysophospholipase D activity (lysoPLD). The introduction of ATX measurements into clinical laboratory testing is urgently needed. Methods Anti-human ATX monoclonal antibodies were produced by immunization of recombinant human ATX expressed in a baculovirus system. An immunoassay for the quantitative determination of ATX was established, and human serum samples were assayed. Results The within-run and between-run precision, interference, detection limit, and linearity studies were satisfactory. The central 95 percentile reference interval for the serum ATX antigen concentration in healthy subjects was 0.468–1.134 mg/l ( n = 120) and was strongly correlated with the serum lysoPLD activity. The ATX concentration was significantly ( p < 0.001) higher in women (0.625–1.323 mg/l) than in men (0.438–0.914 mg/l). The serum ATX concentrations were increased in patients with chronic liver diseases and decreased in postoperative prostate cancer patients but were not altered in nephrosis patients. Thus, serum ATX antigen concentrations could be used to discriminate these hypoalbuminemia conditions. Conclusions The present ATX antigen assay may be useful for clinical laboratory testing.