Levels Of Leucine-rich Α-2-glycoprotein 1 Research Articles

Diet-enhanced LRG1 expression promotes insulin hypersecretion and ER stress in pancreatic beta cells.

Upregulation of serum leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in diet-induced obesity and metabolic disorders. However, its specific hormonal actions remain unclear. This study aimed to determine whether diet-enhanced serum LRG1 levels promote hyperinsulinaemia by directly stimulating insulin secretion from pancreatic beta cells. Human serum samples were obtained from individuals (both male and female) undergoing plastic surgery. Male C57BL/6 wild-type and Lrg1 whole-body knockout (Lrg1KO) mice were fed a 45% high-fat diet, with serum samples collected every 2 weeks to monitor LRG1 and insulin levels throughout diet-induced obesity. MIN6 beta cells were used to investigate the effects of LRG1 on insulin secretion and intracellular Ca2+ release. Antibodies targeting various LRG1 epitopes were used to neutralise LRG1 stimulation in MIN6 cells, and their effectiveness was tested in vivo to assess their ability to prevent LRG1-induced hyperinsulinaemia. We observed a significant positive association between human serum LRG1 levels and both age and BMI, with elevated levels observed in individuals with vs without type 2 diabetes. In mice fed a high-fat diet, LRG1 upregulation in serum was associated with hyperinsulinaemia. Lrg1 knockout protected mice from diet-induced islet hyperplasia and the loss of beta cell mass. Furthermore, neutralising LRG1 activity prevented the onset of diet-induced hyperinsulinaemia and preserved glucose tolerance. Mechanistically, LRG1 induces inositol triphosphate (IP3) production and intracellular Ca2+ release from the endoplasmic reticulum (ER) in a phospholipase C (PLC)-dependent manner, leading to excessive insulin secretion and ER stress in MIN6 beta cells. In summary, this study identifies LRG1 as a significant contributor to hyperinsulinaemia and beta cell dysfunction. Targeting LRG1 activity emerges as a promising therapeutic approach for addressing diet-induced beta cell dysfunction and managing type 2 diabetes.

The importance of leucine-rich α-2 glycoprotein-1 in acute calculus cholecystitis.

The aim of this prospective, single-center cohort study was to analyze serum leucine-rich α-2-glycoprotein-1 (LRG1) expression in patients with acute cholecystitis (AC) and to investigate its variation depending on symptom duration. Participants were divided into patients with AC and a healthy control group. At the time of diagnosis, blood samples were collected, and symptom onset times were questioned. Collected serum LRG1 levels were measured. 30 patients and 30 healthy volunteers were included in the study. LRG1 (p=0.008), white blood cells (WBC) (p<0.001), platelet (p=0.003), neutrophil (p<0.001), lymphocyte (p=0.001), and CRP (p=0.014) were significantly different in AC patients vs. the control group. When the correlations of serum laboratory values with the time of onset of symptoms were compared, LRG1 (p<0.001) was significantly correlated, while no significant correlation was observed in C-reactive protein (CRP) (p=0.572), WBC (p=0.155), and neutrophil (p=0.155). LRG1 expression increases after 24 hours in AC patients. Due to its correlation with symptom duration, we believe it can be helpful for timing cholecystectomy.

Leucine-rich alpha-2-glycoprotein 1 affects bone destruction via IL-6 in mouse periodontitis model.

To investigate the production of leucine-rich α-2-glycoprotein-1 (LRG1) in periodontitis patients and its effectiveness as a new diagnostic marker for periodontitis. In vitro experiments were conducted to analyze LRG1 mRNA expression in human gingival epithelial cells and fibroblasts via quantitative real-time PCR. Invivo experiments were conducted to analyze LRG1 localization in periodontitis patients. The correlation between the serum LRG1 levels and alveolar bone resorption in the mouse periodontitis model was also investigated. A positive correlation existed between the periodontal inflamed surface area and serum LRG1 levels (Spearman's rank correlation coefficient: 0.60). LRG1 mRNA expression in human gingival epithelial cells and fibroblasts was upregulated by Porphyromonas gingivalis stimulation or tumor necrosis factor-α stimulation. Interleukin-6 in human gingival epithelial cells and fibroblasts induced the production of LRG1 and transforming growth factor-β. LRG1 levels in the periodontal tissue and serum in the periodontitis model were higher than those in control mice. LRG1 local administration resulted in alveolar bone resorption, whereas the administration of interleukin-6R antibody inhibited bone resorption. LRG1 levels in serum and periodontal tissue are upregulated in periodontitis and are implicated in periodontal tissue destruction through interleukin-6 production.

High serum levels of leucine-rich α-2 glycoprotein 1 (LRG-1) are associated with poor survival in patients with early breast cancer

BackgroundLeucine-rich α-2 glycoprotein 1 (LRG-1) is a secreted glycoprotein that is mainly produced in the liver. Elevated levels of LRG-1 are found in a multitude of pathological conditions including eye diseases, diabetes, infections, autoimmune diseases, and cancer. In patients with early breast cancer (BC), high intratumoral LRG-1 protein expression levels are associated with reduced survival. In this study, we assessed serum levels of LRG-1 in patients with early BC and investigated its correlation with the presence of disseminated tumor cells (DTCs) in the bone marrow and survival outcomes.MethodsSerum LRG-1 levels of 509 BC patients were determined using ELISA and DTCs were assessed by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. We stratified LRG-1 levels according to selected clinical parameters. Using the log-rank (Mantel–Cox) test and multivariate Cox regression analysis, Kaplan–Meier survival curves and prognostic relevance were assessed.ResultsMean serum levels of LRG-1 were 29.70 ± 8.67 µg/ml. Age was positively correlated with LRG-1 expression (r = 0.19; p < 0.0001) and significantly higher LRG-1 levels were found in patients over 60 years compared to younger ones (30.49 ± 8.63 µg/ml vs. 28.85 ± 8.63 µg/ml; p = 0.011) and in postmenopausal patients compared to premenopausal patients (30.15 ± 8.34 µg/ml vs. 26.936.94 µg/ml; p = 0.002). Patients with no DTCs showed significantly elevated LRG-1 levels compared to the DTC-positive group (30.51 ± 8.69 µg/ml vs. 28.51 ± 8.54 µg/ml; p = 0.004). Overall and BC-specific survival was significantly lower in patients with high serum LRG-1 levels (above a cut-off of 33.63 µg/ml) compared to patients with lower LRG-1 levels during a mean follow-up of 8.5 years (24.8% vs. 11.1% BC-specific death; p = 0.0003; odds ratio 2.63, 95%CI: 1.56—4.36). Multivariate analyses revealed that LRG-1 is an independent prognostic marker for BC-specific survival (p = 0.001; hazard ratio 2.61).ConclusionsThis study highlights the potential of LRG-1 as an independent prognostic biomarker in patients with early BC.

Association Between Plasma LRG1 and Lower Cognitive Function in Asians With Type 2 Diabetes Mellitus.

Leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in the pathogenesis of diabetic complications, but its association with cognitive function remains unclear. Our primary objective is to investigate the longitudinal association between LRG1 and cognitive function in patients with type 2 diabetes mellitus (T2DM). Secondarily, we determine the causal relationship using Mendelian randomization (MR) and the role of arterial stiffness as a potential mediator. T2DM patients (n = 1039; age = 64.1 ± 6.4 years) were followed-up for 5.3 ± 1.2 years. Plasma LRG1 was measured at baseline using enzyme-linked immunosorbent assay. Baseline and follow-up cognitive function was assessed using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). One-sample MR was performed with rs4806985 as plasma LRG1-associated single-nucleotide polymorphism. Mediation analysis was performed to examine if pulse wave velocity (PWV), an arterial stiffness index, mediated the association between plasma LRG1 and follow-up cognitive function. Elevated baseline natural log (Ln)-transformed LRG1 was inversely associated with baseline and follow-up RBANS total score with adjusted coefficients -1.38 (95% CI -2.55 to -.21; P = .021) and -1.38 (95% CI -2.70 to -.07; P = .039), respectively. Genetically predicted higher levels of plasma LRG1 was associated with lower follow-up RBANS total score with coefficient -7.44 (95% CI -14.14 to -.74; P = .030) per unit increase in LnLRG1. Higher PWV accounted for 27.7% of the association between LnLRG1 and follow-up RBANS total score. Baseline plasma LRG1 was associated with lower cognitive function at follow-up in patients with T2DM, mediated by PWV. MR analysis provided evidence of an association between genetically influenced plasma LRG1 and lower cognitive function at follow-up.

Cross-Sectional and Longitudinal Associations of Serum LRG1 with Severity and Prognosis Among Adult Community-Acquired Pneumonia Patients.

Leucine-rich α-2 glycoprotein 1 (LRG1) is associated with various inflammatory lung diseases. Nevertheless, the connection between LRG1 and adult community-acquired pneumonia (CAP) individuals was still not well understood. Through a prospective cohort study, the correlations of serum LRG1 with severity and prognosis were evaluated in CAP patients. The study encompassed 327 patients who received the diagnosis of CAP. We collected fasting venous blood and clinical features. Serum LRG1 was detected by ELISA. CAP severity was assessed using various scoring systems. The prognostic outcomes were observed through follow-up visits. The level of serum LRG1 at admission was gradually increased with CAP severity scores. Serum LRG1 level shown positive associations with inflammatory indices, including C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6). Linear and logistic regression analyses suggested that serum LRG1 at admission was positively associated with severity scores and the risk of death in CAP patients. Serum LRG1 in combination with CAP severity scores significantly increased the predictive powers for severity and death compared with single serum LRG1 or severity scores. The study revealed positive connections of serum LRG1 levels with severity and poor prognosis in CAP patients, suggesting LRG1 partakes into the physiological processes of CAP. Serum LRG1 may be regarded as a potential biomarker in predicting the severity and death among CAP patients.

The Leucine-Rich α2-Glycoprotein-1 Levels in Patients with Multiple Myeloma

Introduction: Angiogenesis is considered important in the pathogenesis of multiple myeloma (MM), as well as in the targeted treatment of the disease. Leucine-rich α2-glycoprotein 1 (LRG1) is a protein that participates in angiogenesis and its effect on solid organ tumors has been investigated recently. This study aimed to investigate the relationship between MM and LRG1. Methods: The MM patients who admitted to Hatay Mustafa Kemal University Hematology Clinic between September 2021 and October 2022 were included in the study. The study consists of a total of 4 groups: newly diagnosed MM (NDMM), relapsed refractory MM (RRMM), MM in remission (Rem-MM), and control group. Demographic data were retrieved from hospital records. Blood samples of our study groups were centrifuged at 1,500 × g for 10 min and serum was collected. LRG1, IL-6, IL-8, TGF-β1, HIF-1α, FGF-2, and VEGF levels were analyzed in all groups by ELISA method, and statistical analysis was performed. Results: A total of 112 individuals, including NDMM (n: 27), RRMM (n: 18), Rem-MM (n: 42), and control group (n: 25), were enrolled in the study. Based on the analyses, the NDMM group exhibited significantly elevated levels of LRG1 (p < 0.001), TGF-1 (p < 0.001), and HIF-1α (p = 0.046, p < 0.001, and p = 0.003 compared to the RRMM, Rem-MM, and control groups, respectively) compared to the other groups. LRG1 levels were positively correlated with creatinine (r: 0.363, p = 0.001), calcium (r: 0.344, p = 0.001), total protein (r: 0.473, p < 0.001), erythrocyte sedimentation rate (r: 0.547, p < 0.001), lactate dehydrogenase (r: 0.321, p = 0.003), beta-2-microglobulin (r: 0.312, p = 0.017), IL-6 (r: 0.478, p < 0.001), IL-8 (r: 0.240, p = 0.03), TGF-β1 (r: 0.521, p < 0.001), and HIF-1α (r: 0.321, p = 0.003) levels and were negatively correlated with hemoglobin (r: −0.512, p < 0.001) and albumin (r: −0.549, p < 0.001) levels. Receiver operating characteristics (ROC) analysis revealed the association of LRG1 with the highest AUC value of 0.959 (95% CI: 0.904–1, p < 0.001) and the optimal cut-off value of 534.95 ng/mL (sensitivity: 93% and specificity: 99%) in the NDMM group compared to the control group. Conclusion: In this study, providing data for the first time on LRG1 levels in the setting of MM. LRG1 levels were found to be significantly higher in NDMM patients and in our study discriminate this patient population from RRMM, Rem-MM, and normal controls. Therefore, LRG1 seems to a potential biomarker that should be evaluated in future studies addressing the diagnosis, staging, follow-up, prognosis, and treatment target of MM.

Correlation of Leucine-Rich-α-2-Glycoprotein- 1 (LRG-1) Level in Urine with Cervical Cancer Stage, Histology Type and Histology Grading

Objective: To determine if the level of LRG-1 in urine correlates with cervical cancer stage, histology type and histology grading Method: This cross-sectional study using ELISA to test urinary LRG-1 of 59 cervical cancer patients. Data were analyzed using Kruskal-Wallis test. Results: From the total of 59 samples, LRG-1 in urine ranged from 0.48 ng/mL to 170.43 ng/mL, with median value 58.42 ng/mL. A median value of 21.42±52.29 ng/mL was found in the urine at early stage and 115.32±59.36 ng/mL at advanced stage. Most patients had cervical cancer at advanced stage (69.4%), squamous cell carcinoma (66.1%), and grade cannot be assessed (45.8%). Median LRG-1 levels were highest in squamous cell carcinoma (66.42±60.89 ng/mL) and poorly differentiated (127.74 ±54.13 ng/mL). LRG-1 levels were significantly correlated with cervical cancer stage (p-value=0.045) but not histological type (p-value=0.940) or histopathological grade (p-value=0.488). Conclusion: The more advanced the cervical cancer stage, the more elevated urinary LRG-1 levels. LRG-1 contributes to angiogenesis and antiapoptotic processes in cancer. Further studies are required to identify and evaluate LRG-1 in urine as an important biomarker for making clinical decisions and developing potential treatments.

LRG1 Associates with Iron Deficiency Anemia Markers in Adolescents.

Leucine-rich α-2 glycoprotein1 (LRG1) has been shown to be associated with several health conditions; however, its association with iron deficiency anemia, especially in children, has not been previously explored. In this study, we investigated the association between LRG1 and several iron deficiency anemia markers, including hemoglobin (Hb), albumin, red cell distribution width (RDW), iron, ferritin, and Hb transferrin saturation. A total of 431 participants were included in this analysis aged between 11 and 14 years. Higher LRG1 levels were observed in children diagnosed with anemia [31.1 (24.6, 43.2) µg/mL] compared to non-anemic children [29.2 (22.7-35.95) µg/mL]. Statistically significant differences of LRG1 level across the three groups (tertiles) of Hb, iron, transferrin saturation, albumin, RDW, ferritin, and WBC were observed. Strong negative correlations were observed between LRG1 and Hb (Spearman's rho = -0.11, p = 0.021), albumin (Spearman's rho = -0.24, p < 0.001), iron (Spearman's rho = -0.25, p < 0.001), and Hb transferrin saturation (Spearman's rho = -0.24, p < 0.001), whereas circulating LRG1 levels were positively associated with RDW (Spearman's rho = 0.21, p < 0.001). In conclusion, our findings demonstrate for the first time the strong association between iron deficiency anemia markers and LRG1 in otherwise healthy school-aged children. However, further studies are needed to corroborate those results and to look for similar associations in other population subgroups.

Plasma leucine-rich α-2-glycoprotein 1 - a novel marker of diabetic kidney disease in children and adolescents with type 1 diabetes mellitus?

Glomerular endothelial dysfunction and neoangiogenesis play a significant role in the pathogenesis of diabetic kidney disease (DKD). Leucine-rich α-2 glycoprotein 1 (LRG1) is a recently discovered protein that participates in the molecular pathway of inflammation and angiogenesis. We aimed to investigate efficacy of LRG1 to predict estimated glomerular filtration rate (eGFR) decrease in children and adolescents with type 1 diabetes mellitus (T1DM). The study comprised 72 participants with diabetes duration for ≥ 2years. At study initiation, LRG1, urine albumin, eGFR (cystatin C-based, and Schwartz), HbA1c, and lipid values were evaluated and diabetes-related clinical features and anthropometric measurements were collected. These results were compared with final control values after ≥ 1year. Patients were divided into subgroups according to presence of albuminuria progression, eGFR decrease, and metabolic control parameters. There was positive correlation between LRG1 level and Schwartz and cystatin C-based eGFR decline (r = 0.360, p = 0.003; r = 0.447, p = 0.001, respectively), and negative correlation between final cystatin C-based eGFR and LRG1 (p = 0.01, r = -0.345). Patients with cystatin C-based eGFR decrease > 10% had significantly higher LRG1 levels (p = 0.03), however, LRG1 was not different between albuminuria progression subgroups. A 0.282μg/ml increase in LRG1 correlated with a 1% decrease in eGFR in simple linear regression analysis (β = 0.282, %CI 0.11-0.45, p = 0.001) and LRG1 was an independent predictor of GFR decline even in the presence of covariates. Our study supports the relationship between plasma LRG1 and eGFR decline and suggests LRG1 may be an early marker of DKD progression in children with T1DM. A higher resolution version of the Graphical abstract is available as Supplementary information.

SIRT2 regulates extracellular vesicle-mediated liver–bone communication

The interplay between liver and bone metabolism remains largely uncharacterized. Here, we uncover a mechanism of liver-bone crosstalk regulated by hepatocyte SIRT2. We demonstrate that hepatocyte SIRT2 expression is increased in aged mice and elderly humans. Liver-specific SIRT2 deficiency inhibits osteoclastogenesis and alleviates bone loss in mouse models of osteoporosis. We identify leucine-rich α-2-glycoprotein 1 (LRG1) as a functional cargo in hepatocyte-derived small extracellular vesicles (sEVs). In SIRT2-deficient hepatocytes, LRG1 levels in sEVs are upregulated, leading to increased transfer of LRG1 to bone-marrow-derived monocytes (BMDMs), and in turn, to inhibition of osteoclast differentiation via reduced nuclear translocation of NF-κB p65. Treatment with sEVs carrying high levels of LRG1 inhibits osteoclast differentiation in human BMDMs and in mice with osteoporosis, resulting in attenuated bone loss in mice. Furthermore, the plasma level of sEVs carrying LRG1 is positively correlated with bone mineral density in humans. Thus, drugs targeting hepatocyte-osteoclast communication may constitute a promising therapeutic strategy for primary osteoporosis.

Diagnostic Utility of Serum Leucine-Rich α-2-Glycoprotein 1 for Acute Appendicitis in Children.

The aim of this study is to assess the diagnostic utility of serum leucine-rich α-2-glycoprotein 1 (LRG1) in pediatric patients with acute abdominal pain, admitted to the emergency surgical unit, in order to make a prompt and accurate diagnosis of acute appendicitis. Pediatric patients older than 5 years of age who presented to the emergency department from 15 October 2021 to 30 June 2022 with acute abdominal pain and suspected acute appendicitis were prospectively recruited in the study. Demographic and clinical data, as well as operative and postoperative data, were recorded. A total of 92 patients were equally distributed into two groups: children with acute appendicitis who underwent laparoscopic appendectomy and non-appendicitis patients, presenting with non-specific abdominal pain. LRG1 levels were determined using a commercially available LRG1 enzyme-linked immunosorbent assay (ELISA) kit. Serum LRG1 levels, as well as other inflammatory markers (white blood cell count (WBC), C-reactive protein (CRP) and absolute neutrophil count) were compared between groups. The median level of LRG1 in serum was significantly higher in the group of children with pathohistologically confirmed acute appendicitis than in the control group, at 350.3 µg/mL (interquartile range (IQR) 165.2-560.3) and 25.7 µg/mL (IQR 14.7-36.8) (p < 0.001), respectively. Receiver operating characteristic area under the curve for LRG1 from serum was 1.0 (95% CI 0.96-1.00; p < 0.001) and the value of >69.1 µg/mL was found to perfectly separate acute appendicitis cases from controls. Additionally, as expected, each of the examined laboratory inflammatory markers provided a significantly higher values in the acute appendicitis group compared to the control group: WBC 14.6 × 109/L (IQR 12.7, 18.7) vs. 7.0 × 109/L (IQR 5.4, 9.0) (p < 0.001), CRP 16.3 mg/dL (IQR 6.9, 50.4) vs. 2.2 mg/dL (IQR 2, 2) (p < 0.001) and absolute neutrophil count 84.6% (IQR 79.5, 89.0) vs. 59.5% (IQR 51.5, 68.6) (p < 0.001). LRG1 in the serum was found to be a promising novel biomarker, with excellent differentiation of acute appendicitis from non-appendicitis cases in children presenting with non-specific abdominal pain.

Associations of non-invasive indices of liver steatosis and fibrosis with progressive kidney impairment in adults with type 2 diabetes

Longitudinal data linking non-alcoholic fatty liver disease to kidney dysfunction in type 2 diabetes (T2D) are limited. This study evaluated the associations of non-invasive indices of liver steatosis and liver fibrosis with kidney impairment, and the mediatory role of the pro-angiogenic factor leucine-rich α-2 glycoprotein 1 (LRG1). T2D adults (n = 2057) were followed for a mean period of 6.1 ± 1.6years. Baseline liver steatosis [(hepatic steatosis index (HSI) and Zhejiang University index (ZJU)] and liver fibrosis [aspartate transaminase/alanine transaminase ratio (AAR) and BARD] indices derived from composite scoring systems were calculated. Plasma LRG1 levels were quantified using immunoassay. The study outcomes were progressive kidney function decline defined as estimated glomerular filtration rate (eGFR) decline of ≥ 40% and albuminuria progression defined as an increase in albuminuria category. Cross-sectionally, liver steatosis and liver fibrosis indices were associated with increased albuminuria (urinary albumin/creatinine ratio ≥ 30µg/mg) and reduced renal function (eGFR < 60mL/min/1.73m2) after covariate adjustment, respectively. Approximately 32% of the participants experienced progressive kidney function decline, while 38% had albuminuria worsening over time. Longitudinal analysis revealed that baseline AAR (hazard ratio: 1.56; 95% CI 1.15-2.11) and BARD (hazard ratio: 1.16, 95% CI 1.04-1.28) predicted progressive kidney function decline, partly mediated by LRG1. In contrast, liver steatosis (HSI and ZJU) but not liver fibrosis (AAR and BARD) indices were independently associated with albuminuria progression. Increased liver steatosis scores were associated with albuminuria deterioration. Conversely, liver fibrosis indices may be associated with progressive kidney function decline, potentially driven by increased inflammation and angiogenesis.

Hepatoprotective effects of moderate-intensity interval training along with ginger juice in an old male rat model.

Aging is a natural process coupled with oxidative stress and chronic inflammation, gradually associated with losing organ function over time. Therefore, the objective of the current work was to peruse the protective effects of 8-week moderate-intensity interval training (MIIT) and ginger extract supplementation on some biomarkers of oxidative stress, inflammation, and lipid metabolism in the liver of elderly males Wistar rats (animal study with ethical code IR.BMSU.REC.1401.015). A total of thirty-two 22-month-aged male Wistar rats were randomly assigned to four groups: (1) control, (2) MIIT, (3) ginger, and (4) MIIT + ginger. After 8weeks of treadmill training and ginger extract supplementation, the biochemical parameters (liver enzyme and lipid profile), inflammatory mediators (leucine-rich α-2 glycoprotein 1 (LRG1), tumor necrosis factor-alpha, and interleukin-6), pro-oxidant (malondialdehyde), antioxidant biomarkers (catalase, superoxide dismutase, total antioxidant capacity), some lipid metabolism regulators (carnitine palmitoyltransferase 1, adipose triglyceride lipase, acetyl-CoA carboxylase, CD36, and AMP-activated protein kinase), and liver histopathological changes were appraised. The acquired findings pointed out that MIIT combined with ginger extract appreciably diminished the serum levels of LRG1, liver enzymes, and lipid profile relative to the other groups after 8weeks of intervention. Furthermore, ginger + MIIT caused a great improvement in the liver levels of antioxidant biomarkers, pro-oxidant, pro-inflammatory biomarkers, lipid metabolism regulators, and liver tissue impairment compared to the other groups. The findings suggested that MIIT + ginger was more effective in improving examined indices relative to the other groups.

Increased LRG1 Levels in Overweight and Obese Adolescents and Its Association with Obesity Markers, Including Leptin, Chemerin, and High Sensitivity C-Reactive Protein.

Leucine-rich α-2 glycoprotein1 (LRG1) is a member of the leucine-rich repeat (LRR) family that is implicated in multiple diseases, including cancer, aging, and heart failure, as well as diabetes and obesity. LRG1 plays a key role in diet-induced hepatosteatosis and insulin resistance by mediating the crosstalk between adipocytes and hepatocytes. LRG1 also promotes hepatosteatosis by upregulating de novo lipogenesis in the liver and suppressing fatty acid β-oxidation. In this study, we investigated the association of LRG1 with obesity markers, including leptin and other adipokines in adolescents (11–14 years; n = 425). BMI-for-age classification based on WHO growth charts was used to define obesity. Plasma LRG1 was measured by ELISA, while other markers were measured by multiplexing assay. Median (IQR) of LRG1 levels was higher in obese (30 (25, 38) µg/mL) and overweight (30 (24, 39) µg/mL) adolescents, compared to normal-weight participants (27 (22, 35) µg/mL). The highest tertile of LRG1 had an OR [95% CI] of 2.55 [1.44, 4.53] for obesity. LRG1 was positively correlated to plasma levels of high sensitivity c-reactive protein (HsCRP) (ρ = 0.2), leptin (ρ = 0.2), and chemerin (ρ = 0.24) with p < 0.001. Additionally, it was positively associated with plasma level of IL6 (ρ = 0.17) and IL10 (ρ = 0.14) but not TNF-α. In conclusion, LRG1 levels are increased in obese adolescents and are associated with increased levels of adipogenic markers. These results suggest the usefulness of LRG1 as an early biomarker for obesity and its related pathologies in adolescents.

Association between Higher Circulating Leucine-Rich α-2 Glycoprotein 1 Concentrations and Specific Plasma Ceramides in Postmenopausal Women with Type 2 Diabetes.

Background: Although ceramides are involved in the pathophysiology of cardiovascular disease and other inflammation-associated disorders, there is a paucity of data on the association between plasma ceramides and inflammatory biomarkers in type 2 diabetes mellitus (T2DM). Therefore, we explored whether there was an association between plasma leucine-rich α-2 glycoprotein 1 (LRG1) concentrations (i.e., a novel proinflammatory signaling molecule) and specific plasma ceramides in postmenopausal women with T2DM. Methods: We measured six previously identified plasma ceramides, which have been associated with increased cardiovascular risk [plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)], amongst 99 Caucasian postmenopausal women with non-insulin-treated T2DM (mean age 72 ± 8 years, mean hemoglobin A1c 6.9 ± 0.7%), who consecutively attended our diabetes outpatient service during a 3-month period. Plasma ceramide and LRG1 concentrations were measured with a targeted liquid chromatography-tandem mass spectrometry assay and a Milliplex® MAP human cardiovascular disease magnetic bead kit, respectively. Results: In linear regression analyses, higher plasma LRG1 levels (1st tertile vs. 2nd and 3rd tertiles combined) were associated with higher levels of plasma Cer(d18:1/16:0) (standardized β coefficient: 0.289, p = 0.004), Cer(d18:1/18:0) (standardized β coefficient: 0.307, p = 0.002), Cer(d18:1/20:0) (standardized β coefficient: 0.261, p = 0.009) or Cer(d18:1/24:1) (standardized β coefficient: 0.343, p < 0.001). These associations remained significant even after adjusting for age, body mass index, systolic blood pressure, total cholesterol level, hemoglobin A1c, insulin resistance and statin use. Conclusions: The results of our pilot exploratory study suggest that higher plasma LRG1 concentration was associated with higher levels of specific high-risk plasma ceramide molecules in elderly postmenopausal women with metabolically well-controlled T2DM, even after adjusting for known cardiovascular risk factors and other potential confounding variables.

The Effect of Aerobic Exercise on Angiogenesis Factors in Middle-aged Women

Background and Aim: Aging is a process, in which the physiological capacity of the body decreases. One of these basic changes is the reduction of blood supply caused by the inability of angiogenesis. This article was conducted to investigate the effect of aerobic exercise on angiogenic factors, including leucine-rich α-2-glycoprotein 1 (LRG-1) and thrombospondin-1 (TSP-1) in middle-aged women. Materials and Methods: This quasi-experimental study was conducted on 18 middle-aged women. The samples were randomly divided into two groups, including the aerobic (n=9) and control (n=9) groups. The experimental group performed aerobic exercise for eight weeks (three sessions per week). Then, 5 mL of blood samples was taken from each person 48 hours before and after training to measure LRG-1 and TSP-1 protein levels. The dependent and independent t-tests were used to analyze the data. Results: The levels of LRG-1 in the experimental group showed a significant increase in post-test compared to the control group. Also, in the experimental group, TSP-1 levels showed a significant decrease in post-test compared to the control group. Conclusion: The results of this study showed that aerobic exercise can increase the levels of LRG-1 protein and decrease the serum TSP-1 protein levels; therefore, by increasing LRG-1 and decreasing TSP-1 levels, the angiogenesis process in the body is enhanced. Accordingly, middle-aged women are advised to do aerobic exercise as a tool to improve angiogenesis and improve blood circulation.

The Prognostic Value of Leucine-Rich α2 Glycoprotein 1 in Pediatric Spinal Cord Injury.

Objective Leucine-rich α2 glycoprotein 1 (LRG1) is a novel cytokine, which is believed to be involved in the inflammatory process of a series of diseases. However, the relationship between LRG1 and spinal cord injury (SCI) has not been reported. The purpose of our study is to determine the predictive value of LRG1 for the prognosis of pediatric SCI (PSCI). Methods This study recruited 64 patients with confirmed PSCI and 40 healthy controls at Foshan Traditional Chinese Medicine Hospital from January 2016 to December 2020. The clinical information of all participants at the time of admission was recorded. Peripheral blood was collected, and commercial reagents were used to detect the level of serum LRG1. At the same time, the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) was used to assess the severity of PSCI. Results All participants were divided into PSCI group (n = 64) and NC group (n = 40). There was no significant difference in clinical information (age, gender, heart rate, systolic blood pressure, diastolic blood pressure, sampling time from injury, white blood cells, and C-reactive protein) between the two groups (p > 0.05). According to the interquartile range of serum LRG1, we compared the motor and sensory scores of ISNCSCI and found that serum LRG1 levels were negatively correlated with the prognosis of PSCI patients (p < 0.001). The results of receiver operating curve (ROC) showed that the sensitivity, specificity, and AUC (Area Under the Curve) of serum LRG1 level in predicting the prognosis of PSCI were 68.4%, 69.1%, and 0.705, respectively. The cut-off value of serum LRG1 level predicting the prognosis of PSCI is 21.1 μg/ml. Conclusions Serum LRG1 level is significantly increased in PSCI patients, and the elevated LRG1 level is negatively correlated with the prognosis of PSCI patients. Serum LRG1 may be a potentially useful biomarker for predicting PSCI.

Association of Genetic Variants for Plasma LRG1 With Rapid Decline in Kidney Function in Patients With Type 2 Diabetes.

Elevated levels of plasma leucine-rich α-2-glycoprotein 1 (LRG1), a component of transforming growth factor beta signaling, are associated with development and progression of chronic kidney disease in patients with type 2 diabetes (T2D). However, whether this relationship is causal is uncertain. To identify genetic variants associated with plasma LRG1 levels and determine whether genetically predicted plasma LRG1 contributes to a rapid decline in kidney function (RDKF) in patients with T2D. We performed a genome-wide association study of plasma LRG1 among 3694 T2D individuals [1881 (983 Chinese, 420 Malay, and 478 Indian) discovery from Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes cohort and 1813 (Chinese) validation from Diabetic Nephropathy cohort]. One- sample Mendelian randomization analysis was performed among 1337 T2D Chinese participants with preserved glomerular filtration function [baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2)]. RDKF was defined as an eGFR decline of 3 mL/min/1.73 m2/year or greater. We identified rs4806985 variant near LRG1 locus robustly associated with plasma LRG1 levels (meta P = 6.66 × 10-16). Among 1337 participants, 344 (26%) developed RDKF, and the rs4806985 variant was associated with higher odds of RDKF (meta odds ratio = 1.23, P = 0.030 adjusted for age and sex). Mendelian randomization analysis provided evidence for a potential causal effect of plasma LRG1 on kidney function decline in T2D (P < 0.05). We demonstrate that genetically influenced plasma LRG1 increases the risk of RDKF in T2D patients, suggesting plasma LRG1 as a potential treatment target. However, further studies are warranted to elucidate underlying pathways to provide insight into diabetic kidney disease prevention.

Serum transforming growth factor β and leucine-rich α-2-glycoprotein 1 as potential biomarkers for diagnosis of uterine leiomyomas

Background and aimTransforming growth factor β (TGF-β) and leucine-rich α-2-glycoprotein 1 (LRG1) play significant roles in the pathogenicity of uterine leiomyomas (ULMs). The current study aimed to assess the diagnostic values of serum TGF-β and LRG1 in terms of the presence and severity of ULMs. MethodsPremenopausal women with ULMs (n=44) together with age-adjusted ULM-free individuals (n=41) were incorporated into the study. ULMs were detected and evaluated using transvaginal ultrasonography. Serum levels of TGF-β and LRG1 were quantified by enzyme-linked immunosorbent assay. ResultsMean concentrations of serum TGF-β and LRG1 were significantly higher in the group of patients with ULMs compared to the control group (p<0.05). The volume of the largest leiomyoma was positively correlated with the levels of TGF-β (r = 0.414, p= 0.005) and LRG1 (r = 0.341, p= 0.023). The receiver-operating characteristics analysis demonstrated moderate and robust values of area under the curve for TGF-β (0.755) and LRG1 (0.90), respectively. ConclusionIncreases in serum levels of TGF-β and LRG1 is associated with the incidence and severity of ULMs. LRG1 in particular but also TGF-β may be able to serve as reliable biomarkers for the diagnosis and monitoring of ULMs.