Mac-2 Binding Protein Glycan Isomer Research Articles

Potential of Mac-2-binding protein glycan isomer as a new therapeutic target in pancreatic cancer.

Pancreatic cancer (PC) is a challenging malignancy to treat. Mac-2-binding protein glycan isomer (M2BPGi) is a novel serum marker of liver fibrosis and hepatocellular carcinoma and is secreted by hepatic stellate and stroma cells. Serum M2BPGi levels are upregulated in PC patients. We measured the expression of M2BPGi in the serum of 27 PC patients and determined whether M2BPGi affects the malignant potential of PC cells invitro. We also examined the effect of M2BP on PC tumor growth and gemcitabine sensitivity invivo. Serum M2BPGi levels in PC patients were higher compared with those of healthy subjects. M2BPGi extraction in cancer-associated fibroblasts (CAFs) was higher compared with that of PC cells. M2BPGi treatment promoted the proliferation and invasion of PC cells. The suppression of galectin-3, which binds to M2BPGi, did not affect the proliferation-promoting effect of M2BPGi in PC cells. The suppression of M2BP reduced tumor growth and enhanced gemcitabine sensitivity in PC-bearing xenograft mice. CAF-derived M2BPGi promotes the proliferation and invasion of PC cells. Targeting M2BPGi may represent a new therapeutic strategy to circumvent refractory PC.

Comparison of Efficacy between Pemafibrate and Omega-3-Acid Ethyl Ester in the Liver: the PORTRAIT Study.

No pharmacotherapeutic treatment has been established for metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). This trial compared the effects of pemafibrate and omega-3-acid ethyl ester on hepatic function in patients with hypertriglyceridemia complicated by MASLD. Patients with hypertriglyceridemia complicated by MASLD were enrolled, randomly assigned to the pemafibrate or omega-3-acid ethyl ester group, and followed for 24 weeks. The primary endpoint was the change in alanine aminotransferase (ALT) from baseline to week 24. The secondary endpoints included other hepatic enzymes, lipid profiles, and hepatic fibrosis biomarkers. A total of 80 patients were enrolled and randomized. The adjusted mean change in ALT from baseline to week 24 was significantly lower in the pemafibrate group (-19.7±5.9 U/L) than in the omega-3-acid ethyl ester group (6.8±5.5 U/L) (intergroup difference, -26.5 U/L; 95% confidence interval, -42.3 to -10.7 U/L; p=0.001). Pemafibrate significantly improved the levels of other hepatic enzymes (aspartate aminotransferase and gamma-glutamyl transpeptidase), lipid profiles (triglycerides, total cholesterol, high-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol), and hepatic fibrosis biomarkers (Mac-2 binding protein glycan isomer and Fibrosis-4 index). No cases of discontinuation due to adverse drug reactions were identified in either group, and there were no safety concerns. Pemafibrate is recommended over omega-3-acid ethyl ester for lipid management and MASLD treatment in patients with hypertriglyceridemia complicated by MASLD. The study results may contribute to the development of future treatment strategies for patients with MASLD/MASH.

1582-P: Association of Low eGFR with Novel Liver Fibrosis Biomarker Mac-2 Binding Protein Glycosylation Isomer in Type 2 Diabetes Patients

Objective: Advanced liver fibrosis, which leads to liver cirrhosis and cancer, has been one of the major causes of death in type 2 diabetes (T2D). Efficient screening system is needed to detect liver fibrosis early and prevent its progression. A novel serum fibrosis biomarker Mac-2 binding protein glycan isomer (M2BPGi) has high sensitivity plus specificity, and can be used in combination with FIB-4 screening index (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]/platelet ratio). This study aimed to investigate the predictive factors for the early detection of liver fibrosis using a combination of these two approaches. Methods: This cross-sectional study consisted of T2D patients, with negative results for hepatitis viruses and no history of heavy drinking. FIB-4 high patients were divided into two groups based on M2BPGi (high, M2BPGi > 1.00; normal level, M2BPGi < 1.00. The levels of clinical biomarkers were measured among two groups and predictive factors were calculated for M2BPGi high patients. Results: From July to December 2021, a total of 311 FIB-4 high T2D patients (male/female, 202/109; age, 71.1 + 9.8; Body Mass Index, 24.5 + 3.9; HbA1c 7.4 + 3.3 %) were enrolled in this study. The M2BPGi high group (44,3%, n=138) showed a significantly longer duration of diabetes, high alkaline phosphatase (ALP), AST, ALT, and low eGFR than M2BPGi normal group (55.7%, n=173). In multiple logistic regression analysis, eGFR < 60 mL/min/1.73m2 was independently identified as a predictive factor for M2BPGi high (Odds Ratio [OR] 2.61, 95% C.I. 1.55-4.39 P < 0.01) as well as AST > 30 IU/ml (OR, 3.37) and ALP > 113 IU/ml (OR, 1.88). Conclusions: low eGFR is associated with liver fibrosis in type 2 diabetes patients, and requires more careful attention to liver related disease. Disclosure E.Suzuki: None. Y.Shinya: None. B.Kanari: None. M.Kambara: None. H.Takahashi: None.

Effect of Selenium Deficiency on the Development of Overt Hepatic Encephalopathy in Patients with Chronic Liver Disease.

Selenium is an essential trace element to maintain good health. This retrospective study investigated the prevalence of selenium deficiency and its effect on overt hepatic encephalopathy (OHE) in patients with chronic liver disease (CLD). Patients who underwent serum selenium level measurement between January 2021 and April 2022 were enrolled. The factors associated with selenium deficiency (≤10 µg/dL) and the association between selenium deficiency and OHE were analyzed. Among 98 eligible patients, 24% were observed to have selenium deficiency, with a median serum selenium level of 11.8 µg/dL. The serum selenium levels were significantly lower in patients with cirrhosis than in those with chronic hepatitis (10.9 µg/dL vs. 12.4 µg/dL; p = 0.03). The serum selenium levels were negatively correlated with mac-2 binding protein glycan isomer, the FIB-4 index, albumin-bilirubin (ALBI) score, and Child-Pugh score. The ALBI score remained significantly associated with selenium deficiency (odds ratio, 3.23; 95% confidence interval [CI], 1.56-6.67). During a median follow-up period of 2.9 months, nine patients experienced OHE. Selenium deficiency was associated with OHE (hazard ratio, 12.75; 95% CI, 2.54-70.22). Selenium deficiency is highly prevalent in patients with CLD and is associated with an increased risk of OHE development.

The presence of high-risk varices after sclerotherapy in biliary atresia.

Esophagogastric varices (EGVs) may develop as a result of portal hypertension in children with biliary atresia (BA). Although endoscopic injection sclerotherapy (EIS) with ethanolamine oleate (EO) is reported useful for children, risk factors associated with the presence of high-risk EGVs after treatment remain unknown. The subjects were BA patients under 15 years of age who underwent EO-EIS. We retrospectively reviewed a total of 28 treatment sessions of EGVs with red signs and those larger than F2, which were considered to be at high risk of bleeding. Survival analysis was performed for the presence of high-risk EGVs at the time of follow-up endoscopy as the occurrence of an event. Univariate analysis showed a significantly increased risk of the presence of high-risk EGVs post-EO-EIS in patients with increased liver stiffness (LS) and Mac-2 binding protein glycan isomer (M2BPGi), with hazard ratios of 1.48 and 1.15, respectively. The median presence-free period was significantly shorter in the LS ≥ 2.8m/s patients than in those with LS <2.8m/s (189 vs. 266 days). Similarly, the median presence-free period was significantly shorter in patients with M2BPGi ≥ 4.0 than in those with M2BPGi < 4.0 (182 vs. 203 days). The results of multivariate analysis revealed that the risk of the presence of high-risk EGVs was significantly higher only in the high-LS group, with a hazard ratio of 2.76. Increased LS is associated with risk of the presence of high-risk EGVs following EO-EIS in children with BA.

Mac-2 binding protein glycan isomer is new serum biomarker for assessing liver fibrosis: non-invasive method

Mac-2 binding protein glycan isomer is new serum biomarker for assessing liver fibrosis: non-invasive method

A new liver regeneration molecular mechanism involving hepatic stellate cells, Kupffer cells, and glucose-regulated protein 78 as a new hepatotrophic factor.

To overcome liver failure, we focused on liver regeneration mechanisms by the activation of hepatic stellate cells (HSCs) and Kupffer cells (KCs). It is known that the HSC-secreted Mac-2-binding protein glycan isomer (M2BPGi) activates KC in the fibrotic liver. However, its importance for liver regeneration of the HSCs/M2BPGi/KCs axis after hepatectomy is still unknown. The aim of this study was to clarify whether the HSC-derived M2BPGi can activate KCs after hepatectomy, and elucidate the new molecular mechanism of liver regeneration. We examined the effect of M2BPGi on human hepatocytes and KCs, and explored secretory factors from M2BPGi-activated KCs using proteomics. Furthermore, the effect on liver regeneration of glucose-regulated protein 78 (GRP78) as one of the M2BPGi-related secreted proteins was examined in vitro and in murine hepatectomy models. Although M2BPGi had no hepatocyte-promoting effect, M2BPGi promoted the production of GRP78 in KCs. The KC-driven GRP78 promoted hepatocyte proliferation. GRP78 administration facilitated liver regeneration after 70% hepatectomy and increased the survival rate after 90% hepatectomy in mice. The M2BPGi-activated KCs secrete GRP78, which facilitates liver regeneration and improves the survival in a lethal mice model. Our data suggest that the new hepatotrophic factor GRP78 may be a promising therapeutic tool for lethal liver failure.

Mac-2-binding protein glycan isomer predicts all malignancies after sustained virological response in chronic hepatitis C.

Despite reports of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) infection after achieving sustained virological response (SVR), only few studies have demonstrated the incidence of other (non‐HCC) malignancies. This study aimed to clarify the incidence, survival probability, and factors associated with malignancy, especially non‐HCC malignancies, in patients with chronic HCV infection after achieving SVR. In this retrospective study, records of 3580 patients with chronic HCV infection who achieved SVR following direct‐acting antiviral (DAA) treatment were analyzed. The cumulative post‐SVR incidence of non‐HCC malignancies was 0.9%, 3.1%, and 6.8% at 1, 3, and 5 years, respectively. The survival probability for patients with non‐HCC malignancies was 99.1%, 78.8%, and 60.2% at 1, 3, and 5 years, respectively, and the rate was significantly lower than that for patients with HCC. The Cox proportional hazards regression model identified Mac‐2‐binding protein glycan isomer (M2BPGi) cutoff index (COI) ≥ 1.90 at baseline and ≥ 1.50 at 12 weeks following DAA treatment as significant and independent factors associated with the post‐SVR incidence of non‐HCC malignancies. Furthermore, patients with either M2BPGi COI ≥ 1.90 at baseline or M2BPGi COI ≥ 1.50 at SVR12 had a significantly higher risk of post‐SVR incidence of non‐HCC malignancies than of HCC. Conclusion: M2BPGi measurements at baseline and SVR12 may help predict the post‐SVR incidence of non‐HCC malignancies in patients with chronic HCV infection who achieved SVR following DAA treatment. Early identification of these patients is critical to prolong patient survival.

The impact of elastography with virtual touch quantification of future remnant liver before major hepatectomy.

Liver elastography with virtual touch quantification (VTQ) measures the velocity of the shear wave generated by a short-duration acoustic force impulse, with values expressed in units of velocity (m/s). VTQ can evaluate right or left hepatic lobes separately. VTQ might be appropriate for the evaluation of future remnant liver after hepatectomy. We analyzed 95 patients underwent liver elastography with VTQ and both future remnant liver and resected side before hepatectomy of more than two sections, except for central bisectionectomy. We divided the patients into a high VTQ group (≥1.52 m/s, n=37, 39%) and a low VTQ group (<1.52 m/s, n=58, 61%) according to the VTQ of future remnant liver. Transient elastography could not be performed in 22 cases due to tumor size. We defined the group with liver stiffness measurement (LSM) ≥7.9 kPa as the high LSM group (n=29, 40%) and those with LSM <7.9 kPa as the low LSM group (n=44, 60%). We investigated the outcome after hepatectomy and the correlations between the VTQ of future remnant liver and other indicators for hepatic fibrosis. The high VTQ group showed significantly higher postoperative ascites (19% vs. 3%; P=0.01), pathological fibrosis (19% vs. 5%; P=0.03), and rates of patients with postoperative T-bil ≥2.0 mg/dL (70% vs. 40%; P<0.01). The high LSM group showed no significant postoperative outcomes compared to the low LSM group. The high VTQ group showed a higher frequency of male gender (78% vs. 57%; P=0.03), higher indocyanine green retention rate at 15 min (ICGR15) (10.5% vs. 6.3%; P<0.01), hyaluronic acid (100 vs. 67 ng/mL; P=0.02), type IV collagen 7S (7.6 vs. 5.1 ng/mL; P<0.01), Mac-2 binding protein glycan isomer (M2BPGi) (1.19 vs. 1.00; P=0.01), Fibrosis-4 (FIB-4) index (2.25 vs. 1.76; P=0.01), and aspartate aminotransferase to platelet ratio index (APRI) score (0.64 vs. 0.41; P<0.01). We also observed an especially strong positive correlation between the high VTQ and hyaluronic acid or type IV collagen 7S. Elastography with VTQ for future remnant liver before major hepatectomy is an accurate and useful method as a preoperative evaluation.

Mac-2 binding protein glycan isomer as noninvasive tool to assess liver fibrosis in children with chronic liver disease.

This study is aimed to measure the value of serum Mac-2 binding protein glycan isomer (M2BPGI) in children with chronic liver diseases in comparison with liver biopsy and serum biomarkers. Comparative cross-sectional study included 100 children with chronic liver diseases and 50 healthy age/sex-matched control group. All subjects were evaluated via medical history, clinical, radiological and laboratory examinations. Liver biopsy was performed for studied patients and serum M2BPGI level was measured by Enzyme Linked Immune Sorbent Assay (ELISA) in all studied subjects. Serum M2BPGI level increased more significantly in chronic liver disease patients (6.04±2.72ng/ml) than in healthy controls (1.12±0.83ng/ml) (P<0.001). M2BPGI level was significantly elevated with progressive fibrosis (P<0.001), and differed significantly between high and low Child-Pugh score, pediatric end-stage liver disease score and model for end-stage liver disease score score. Serum M2BPGI was correlated with serum biomarkers and degree of fibrosis in patients. M2BPGI could be used as one of noninvasive tools for detecting and staging of hepatic fibrosis in Egyptian children with chronic liver disease.

Clinical implications of serum Mac-2-binding protein glycan isomer as a novel biomarker of advanced hepatic fibrosis in diabetes.

BackgroundAppropriate strategy for screening, identification, and linkage to care of patients with advanced fibrosis in the general population is a current issue. The aim of this study was to find reference values and the clinical role of Mac-2 binding protein glycan isomer (M2BPGi) in a health check-up setting.MethodsThis study was designed as cross-sectional study. Adult subjects (n=1,073) who underwent a health check-up were included in the final analysis, and 952 subjects with risk factors for liver disease and insufficient data were excluded. M2BPGi quantification was based on a lectin antibody sandwich immunoassay. Fatty liver was diagnosed using abdominal sonography.ResultsThe reference value of M2BPGi was 0.5–1.0 cut off index (COI) in the average risk group. Serum M2BPGi showed a positive correlation with metabolic parameters as well as age. Prevalence of abnormal M2BPGi (>1.0) was higher in low muscle mass (4.7%, vs. 17.4%, P=0.002), metabolic syndrome (14.2% vs. 30.4%, P=0.003), and hypertension (21.8%, vs. 58.7%, P<0.001) compared to healthy controls. M2BPGi was positively correlated with estimated fibrosis values such as FIB-4 (R=0.293, P<0.001) and NAFLD fibrosis score (R=0.248, P<0.001). Although the prevalence of advanced fibrosis in the total population was just 1.6% (FIB-4 >2.65), the prevalence of advanced fibrosis increased to 50% in the high M2BPGi (>1.0) group with diabetes. This value was 31.25 times higher than in the total population group.ConclusionsThe results indicated a high possibility of advanced hepatic fibrosis in diabetic subjects with abnormal M2BPGi level (>1.0).

Sequential Combination of FIB-4 Followed by M2BPGi Enhanced Diagnostic Performance for Advanced Hepatic Fibrosis in an Average Risk Population.

The fibrosis-4 (FIB-4) index is the most widely used estimated formula to screen for advanced hepatic fibrosis; however, it has a considerable intermediate zone. Here, we propose an algorithm to reduce the intermediate zone and improve the diagnostic performance of screening for advanced liver fibrosis by incorporating Mac-2-binding protein glycan isomer (M2BPGi) into a FIB-4 based screening strategy in an average risk group. Four-hundred eighty-eight healthy and chronic liver disease subjects were analyzed using a 1:1 propensity score matched for age and sex. Advanced liver fibrosis (≥F3) was defined by magnetic resonance elastography (MRE, ≥3.6 kPa). Classification tree analysis was employed to improve diagnostic performance using a combination of the FIB-4 index and M2BPGi. The median serum M2BPGi levels of healthy subjects, patients without advanced fibrosis, and those with the condition were 0.48, 0.94, and 2.93, respectively. The area under the receiver operating characteristic (AUROC) curve of M2BPGi (0.918) for advanced fibrosis was the highest compared to those of the FIB-4 index (0.887), APRI (0.873), and AST/ALT ratio (0.794). When M2BPGi was incorporated following the FIB-4 index, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 87.1%, 82.5%, 54.0%, and 96.4%, respectively. Moreover, 74.3% (133/179) of cases in the intermediate zone of the FIB-4 index avoided unnecessary referrals. Two-step pathway (FIB-4 followed by M2BPGi) could reduce unnecessary referrals and/or liver biopsies in an average-risk population.

Rule of Mac-2 Binding Protein Glycan Isomer in Assessment of Liver Fibrosis in Children with Chronic Liver Disease

Rule of Mac-2 Binding Protein Glycan Isomer in Assessment of Liver Fibrosis in Children with Chronic Liver Disease

Increased Mac-2 binding protein glycan isomer in patients at risk for late nonrelapse mortality after HSCT

AbstractMacrophages play a crucial role in the pathogenesis of chronic graft-versus-host disease (cGVHD). We hypothesized that galectin-3, Mac-2 binding protein (M2BP), or Wisteria floribunda agglutinin (WFA)+-M2BP, called M2BP glycan isomer (M2BPGi), might contribute to macrophage activation, and fibrosis would be associated with cGVHD and nonrelapse mortality (NRM) in hematopoietic stem cell transplant (HSCT) recipients. Patients who underwent their first allogeneic HSCT and survived for >180 days without relapse were included. The predictive potential of the 3 markers for NRM was assessed using the discovery cohort (n = 55) and validation cohort 1 (n = 55). When we used the threshold determined by a receiver operating characteristics curve analysis in the discovery cohort, only M2BPGi at day +180 was significantly associated with a higher NRM in the discovery cohort (15.0% vs 0.0% at 5 years, P = .001) and in validation cohort 1 (34.0% vs 8.4% at 5 years, P = .014). This result was confirmed in validation cohort 2 (n = 50). M2BPGi was not increased in healthy individuals or in patients who received autologous HSCT. In the entire cohort (N = 110), M2BPGi was significantly related to liver cGVHD but not to other organ involvement. In multivariate analyses, M2BPGi was an independent risk factor for NRM. In immunofluorescence staining of autopsy cases, WFA+-M2BP–positive macrophages were found only in the liver sections with cGVHD. In conclusion, M2BPGi could be a promising predictor of late NRM after HSCT and was associated with liver involvement.

Increased Mac 2-Binding Protein Glycan Isomer (M2BPGi) Would Predict Late Non-Relapse Mortality after Allogeneic Hematopoietic Cell Transplantation

Increased Mac 2-Binding Protein Glycan Isomer (M2BPGi) Would Predict Late Non-Relapse Mortality after Allogeneic Hematopoietic Cell Transplantation

Circulating let-7 Levels in Serum Correlate With the Severity of Hepatic Fibrosis in Chronic Hepatitis C.

BackgroundEvaluating the progression of hepatic fibrosis in chronic hepatitis C (CHC) is critical, and identifying a predictive biomarker for fibrosis will be helpful for implementing personalized surveillance of hepatocellular carcinoma after the elimination of hepatitis C virus by antiviral therapy. This study aimed to investigate the association of circulating let-7a-5p levels with severity of hepatic fibrosis. MethodsWe analyzed circulating let-7a-5p levels in serum and serum-derived extracellular vesicles (EVs) in 84 Japanese CHC patients who underwent a liver biopsy by quantitative real-time polymerase chain reaction, and investigated the association of its levels with histological hepatic fibrotic stage, liver stiffness, and several hepatic fibrotic markers.ResultsThe levels of let-7a-5p in serum and EVs were significantly lower in patients with liver cirrhosis. Additionally, the serum let-7a-5p level correlated significantly with hepatic fibrotic markers, Mac-2 binding protein glycan isomer (M2BPGi), fibrosis-4 (FIB-4) index, aspartate aminotransferase-to-platelet ratio index (APRI), and liver stiffness, evaluated by transient elastography. Furthermore, the serum let-7a-5p level was superior to M2BPGi, FIB-4, and APRI and was comparable to liver stiffness in discriminating liver cirrhosis. ConclusionsThese results provide evidence that circulating let-7a-5p in serum may serve as a surrogate marker for severity of hepatic fibrosis in CHC.

Mac-2 binding protein glycan isomer (M2BPGi) is a new serum biomarker for assessing liver fibrosis: more than a biomarker of liver fibrosis

Assessing liver fibrosis is important for predicting the efficacy of antiviral therapy and patient prognosis. Liver biopsy is the gold standard for diagnosing liver fibrosis, despite its invasiveness and problematic diagnostic accuracy. Although noninvasive techniques to assess liver fibrosis are becoming important, reliable serum surrogate markers are not available. A glycoproteomics study aimed at identifying such markers discovered Mac 2-Binding Protein Gylcan Isomer (M2BPGi), which is a reliable marker for assessing liver fibrosis in patients with viral hepatitis and other fibrotic liver diseases such as primary biliary cholangitis, biliary atresia, autoimmune hepatitis, and nonalcoholic fatty liver disease. M2BPGi predicts the development of hepatocellular carcinoma (HCC) in patients infected with hepatitis B and C as well as the prognosis of liver cirrhosis in those with HCC after therapy. The unique features of M2BPGi are as follows: (1) cut-off values differ for the same stages of fibrosis according to the cause of fibrosis; and (2) M2BPGi levels rapidly decrease after patients achieve a sustained antiviral response to hepatitis C virus. These observations cannot be explained if M2BPGi levels reflect the amount of fibrotic tissue. Hepatic stellate cells (HSCs) secrete M2BPGi, which may serve as a messenger between HSCs and Kupffer cells via Mac-2 (galectin 3) that is expressed in Kupffer cells during fibrosis progression. Here we show that M2BPGi is a surrogate marker for assessing HSC activation. These findings may reveal the roles of HSCs in extrahepatic fibrotic disease progression.