heparitin-sulfate and Liver-Diseases

Proteoglycans are macromolecules formed by a protein core to which sugar chains are covalently attached. They are present on the cell surface and in the ECM of living things. In normal liver syndecan-1 is the dominant transmembrane proteoglycan, trace amounts of ECM proteoglycans are in the stromal components. The amounts of proteoglycans we studied increase in liver cirrhosis. In liver cancer abnormal localization of syndecan-1 and stroma rich in agrin was characteristic. The core proteins as well as the sugar chains of proteoglycans interact with and modulate the effect of regulatory factors. This implies that structural alterations of proteoglycans contribute to the development of malignant phenotype. Heparan sulfate chains of liver cancer are undersulfated with decreased or altered biological activity. Their binding capacity for transcription factor decreases, and they do not inhibit topoisomerase I enzyme. Truncated form of syndecan-1 lacking the extracellular domain of the molecule induces differentiation of hepatoma cell line and inhibits the shedding of syndecan-1. This phenomenon calls attention to the importance of syndecan-1 shedding in the regulation of cell behavior.

Topics: Animals; Cell Differentiation; Cell Transformation, Neoplastic; Heparitin Sulfate; Humans; Liver; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Membrane Glycoproteins; Proteoglycans; Signal Transduction; Syndecan-1; Syndecans

Heparan sulfate (HS) is a sulfated glycosaminoglycan abundant on the cell surface and in the extracellular matrix and has several biological activities including anticoagulation and anti-inflammation. Liver ischemia reperfusion injury is associated with coagulation and inflammatory responses. Here, we synthesized HS oligosaccharides with defined sulfation patterns and show that synthetic anticoagulant HS oligosaccharides limit liver ischemia reperfusion injury in a mouse model. Using a small targeted HS library, we demonstrate that an oligosaccharide that possesses both anticoagulant activity and binding affinity to HMGB1, the inflammatory target, decreases injury greater than oligosaccharides that only bind to HMGB1 or only have anticoagulant activity. HS oligosaccharides may represent a potential new therapeutic option for decreasing liver damage resulting from ischemia reperfusion injury.

Topics: Animals; Anticoagulants; Blood Coagulation; Extracellular Matrix; Heparitin Sulfate; HMGB1 Protein; Liver; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Oligosaccharides; Reperfusion Injury

Biochemical tests such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are useful for diagnosing patients with liver disease. In this study, we tested the association between copy number variation and the hepatic biomarkers AST and ALT based on 8,842 samples from population-based cohorts in Korea. We used Affymetrix Genome-Wide Human 5.0 arrays and identified 10,534 CNVs using HelixTree software. Of the CNVs tested using univariate linear regression, 100 CNVs were significant for AST and 16 were significant for ALT (P < 0.05). We identified 39 genes located within the CNV regions. DKK1 and HS3ST3B1 were shown to play roles in heparan sulfate biosynthesis and the Wnt signaling pathway, respectively. NAF1 and NPY1R were associated with glycoprotein processes and neuropeptide Y receptor activity based on GO categories. PTER, SOX14 and TM7SF4 were expressed in liver. DPYS and CTSC were found to be associated with dihydropyrimidinuria and Papillon-Lefevre syndrome phenotypes using OMIM. NPY5R was found to be associated with dyslipidemia using the Genetic Association Database.

Topics: Adult; Alanine Transaminase; Asian People; Aspartate Aminotransferases; Biomarkers; Cohort Studies; Databases, Genetic; DNA Copy Number Variations; Female; Gene Frequency; Genome-Wide Association Study; Genome, Human; Glycoproteins; Heparitin Sulfate; Humans; Liver Diseases; Male; Middle Aged; Receptors, Neuropeptide Y; Republic of Korea; Signal Transduction; Software; Wnt Proteins

In this study, we carried out an immunohistochemical investigation of time-dependent alterations in the distribution of proteoglycans, and the proliferation profiles of hepatocytes and fat-storing cells (FSCs) in the livers of rats intoxicated with D-galactosamine (GalN). The proliferative cells were analyzed by proliferative cell nuclear antigen (PCNA) staining. In untreated rats, heparan sulfate, dermatan sulfate, and chondroitin/chondroitin sulfate were detected within the portal spaces and the central veins, and, with the exception of chondroitin, also within the reticular fibers. After administration of GalN, the number of PCNA-positive cells (FSCs and hepatocytes) and FSCs increased, reaching maximal on the 2nd and 3rd days, respectively. Heparan sulfate showed complicated changes. Dermatan sulfate decreased in portal spaces from the 2nd to the 3rd day, and in reticular fibers from 12 h to the 6th day. Chondroitin/chondroitin sulfate staining was observed from 2 h to the 6th day in the sinusoidal endothelia, which suggests that the sinusoidal endothelia may produce chondroitin/chondroitin sulfate transiently during liver damage as part of the mechanism of regeneration. Heparan sulfate and chondroitin/chondroitin sulfate were detected in necrotic regions, but dermatan sulfate was not. These observations suggest that heparan sulfate and chondroitin/chondroitin sulfate are involved in cell proliferation or morphogenesis and that the dermatan sulfate plays a role in the differentiation or functional maintenance of cells in liver regeneration.

Topics: Alanine Transaminase; Animals; Chemical and Drug Induced Liver Injury; Dermatan Sulfate; Disease Models, Animal; Extracellular Matrix; Galactosamine; Heparitin Sulfate; Immunohistochemistry; Liver; Liver Diseases; Male; Microscopy, Electron; Proliferating Cell Nuclear Antigen; Proteoglycans; Rats; Rats, Sprague-Dawley

Proteoglycans were isolated from human amyloidotic liver by extraction with guanidine, followed by trichloroacetic acid precipitation, DEAE-Sephacel ion-exchange chromatography, and Sepharose CL-6B gel chromatography. A significant portion of the material was found to be free chondroitin/dermatan sulphate chains (30%), whereas the predominant part was heparan sulphate proteoglycan (HSPG) (70%). The approx. molecular mass of the HSPG was 200 kDa, as measured by gel electrophoresis and gel chromatography. The molecular mass of the core protein was shown to be 60 kDa by SDS/PAGE following de-aminative cleavage of the heparan sulphate chains. The heparan sulphate chains were liberated from the core protein by alkali treatment and found to have a molecular mass of approx. 35 kDa by Sepharose CL-6B gel chromatography. The core protein was shown, by immunoblotting, to react with a monoclonal antibody against bovine basement membrane HSPG. The presence of HSPG in amyloid deposits was further confirmed by immunohistochemistry on tissue sections from amyloidotic liver using the same antibody.

Topics: Amyloid; Amyloidosis; Child; Child, Preschool; Chromatography; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Immunohistochemistry; Liver; Liver Diseases; Male; Molecular Weight; Polysaccharides; Proteoglycans

The synthesis of glycosaminoglycans in slices from normal and acutely injured rat liver was studied. The rates of incorporation of [14C]-glucosamine into specific types of glycosaminoglycans varied markedly; nearly 90% was incorporated into a fraction containing predominantly heparan sulfate and far less if any heparin; about 9.5% was incorporated into chondroitin 4-and 6-sulfate, and only 0.2% of the radioactivity was found in hyaluronic acid. The rate of synthesis of a fraction having several of the characteristics of keratan sulfate comprised only 0.3% of the synthesis of total glycosaminoglycans. No [14C]hexosamine was incorporated into dermatan sulfate. Following acute hepatic injury, the synthesis of glycosaminoglycans was stimulated by 80 to 100%, and the proportions of various types changed. If calculated on the basis of the specific activity of the precursors of glycosaminoglycans, which was found to be strongly reduced in injured liver, the maximum enhancement of total glycosaminoglycan synthesis was 6.6-fold 5 days after onset of liver injury.

Topics: Acetamides; Animals; Chemical and Drug Induced Liver Injury; Glucosamine; Glycosaminoglycans; Heparin; Heparitin Sulfate; In Vitro Techniques; Liver; Liver Diseases; Male; Rats; Thioacetamide