Alteration of protein glycosylation in liver diseases
2008; Elsevier BV; Volume: 50; Issue: 3 Linguagem: Inglês
10.1016/j.jhep.2008.12.010
ISSN1600-0641
AutoresBram Blomme, Christophe Van Steenkiste, Nico Callewaert, Hans Van Vlierberghe,
Tópico(s)Endoplasmic Reticulum Stress and Disease
ResumoChronic liver diseases are a serious health problem worldwide. The current gold standard to assess structural liver damage is through a liver biopsy which has several disadvantages. A non-invasive, simple and non-expensive test to diagnose liver pathology would be highly desirable. Protein glycosylation has drawn the attention of many researchers in the search for an objective feature to achieve this goal. Glycosylation is a posttranslational modification of many secreted proteins and it has been known for decades that structural changes in the glycan structures of serum proteins are an indication for liver damage. The aim of this paper is to give an overview of this altered protein glycosylation in different etiologies of liver fibrosis / cirrhosis and hepatocellular carcinoma. Although individual liver diseases have their own specific markers, the same modifications seem to continuously reappear in all liver diseases: hyperfucosylation, increased branching and a bisecting N-acetylglucosamine. Analysis at mRNA and protein level of the corresponding glycosyltransferases confirm their altered status in liver pathology. The last part of this review deals with some recently developed glycomic techniques that could potentially be used in the diagnosis of liver pathology. Chronic liver diseases are a serious health problem worldwide. The current gold standard to assess structural liver damage is through a liver biopsy which has several disadvantages. A non-invasive, simple and non-expensive test to diagnose liver pathology would be highly desirable. Protein glycosylation has drawn the attention of many researchers in the search for an objective feature to achieve this goal. Glycosylation is a posttranslational modification of many secreted proteins and it has been known for decades that structural changes in the glycan structures of serum proteins are an indication for liver damage. The aim of this paper is to give an overview of this altered protein glycosylation in different etiologies of liver fibrosis / cirrhosis and hepatocellular carcinoma. Although individual liver diseases have their own specific markers, the same modifications seem to continuously reappear in all liver diseases: hyperfucosylation, increased branching and a bisecting N-acetylglucosamine. Analysis at mRNA and protein level of the corresponding glycosyltransferases confirm their altered status in liver pathology. The last part of this review deals with some recently developed glycomic techniques that could potentially be used in the diagnosis of liver pathology. 1. IntroductionOver the years it has become apparent that changes in protein glycosylation play an important role in the pathogenesis and progression of various liver diseases. In order to comprehend the relationship between glycosylation and liver diseases, some basic insight into this complex phenomenon is necessary. Therefore, a short introduction is provided, which covers basic biochemical aspects of glycosylation (see Fig. 1).In general, glycosylation consists of co- and posttranslational modification steps, in which individual glycans are added to proteins translated into the endoplasmic reticulum (ER), forming oligosaccharide chains. This is an enzyme-directed and a site-specific process. Two types of protein glycosylation exist: N-glycosylation to the amide nitrogen of asparagine (Asn) side chains and O-glycosylation to the hydroxyl groups of serine (Ser) and threonine (Thr) side chains. Most proteins in human serum contain one or more N-linked glycans, with the exception of albumin and C-reactive protein. O-glycans are found in mucins, which are abundantly present on mucosal surfaces and saliva. Most modifications of glycosylation in liver diseases that have been studied affect N-glycosylated proteins and these will primarily be discussed. The N-oligosaccharide chain is attached to asparagine occurring in the tripeptide sequence Asn-X-Ser, in which X could be any amino acid except proline [1Ploegh H. Neefjes J.J. Protein glycosylation.Curr Opin Cell Biol. 1990; 2: 1125-1130Crossref PubMed Scopus (4) Google Scholar, 2Hebert D.N. Garman S.C. Molinari M. The glycan code of the endoplasmic reticulum: asparagine-linked carbohydrate as protein maturation and quality-control tags.Trends in Cell Biol. 2005; 15: 364-370Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 3Kornfeld S. Diseases of abnormal protein glycosylation: an emerging area.J Clin Invest. 1998; 101: 1293-1295Crossref PubMed Scopus (46) Google Scholar, 4Lis H. Sharon N. Protein glycosylation: structural and functional aspects.Eur J Biochem. 1993; 218: 1-27Crossref PubMed Scopus (796) Google Scholar].The biosynthesis of N- and O-glycans take place in the ER and the Golgi apparatus and it can be roughly divided in three steps [[5]Schachter H. The subcellular sites of glycosylation.Biochem Soc Symp. 1974; 40: 57-71PubMed Google Scholar]. The first step in N-glycosylation is carried out in the ER and consists of the formation of an oligosaccharide-lipid complex containing three glucoses, nine mannoses and two N-acetylglucosamines (GlcNAc). The lipid portion (dolichol) acts as a carrier molecule. The second step is the transfer of the oligosaccharide portion to a growing nascent polypeptide and the simultaneous removal of the three glucose residues and 1 mannose residue. The premature glycoprotein is then mediated to the Golgi apparatus where residual monosaccharides are removed until a (mannose)5(GlcNAc)2 heptasaccharide chain is formed. From here on, specific glycosyltransferases (Table 1 and [9Javaud C. Dupuy F. Maftah A. Julien R. Petit J.M. The fucosyltransferase gene family: an amazing summary of the underlying mechanisms of gene evolution.Genetica. 2003; 118: 157-170Crossref PubMed Scopus (54) Google Scholar, 10Taniguchi N. Miyoshi E. Ko J.H. Ikeda Y. Ihara Y. Implication of N-acetylglucosaminyltransferases III and V in cancer: gene regulation and signaling mechanism.Biochim Biophys Acta. 1999; 1455: 287-300Crossref PubMed Scopus (137) Google Scholar, 11Harduin-Lepers A. Vallejo-Ruiz V. Krzewinski-Recchi M.A. Samyn-Petit B. Julien S. Delannoy P. The human sialyltransferase family.Biochimie. 2001; 83: 727-737Crossref PubMed Scopus (429) Google Scholar]) and glycosidases will further modify the core-structure by adding or removing monosaccharides, respectively [[6]Paulson J.C. Colley K.J. Glycosyltransferases – structure, localization, and control of cell type-specific glycosylation.J Biol Chem. 1989; 264: 17615-17618Abstract Full Text PDF PubMed Google Scholar]. Glycosyltransferases make use of nucleotides sugars (donors) in order to incorporate monosaccharides into the N-glycan. Glycosidases on the other hand, catalyze the hydrolysis of the glycosidic linkage. In addition, glycans can have various branches (2–5) and are termed bi-, tri-, tetra- and penta-antennary, respectively. The enzymatic addition and removal of monosaccharides allow the formation of glycans with various length, composition and structure [7Spiro R.G. Protein glycosylation: nature, distribution, enzymatic formation, and disease implications of glycopeptides bonds.Glycobiology. 2002; 12: 43R-56RCrossref PubMed Scopus (1042) Google Scholar, 8Burda P. Aebi M. The dolichol pathway of N-linked glycosylation.Biochem Biophys Acta. 1999; 1426: 239-257Crossref PubMed Scopus (523) Google Scholar].Table 1Glycosyltransferases that are important in the modification of N-glycans on serum proteins.Glycosyltransferase familyMammalian glycosyltransferasesSubstrate specificityα1,2-Fucosyltransferase⁎Different glycosyltransferases of this class are known.α1,2 Linkage to the terminal Gal residue in N- or O-glycansFucosyltransferases [9]Javaud C. Dupuy F. Maftah A. Julien R. Petit J.M. The fucosyltransferase gene family: an amazing summary of the underlying mechanisms of gene evolution.Genetica. 2003; 118: 157-170Crossref PubMed Scopus (54) Google Scholarα1,3/4-Fucosyltransferase⁎Different glycosyltransferases of this class are known.α1,3 or α1,4 Linkage to GlcNAc in GlcNAc-Gal structuresα1,6-Fucosyltransferaseα1,6 Linkage to the innermost (core) GlcNAc in N-glycansN-Acetylglucosaminyltransferase IIIGnT-III catalyzes the addition of GlcNAc via β1-4 linkage to the β-mannose core of N-glycansN-Acetylglucosaminyltransferases [10]Taniguchi N. Miyoshi E. Ko J.H. Ikeda Y. Ihara Y. Implication of N-acetylglucosaminyltransferases III and V in cancer: gene regulation and signaling mechanism.Biochim Biophys Acta. 1999; 1455: 287-300Crossref PubMed Scopus (137) Google ScholarN-Acetylglucosaminyltransferase IV⁎Different glycosyltransferases of this class are known.GnT-IV catalyzes the formation of GlcNac-β1-4 branches at the Man α1-3 side of the trimannosyl core of N-glycansN-Acetylglucosaminyltransferase VGnT-V catalyzes the formation of GlcNAc-β1-6 branches at the Man α1-6 side of the trimannosyl core of N-glycansSialyltransferases [11]Harduin-Lepers A. Vallejo-Ruiz V. Krzewinski-Recchi M.A. Samyn-Petit B. Julien S. Delannoy P. The human sialyltransferase family.Biochimie. 2001; 83: 727-737Crossref PubMed Scopus (429) Google Scholarα2,6-Sialyltransferase⁎Different glycosyltransferases of this class are known.ST6GalI mediates the transfer of sialic acid residue with an α2,6-linkage to a terminal Gal residueα2,3-Sialyltransferase⁎Different glycosyltransferases of this class are known.ST3GalI mediates the transfer of sialic acid to a Gal residue of a terminal Galβ1-3GalNAc oligosaccharide Different glycosyltransferases of this class are known. Open table in a new tab The functional role(s) of the N-linked carbohydrate moieties of glycoproteins is/are often not well understood. However, glycosylation is a necessity in the correct folding of certain proteins. Aberrant protein folding affects various physiochemical and functional properties of proteins: protein stability, protein solubility, protein inter-/intracellular transport and half-life in blood. The opposite can also be true. Carbohydrate moieties on glycoproteins also fulfill a role in intercellular contact and communication, which is an important aspect of host immunity as well as cancer [12Zhao Y. Takahashi M. Gu J. Miyoshi E. Matsumoto A. Kitazume S. et al.Functional roles of N-glycans in cell signaling and cell adhesion in cancer.Cancer Sci. 2008; 99: 1304-1310Crossref PubMed Scopus (310) Google Scholar, 13Varki A. Biological roles of oligosaccharides: all of the theories are correct.Glycobiology. 1993; 3: 97-130Crossref PubMed Scopus (4963) Google Scholar, 14Dwek R.A. Glycobiology: ‘towards understanding the function of sugars’.Biochem Soc Trans. 1995; 23: 1-25Crossref PubMed Scopus (155) Google Scholar, 15Taniguchi N. Miyoshi E. Gu J. Honke K. Matsumoto A. Decoding sugar functions by identifying target glycoproteins.Curr Opin Struct Biol. 2006; 16: 561-566Crossref PubMed Scopus (97) Google Scholar].The liver contains various receptors on sinusoidal and hepatocyte surfaces. A lot of proteins that bind to these receptors rely on their carbohydrate moieties. Besides changes in glycosylation patterns, the changes in receptor concentration and distribution also occur in various chronic liver diseases (cirrhosis, hepatocellular carcinoma (HCC) and alcoholic liver diseases (ALD)). This leads to an accumulation of certain glycoproteins in the circulation [16Sawamura T. Nakada H. Hazama H. Shiozaki Y. Sameshima Y. Tashiro Y. Hyperasialoglycoproteinemia in patients with chronic liver-diseases and or liver-cell carcinoma – asialoglycoprotein receptor in cirrhosis and liver-cell carcinoma.Gastroenterology. 1984; 87: 1217-1221Abstract Full Text PDF PubMed Scopus (167) Google Scholar, 17Burgess J.B. Baenziger J.U. Brown W.R. Abnormal surface distribution of the human asialoglycoprotein receptor in cirrhosis.Hepatology. 1992; 15: 702-706Crossref PubMed Scopus (75) Google Scholar].In the following sections we will discuss the role of glycosylation in liver fibrosis and its relation to various liver pathologies (ALD, hepatitis B, bile-related diseases and obesity) and its role in HCC. The last section will deal with analytical advances in glycoresearch in recent years which now allows the rapid and detailed mapping of the complex mixtures present within biofluid samples.2. Alteration of glycosylation in fibrosis – cirrhosisThe gold standard to assess liver fibrosis is through a liver biopsy, which involves the removal of a small liver sample. It is well known that this procedure is accompanied by several complications. Changes in glycosylation of serum proteins have been extensively used as a non-invasive alternative and this has resulted in the development of sensitive and discriminating clinical tests for diagnostic purposes. The rationale for these tests is that the majority of glycosylated serum proteins are synthesized by the liver and in all major liver diseases, changes in this glycosylation occur.While early glycome studies were confined to the study of sialylation patterns, glycomics has evolved ever since [[18]Martinez J. Barsigian C. Carbohydrate abnormalities of N-linked plasma glycoproteins in liver-disease.Lab Invest. 1987; 57: 240-257PubMed Google Scholar]. In the past two decades, the main way of investigating glycosylation was by using lectins [19Turner G.A. N-glycosylation of serum–proteins in disease and its investigation using lectins.Clin Chim Acta. 1992; 208: 149-171Crossref PubMed Scopus (216) Google Scholar, 20Van Damme E.J.M. Peumans W.J. Bardocz S. Pusztai A. Handbook of plant lectins: properties and biomedical applications. John Wiley & Sons, Amsterdam1998Google Scholar]. These lectins bind with a particular glycan structure (core-fucosylated glycans, complex glycans,…) (Table 2). Today, with the advent of high-throughput glycomic techniques, we are progressing towards a system biology approach comprising genomics and proteomics in order to draw general conclusions about a particular pathology.Table 2Commonly used lectins for the study of altered glycan structures in chronic liver diseases [20]Van Damme E.J.M. Peumans W.J. Bardocz S. Pusztai A. Handbook of plant lectins: properties and biomedical applications. John Wiley & Sons, Amsterdam1998Google Scholar.LectinCommon nameSpecificityApplicationCanavalia ensiformis (Concanavalin A, Con A)Jack BeanMan/Glc (Man > Glc > GlcNAc)Con A has been extensively used in the isolation and structural studies of glycoconjugates and it has some clinical uses such as crossed affinity immunoelectrophoresisLens culinaris (LCA)LentilMan/Glc (Man > Glc > GlcNAc)Lens lectin is used for the isolation and analysis of glycoproteins. It is also a useful tool for the determination of the degree of fucosylation of alpha-fetoprotein and the histochemical staining of glycoconjgatesLotus tetragonolobus (LTA)Asparagus peaFuc (α-L-Fuc)The Lotus lectins have specifically been used for the recognition of fucosylated glycansPhaseolus vulgaris: erythroagglutinating (E-type, E-PHA)Kidney beanComplex (Galβ(1,4)GlcNAcβ(1,2)Man)Especially used for the identification of glycans with a bisecting modificationPhaseolus vulgaris: leuco-agglutinating (L-type, L-PHA)Kidney beanComplex (Galβ(1,4)GlcNacβ(1,2) [Galβ(1,4)GlcNAcβ(1,6)]Man)As L-PHA is reactive with β(1,6) branched structures of trimannosyl core asparagine-linked glycans which are highly selective markers of the metastatic potential of tumor cells, this lectin is used in cancer diagnosis Open table in a new tab 2.1 Alcoholic liver diseaseCarbohydrate-deficient transferrin (CDT) is the most used marker of chronic alcohol abuse. Human serum transferrin is a glycoprotein synthesized by the liver and involved in iron transport between sites of absorption and delivery [[21]De Jong G. Van Dijk J.P. Van Eijk H.G. The biology of transferrin.Clin Chim Acta. 1990; 190: 1-46Crossref PubMed Scopus (333) Google Scholar]. Chronic ethanol intake alters the normal microheterogeneity pattern of transferrin as a consequence of changes in the sialic acid contents [22Flahaut C. Michalski J.C. Danel T. Humbert M.H. Klein A. The effects of ethanol on the glycosylation of human transferrin.Glycobiology. 2003; 13: 191-198Crossref PubMed Scopus (65) Google Scholar, 23Storey E.L. Anderson G.J. Mack U. Powell L.W. Halliday J.W. Desialylated transferrin as a serological marker of chronic excessive alcohol ingestion.Lancet. 1987; 1: 1292-1294Abstract Full Text PDF PubMed Scopus (91) Google Scholar] (See Table 3 for an overview of the assays that were used to investigate the glycan status). A decreased level of dolichol has been observed in rats fed ethanol [[24]Cottalasso D. Domenicotti C. Traverso N. Pronzato M.A. Nanni G. Influence of chronic ethanol consumption on toxic effects of 1,2-dichloroethane: glycolipoprotein retention and impairment of dolichol concentration in rat liver microsomes and Golgi apparatus.Toxicology. 2002; 178: 229-240Crossref PubMed Scopus (14) Google Scholar]. The abnormal terminal sialylation can be explained by a decrease in β-galactoside α2,6 sialyltransferase (ST6GalI) mRNA and protein expression and/or an increase in hepatocyte membrane associated sialidase observed during chronic alcohol abuse [25Rao M. Lakshman M.R. Chronic ethanol consumption leads to destabilization of rat liver β-galactoside-sialyltransferase mRNA.Metabolism. 1999; 48: 797-803Abstract Full Text PDF PubMed Scopus (19) Google Scholar, 26Xin Y. Lasker J.M. Lieber C.S. Serum carbohydrate-deficient transferrin – mechanism of increase after chronic alcohol intake.Hepatology. 1995; 22: 1462-1468PubMed Google Scholar, 27Gong M. Garige M. Hirsch K. Lakshman M.R. Liver Gal beta 1,4GlcNAc alpha 2,6-sialyltransferase is down-regulated in human alcoholics: possible cause for the appearance of asialoconjugates.Metabolism. 2007; 56: 1241-1247Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]. Oxidation products of ethanol such as acetaldehyde interfere with the N-glycan biosynthesis and/or transfer by binding the involved enzymes. Therefore, CDT is likely the result of changes in glycosylation during biosynthesis and catabolism. Although CDT is recognized as a marker of chronic alcohol consumption, the reliability of this marker is largely dependent on the analytical fractionation method (capillary electrophoresis). Alterations in glycosylation and lack of clinical analytical standard methods might contribute to the discrepancy and sensitivity of CDT in clinical settings [28Liu Y.S. Xu G.Y. Cheng D.Q. Li Y.M. Determination of serum carbohydrate-deficient transferrin in the diagnosis of alcoholic liver disease.Hepatobiliary Pancreat Dis Int. 2005; 4: 265-268PubMed Google Scholar, 29Stadheim L.M. O’Brien J.F. Lindor K.D. Gores G.J. McGill D.B. Value of determining carbohydrate-deficient transferrin isoforms in the diagnosis of alcoholic liver disease.Mayo Clin Proc. 2003; 78: 703-707Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar].Table 3Overview of the main assays used to investigate the glycan status at protein or genetic level in different etiologies of chronic liver diseases.EtiologiesAlcoholic liver diseasesFatty liver diseases – bile related diseasesViral liver diseasesHepatocellular carcinomaHPAEC-PAD [32]Mann A.C. Record C.O. Self C.H. Turner G.A. 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