Editorial
Copyright ©The Author(s) 2015.
World J Gastroenterol. Jan 21, 2015; 21(3): 711-725
Published online Jan 21, 2015. doi: 10.3748/wjg.v21.i3.711
Table 1 List of enzymes of the Class-I pyridoxal-phosphate-dependent aminotransferase family: Evidence from the human proteome
Protein nameGene nameChromosomeNumber of isoforms
1-aminocyclopropane-1-carboxylate synthase-like protein 1ACCS11p11.21
Alanine aminotransferase 1GPT18q24.31
Alanine aminotransferase 2GPT216q11.22
Aspartate aminotransferase, cytoplasmicGOT110q24.21
Aspartate aminotransferase, mitochondrialGOT216q212
Kynurenine/alpha-aminoadipate aminotransferase, mitochondrialAADAT4q332
Kynurenine--oxoglutarate transaminase 1CCBL19q34.113
Kynurenine--oxoglutarate transaminase 3CCBL21p22.23
Probable inactive 1-aminocyclopropane-1-carboxylate synthase-like protein 2ACCSL11p11.21
Putative aspartate aminotransferase, cytoplasmic 2GOT1L18p11.231
Tyrosine aminotransferaseTAT16q22.21
Table 2 Comparison of biological and protein function of ALT1 and ALT2: Background information and recent findings
Features and functionGlutamic-pyruvate transaminase 1 (alanine aminotransferase 1) GPT1Glutamic pyruvate transaminase 2 (alanine aminotransferase) 2 GPT2
Gene and protein Id in data-basesEntrez gene: 2875Entrez gene: 84706
Ensembl gene: ENSG00000167701Ensemble: ENSG00000166123
UniProtKB: P24298UniProtKB: Q8TD30
Genomic locationEntrez gene cytogenetic band: 8q24.3Entrez gene cytogenetic band: 16q12.1
Number of gene transcripts7 transcripts (splice variants), 28 exons on the forward strand5 transcripts (splice variants), 26 exons on the forward strand
VariationGPT1 has 210 SNPsGPT2 has 819 SNPs
OrthologuesGPT1 has 69 orthologues in EnsemblGPT2 has 63 orthologues in Ensembl
RegulationThere are 2 regulatory elements located in the region of GPT1 geneThere are 13 regulatory elements located in the region of GPT2
miR-122 may interact with GPT1 at multiple sites of the coding region to enhance translation[21]GPT2 promoter has a putative ATF4 (Activating transcription factor 4 binding site[69]
Microsomal triglyceride transfer protein inhibition augments plasma ALT/AST levels in response to endoplasmic reticulum stress[66]GPT2 is regulated by androgens in non-hepatic tissues[70]
GPT1, but not GPT2 promoter is induced by PPAR agonists[67]
ALT1 catalytic activity is inhibited by the effect of glycation[68]
Protein featuresSize: 496 amino acids; 54637 DaSize: 523 amino acids; 57904 Da
Cofactor: Pyridoxal phosphateCofactor: Pyridoxal phosphate
Subunit: HomodimerSubunit: Homodimer (By similarity)
Cellular localization in human cells1Cytosol of hepatocytes[18]ER and mitochondrial fraction[18]
Measurement in plasma (catalytic activity)Represents 90% of total ALT in circulation[17,18]Represents 10% of total ALT in circulation[17,18]
Tissue expression in humansEvidence: WB: Liver and kidney[18]Evidence: WB and IHQ (protein): Pancreas (islets of Langerhans), brain, adrenal gland, skeletal muscle, heart (cardiomyocytes)[18]
Evidence: NB: GPT mRNA is moderately expressed in kidney, liver, heart, and fat[15]Evidence: NB: mRNA is expressed at high levels in muscle, fat, kidney, and brain, and at lower levels in liver and breast[15]
Tissue expression in rodentsEvidence: NB (mRNA): Highly expressed in liver and moderately expressed in white adipose tissue (WAT), intestine, and colon[71]Evidence: NB (mRNA): muscle, liver, and white adipose tissue (WAT), at moderate levels in brain and kidney, and at a low level in heart[71]
Gene expression analysis suggests a sex-dependent difference in GPT2-mRNA in the liver and muscle[15]
Hepatic and muscle ALT2 protein activity was higher in males than in females; while no sex-dependent difference was noted in the liver for ALT1, it appears 20% higher in muscle in females[15]
Biological meaning and metabolic functionALT1 contributes to “basal” serum ALT activity, most likely associated with normal cell turnover in liver and other tissues that would release ALT1 into the circulation[15,17-19]Generation of pyruvate for gluconeogenesis under stressful living conditions, such as starvation[18]
ALT2 is involved in the metabolic adaptation of the cell to stress[69]
ALT2 is associated with a liver progluconeogenic metabolic adaptive response without hepatocellular necrosis after exposure to dexamethasone[72]
ALT2 may participate in the generation of pyruvate and glyceroneogenesis, contributing to the homeostasis of fatty acid metabolism and storage[16]
Biological meaning in human diseaseNAFLD: ALT1 represented 94% of total ALT levels in circulation[19]NAFLD: ALT2 represented 6% of total ALT levels in circulation[19]
HCV: High levels in circulation of ALT1 (about 5-fold increase as compared to the controls)[19]HCV: Moderate levels in circulation of ALT1 (about 2.5 fold increase as compared to the controls)[19]
Ultra-endurance exercise: no significant changes after exercise[19]Ultra-endurance exercise: High levels in circulation of ALT2 (about 2-fold increase as compared to the baseline conditions)[19]
Biological meaning in experimental models of diseaseNAFLD (ob/ob): Compared to the normal liver of lean mice, the expression of GPT1 mRNA remained unchanged[71]NAFLD (ob/ob): Compared to the normal liver of lean mice, the expression of GPT2 mRNA was elevated by about 2-fold, suggesting ALT2 induction during fatty liver[71]
Both ALT1 and ALT2 increased in the liver of mice induced liver steatosis by a deficient methionine-choline diet[73]
Table 3 Evidence from genome-wide association studies on the heritability of circulating levels of alanine-aminotransferase and aspartate-aminotransferase
Ref.Number of participants/study designGWAS strategy (genotyping)Number of variantsPhenotypeIdentified locus
Chambers et al[36]n = 61089Affymetrix, Illumina and perlegen sciences arraysAbout 2.6 million directly genotyped or imputed autosomal SNPsPlasma levels of ALTHSD17B13, MAPK10, TRIB1, CPN1, PNPLA3, SAMM50
Population-based
Adults
Yuan et al[74]Initial study n = 7715Affymetrix-Plasma levels of ALTCHUK, PNPLA3, SAMM50, CPN1
Replication n = 704
Population-based
Adults
Park et al[75]n = 532Illumina HumanOmni1-Quad BeadChip747076 SNPsPlasma levels of ALTST6GALNAC3, MMADHC, CCDC102B, RGS5, BRD7, GALNT13, SIRPA, CD93, SLC39A11, ADAMTS9, CELF2
Population-based ChildrenPlasma levels of ASTCYB5APS, CELF2, GOT1, ST6GALNAC3, ADAMTS9, THSD7B, EIF4A1P1, ROBO1, THSD7B
Shen et al[76]n = 866Affymetrix GeneChip Human Mapping 500 K Array set500568 SNPsPlasma levels of ASTGOT1
Population-based
adults
Table 4 Summary of the variants associated with alanine-aminotransferase and aspartate-aminotransferase levels in population-based genome-wide association studies: Biological function and variants characteristics
Variant IDVariant featuresSignificant P value for GWAS associationGene or nearest geneReported biological function of the associated locus
ALT
rs6834314Intergenic3.1 × 10-9HSD17B13/MAPK10Oxidoreductase involved in the metabolism of steroid hormones, prostaglandins, retinoids, lipids and xenobiotics
A member of the MAP kinase family
rs2954021Intron variant5.3 × 10-9TRIB1Involved in protein amino acid phosphorylation and controlling mitogen-activated protein kinase cascades. Potent negative regulator of MAPK pathways influencing apoptosis. Regulates hepatic lipogenesis and very low density lipoprotein production
rs10883437Intergenic4.0 × 10-9CPN1A plasma metallo-protease that cleaves basic amino acids from the C terminal of peptides and proteins
rs11597390intergenic2.9 × 10-8
rs738409Missense1.2 × 10-45PNPLA3Acylglycerol O-acyltransferase and triacylglycerol lipase that mediates triacylglycerol hydrolysis
p.Ile148Met
rs2281135Intron variant8.2 × 10-12
rs3761472Missense3.7 × 10-29SAMM50Component of the sorting and assembly machinery (SAM) of the mitochondrial outer membrane
p.Asp110Gly
rs2143571Intron variant9.4 × 10-7
rs11597086Non coding exon variant3.6 × 10-7CHUKMember of the serine/threonine protein kinase family; a component of a cytokine-activated protein complex that is an inhibitor of the essential transcription factor NF-kappa-B complex
rs11591741Intron variant4.5 × 10-7
rs4949718Intron variant1.87 × 10-7ST6GALNAC3Transfer sialic acids from CMP-sialic acid to terminal positions of carbohydrate groups in glycoproteins and glycolipids
rs17801127Intergenic2.37 × 10-7MMADHCMitochondrial protein that is involved in an early step of vitamin B12 metabolism
rs1539893Intron variant3.40 × 10-6CCDC102BRGS5Unknown Member of the regulators of G protein signaling (RGS) family
rs12035879Intron variant3.97 × 10-6
rs9941219Intergenic4.06 × 10-6BRD7Member of the bromodomain-containing protein family
rs731660Intergenic
rs12621256Intron variant4.36 × 10-6GALNT13Member of the glycosyltransferase 2 family; catalyzes the initial reaction in oligosaccharide biosynthesis; neurons cell biogenesis
rs6035126Intergenic4.94 × 10-6SIRPAReceptor-type transmembrane glycoproteins involved in the negative regulation of receptor tyrosine kinase-coupled signaling processes
rs13433286Intergenic
rs844917Intergenic5.64 × 10-6CD93Cell-surface glycoprotein and type I membrane protein
rs844914Intergenic5.98 × 10-6
rs903107Intron variant6.11 × 10-6SLC39A11Mediates zinc uptake
rs80311637Missense p.Val653Met7.18 × 10-6ADAMTS9Disintegrin and metalloproteinase with thrombospondin motifs
rs596406Intron variant9.18 × 10-6CELF2RNA-binding protein implicated in the regulation of several post-transcriptional events
AST
rs11597390Intergenic0.0009CHUKExplained previously
rs2281135Intron variant5.7 × 10-6PNPLA3Explained previously
rs862946Intergenic2.41 × 10-7CYB5AP5Pseudogene
rs596406Intron variant3.69 × 10-7CELF2Explained previously
rs76850691Missense p.Gln349Glu8.55 × 10-7GOT1Biosynthesis of L-glutamate from L-aspartate or L-cysteine
rs17109512Intergenic2.80 × 10-14
rs4949718Intron variant1.49 × 10-6ST6GALNAC3Explained previously
rs80311637Missense p.Val1597Met1.85 × 10-6ADAMTS9Explained previously
rs892877Intron variant3.75 × 10-6THSD7BUnknown
rs984295Intron variant5.86 × 10-6
rs457603Intergenic4.57 × 10-6EIF4A1P1Pseudogene
rs452621Intergenic
rs7617400Intron variant6.16 × 10-6ROBO1Neuronal development
rs11924965Intron variant
rs7644918Intron variant
Table 5 PNPLA3-rs738409 metabolite trait associations from the genome-wide association studies catalog
Variant IDLD with rs738409Metabolite ratioP value for association
rs124839590.657Cholesterol/gamma-glutamyltyrosine7.76 × 10-6
rs20762110.657Cholesterol/gamma-glutamyltyrosine1.19 × 10-5
rs20762110.657Aspartylphenylalanine/docosapentaenoate (n3 DPA; 22:5n3)5.26 × 10-6
rs22949220.657Docosapentaenoate (n3 DPA; 22:5n3)/eicosapentaenoate (EPA; 20:5n3)4.64 × 10-7
rs20730810.5683-methoxytyrosine/gamma-glutamylthreonine2.14 × 10-5
rs22811350.609Glycocholate/levulinate (4-oxovalerate)3.26 × 10-5
rs10100230.609Docosapentaenoate (n3 DPA; 22:5n3)/phenylacetylglutamine1.43 × 10-5
rs9266330.609Docosapentaenoate (n3 DPA; 22:5n3)/myristate (14:0)1.08 × 10-5
rs28960190.607Aspartylphenylalanine/docosapentaenoate (n3 DPA; 22:5n3)1.31 × 10-5