Liver enzymes, metabolomics and genome-wide association studies: From systems biology to the personalized medicine

Table 2 Comparison of biological and protein function of ALT1 and ALT2: Background information and recent findings

Features and function	Glutamic-pyruvate transaminase 1 (alanine aminotransferase 1) GPT1	Glutamic pyruvate transaminase 2 (alanine aminotransferase) 2 GPT2
Gene and protein Id in data-bases	Entrez gene: 2875	Entrez gene: 84706
	Ensembl gene: ENSG00000167701	Ensemble: ENSG00000166123
	UniProtKB: P24298	UniProtKB: Q8TD30
Genomic location	Entrez gene cytogenetic band: 8q24.3	Entrez gene cytogenetic band: 16q12.1
Number of gene transcripts	7 transcripts (splice variants), 28 exons on the forward strand	5 transcripts (splice variants), 26 exons on the forward strand
Variation	GPT1 has 210 SNPs	GPT2 has 819 SNPs
Orthologues	GPT1 has 69 orthologues in Ensembl	GPT2 has 63 orthologues in Ensembl
Regulation	There are 2 regulatory elements located in the region of GPT1 gene	There 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 features	Size: 496 amino acids; 54637 Da	Size: 523 amino acids; 57904 Da
	Cofactor: Pyridoxal phosphate	Cofactor: Pyridoxal phosphate
	Subunit: Homodimer	Subunit: Homodimer (By similarity)
Cellular localization in human cells1	Cytosol 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 humans	Evidence: 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 rodents	Evidence: 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 function	ALT1 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 disease	NAFLD: 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 disease	NAFLD (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]

¹Cellular localization differs among species. ER: Endoplasmic reticulum; WB: Western blotting; IHQ: Immunohistochemistry; NB: Northern blot analysis; HCV: Hepatitis C virus; NAFLD: Non-alcoholic fatty liver disease.