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APOA5
Apolipoprotein A-V is a protein that in humans is encoded by the APOA5 gene on chromosome 11. It is significantly expressed in liver. The protein encoded by this gene is an apolipoprotein and an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of several lipoprotein fractions including VLDL, HDL, chylomicrons. It is believed that apoA-V affects lipoprotein metabolism by interacting with LDL-R gene family receptors. Considering its association with lipoprotein levels, APOA5 is implicated in metabolic syndrome. The APOA5 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
The gene for apolipoprotein A5 (APOA5, gene ID 116519, OMIM accession number – 606368) was originally found by comparative sequencing of human and mice DNA as a last member of the gene cluster of apolipoproteins APOA1/APOC3/APOA4/APOA5, located on human chromosome 11 at position 11q23. The creation of two mice models (APOA5 transgenic and APOA5 knock-out) confirmed the important role of this gene in plasma triglyceride determination. The transgenic mice had lower and the knock-out mice higher levels of plasma triglycerides, while plasma cholesterol levels remained unchanged in both animal models. A Dutch group simultaneously described an identical gene as apolipoprotein which it is associated with the early phase of liver regeneration, but failed to recognise its important role in the determination of plasma triglyceride levels.
The APOA5 gene resides on chromosome 11 at the band 11q23 and contains 4 exons and 3 introns. This gene uses alternate polyadenylation sites and is located proximal to the apolipoprotein gene cluster on chromosome 11q23.
This protein belongs to the apolipoprotein A1/A4/E family and contains 2 coiled coil domains. Overall, APOA5 is predicted to have approximately 60% a-helical content. The mature APOA5 protein spans a length of 366 amino acid residues, of which 23 amino acids code for the signal peptide. The molecular mass of the precursor was calculated to be 41 kDa, while the mature APOA5 protein was calculated to be 39 kDa.
In humans, APOA5 is expressed almost exclusively in the liver tissue; some minor expressions have also been detected in the small intestine. Nothing is known about the existence of the potential alternative splicing variants of this gene. In comparison with other apolipoproteins, plasma concentration of APOA5 is very low (less than 1 μg/mL). This suggests that it has more catalytic than structural functions, since there is less than one APOA5 molecule per one lipoprotein particle. APOA5 is associated predominantly with TG-rich lipoproteins (chylomicrons and VLDL) and has also been detected on HDL particles.
APOA5 mainly functions to influence plasma triglyceride levels. The first suggested mechanism supposes that APOA5 functions as an activator of lipoprotein lipase (which is a key enzyme in triglyceride catabolism) and, through this process, enhances the metabolism of TG-rich particles. The second is the possible effect of APOA5 on the secretion of VLDL particles, since APOA5 reduces hepatic production by inhibiting VLDL-particle production and assembly by binding to cellular membranes and lipids. Finally, the third possibility relates to the acceleration of the hepatic uptake of lipoprotein remnants and it has been shown that APOA5 binds to different members of the low-density lipoprotein receptor family. In addition to its TG-lowering effect, APOA5 also plays a significant role in modulating HDL maturation and cholesterol metabolism. Increased APOA5 levels were associated with skewed cholesterol distribution from VLDL to large HDL particles. APOA5 mRNA is upregulated during liver regeneration and this suggests that APOA5 serves a function in hepatocyte proliferation. It's also reported that APOA5 could enhance insulin secretion in beta-cells and the cell surface midkine could be involved in APOA5 endocytosis.
Within the APOA5 gene, a couple of important SNPs with a widely confirmed effect on plasma TG levels as well as rare mutations have been described. In Caucasians, the common variants are inherited mostly in three haplotypes, which are characterised by two SNPs, namely rs662799 (T-1131>C; in almost complete LD with A-3>G, where the minor allele is associated with about 50% lower gene expression) and rs3135506 (Ser19>Trp; C56>G; alters the signal peptide and influences APOA5 secretion into plasma). There are also a further three common variants (A-3>G, IVS+476 G>A and T1259>C) which are not necessary for haplotype characterisation. Population frequencies of common APOA5 alleles exhibit large interethnic differences. For example, there are about 15% of carriers of the rs66299(C) allele among Caucasians, but the frequency could reach even between 40% and 50% among Asians. In contrast, the Trp19 allele is very rare in the Asian population (less than 1% of carriers) but is common in Caucasians (about 15% of carriers). Vice versa, important SNP (rs2075291, G553T, Gly185>Cys) with a population frequency of about 5% has been detected among Asians, but it is extremely rare among Caucasians. Sporadic publications refer to some other common polymorphisms, e.g. Val153>Met (rs3135507, G457A) and also suggest significant sex-dependent associations with plasma lipids. Rare variants within the APOA5 gene have been described in a couple of different populations. Among the "common mutations/rare SNPs", one of the most characterised on a population level is the Ala315>Val exchange. Originally detected in patients with extreme TG levels over 10 mmol/L, it was also found in about 0.7% of the general population (mostly in individuals with normal TG values), which suggests a low penetrance of this variant. More than twenty other rare variants (mutations) have been described within the human APOA5 gene. They cover a wide spectrum that includes premature stop codons, amino acid changes as well as insertions and deletions. These mutations are generally associated with hypertriglyceridaemia, but penetration is usually not 100%. Individual mutations have been found mostly in one pedigree only.
Not all the SNPs have a detrimental effect on TG levels. A recent report, showed that, in the Sardinian population, the missense mutation Arg282Ser in the APOA5 gene correlates with a decrease in TG levels. The authors believe that this point mutation is a major modulator of TG values in this population.
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APOA5
Apolipoprotein A-V is a protein that in humans is encoded by the APOA5 gene on chromosome 11. It is significantly expressed in liver. The protein encoded by this gene is an apolipoprotein and an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of several lipoprotein fractions including VLDL, HDL, chylomicrons. It is believed that apoA-V affects lipoprotein metabolism by interacting with LDL-R gene family receptors. Considering its association with lipoprotein levels, APOA5 is implicated in metabolic syndrome. The APOA5 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
The gene for apolipoprotein A5 (APOA5, gene ID 116519, OMIM accession number – 606368) was originally found by comparative sequencing of human and mice DNA as a last member of the gene cluster of apolipoproteins APOA1/APOC3/APOA4/APOA5, located on human chromosome 11 at position 11q23. The creation of two mice models (APOA5 transgenic and APOA5 knock-out) confirmed the important role of this gene in plasma triglyceride determination. The transgenic mice had lower and the knock-out mice higher levels of plasma triglycerides, while plasma cholesterol levels remained unchanged in both animal models. A Dutch group simultaneously described an identical gene as apolipoprotein which it is associated with the early phase of liver regeneration, but failed to recognise its important role in the determination of plasma triglyceride levels.
The APOA5 gene resides on chromosome 11 at the band 11q23 and contains 4 exons and 3 introns. This gene uses alternate polyadenylation sites and is located proximal to the apolipoprotein gene cluster on chromosome 11q23.
This protein belongs to the apolipoprotein A1/A4/E family and contains 2 coiled coil domains. Overall, APOA5 is predicted to have approximately 60% a-helical content. The mature APOA5 protein spans a length of 366 amino acid residues, of which 23 amino acids code for the signal peptide. The molecular mass of the precursor was calculated to be 41 kDa, while the mature APOA5 protein was calculated to be 39 kDa.
In humans, APOA5 is expressed almost exclusively in the liver tissue; some minor expressions have also been detected in the small intestine. Nothing is known about the existence of the potential alternative splicing variants of this gene. In comparison with other apolipoproteins, plasma concentration of APOA5 is very low (less than 1 μg/mL). This suggests that it has more catalytic than structural functions, since there is less than one APOA5 molecule per one lipoprotein particle. APOA5 is associated predominantly with TG-rich lipoproteins (chylomicrons and VLDL) and has also been detected on HDL particles.
APOA5 mainly functions to influence plasma triglyceride levels. The first suggested mechanism supposes that APOA5 functions as an activator of lipoprotein lipase (which is a key enzyme in triglyceride catabolism) and, through this process, enhances the metabolism of TG-rich particles. The second is the possible effect of APOA5 on the secretion of VLDL particles, since APOA5 reduces hepatic production by inhibiting VLDL-particle production and assembly by binding to cellular membranes and lipids. Finally, the third possibility relates to the acceleration of the hepatic uptake of lipoprotein remnants and it has been shown that APOA5 binds to different members of the low-density lipoprotein receptor family. In addition to its TG-lowering effect, APOA5 also plays a significant role in modulating HDL maturation and cholesterol metabolism. Increased APOA5 levels were associated with skewed cholesterol distribution from VLDL to large HDL particles. APOA5 mRNA is upregulated during liver regeneration and this suggests that APOA5 serves a function in hepatocyte proliferation. It's also reported that APOA5 could enhance insulin secretion in beta-cells and the cell surface midkine could be involved in APOA5 endocytosis.
Within the APOA5 gene, a couple of important SNPs with a widely confirmed effect on plasma TG levels as well as rare mutations have been described. In Caucasians, the common variants are inherited mostly in three haplotypes, which are characterised by two SNPs, namely rs662799 (T-1131>C; in almost complete LD with A-3>G, where the minor allele is associated with about 50% lower gene expression) and rs3135506 (Ser19>Trp; C56>G; alters the signal peptide and influences APOA5 secretion into plasma). There are also a further three common variants (A-3>G, IVS+476 G>A and T1259>C) which are not necessary for haplotype characterisation. Population frequencies of common APOA5 alleles exhibit large interethnic differences. For example, there are about 15% of carriers of the rs66299(C) allele among Caucasians, but the frequency could reach even between 40% and 50% among Asians. In contrast, the Trp19 allele is very rare in the Asian population (less than 1% of carriers) but is common in Caucasians (about 15% of carriers). Vice versa, important SNP (rs2075291, G553T, Gly185>Cys) with a population frequency of about 5% has been detected among Asians, but it is extremely rare among Caucasians. Sporadic publications refer to some other common polymorphisms, e.g. Val153>Met (rs3135507, G457A) and also suggest significant sex-dependent associations with plasma lipids. Rare variants within the APOA5 gene have been described in a couple of different populations. Among the "common mutations/rare SNPs", one of the most characterised on a population level is the Ala315>Val exchange. Originally detected in patients with extreme TG levels over 10 mmol/L, it was also found in about 0.7% of the general population (mostly in individuals with normal TG values), which suggests a low penetrance of this variant. More than twenty other rare variants (mutations) have been described within the human APOA5 gene. They cover a wide spectrum that includes premature stop codons, amino acid changes as well as insertions and deletions. These mutations are generally associated with hypertriglyceridaemia, but penetration is usually not 100%. Individual mutations have been found mostly in one pedigree only.
Not all the SNPs have a detrimental effect on TG levels. A recent report, showed that, in the Sardinian population, the missense mutation Arg282Ser in the APOA5 gene correlates with a decrease in TG levels. The authors believe that this point mutation is a major modulator of TG values in this population.
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