APOA4 explained

Apolipoprotein A-IV (also known as apoA-IV, apoAIV, or apoA4) is plasma protein that is the product of the human gene APOA4.^{[1] [2]}

Gene

APOA4 resides on chromosome 11 in close linkage to APOA1 and APOC3. APOA4 contains 3 exons separated by two introns, and is polymorphic, although most of the reported sequence polymorphisms occur in exon 3. The best validated and studied non-synonymous SNPs are a glutamine → histidine substitution at codon 360 and a threonine → serine substitution at codon 347; a sequence polymorphism has also been identified in the 3'UTR of the third exon. Intra-species comparative gene sequence analysis suggests that the APOA4 gene arose from APOA1 by gene duplication approximately 270 MYA.^[3]

Function

The primary translation product of the APOA4 gene is a 396-residue preprotein, which undergoes proteolytic processing to yield apo A-IV, a 376-residue mature O-linked glycoprotein. In most mammals, including humans, apo A-IV synthesis is confined to the intestine; however in mice and rats hepatic synthesis also occurs. Apo A-IV is secreted into circulation on the surface of newly synthesized chylomicron particles. Intestinal fat absorption dramatically increases the synthesis and secretion of apo A-IV. Although its primary function in human lipid metabolism has not been established, apo A-IV has been found to:

• activate lecithin-cholesterol acyltransferase and cholesterylester transfer protein in vitro;
• play a role in the regulation of appetite and satiety in rodent models;
• display anti-oxidant and anti-atherogenic properties in vitro and in rodent models;
• modulate the efficiency of enterocyte and hepatic transcellular lipid transport in vitro.^[4]

Human apo A-IV deficiency has not been reported.

Interactions

APOA4 has been shown to interact with GPLD1.^[5]

Further reading

• von Eckardstein A, Funke H, Schulte M . Nonsynonymous polymorphic sites in the apolipoprotein (apo) A-IV gene are associated with changes in the concentration of apo B- and apo A-I-containing lipoproteins in a normal population. . American Journal of Human Genetics . 50 . 5 . 1115–28 . 1992 . 1349197 . 1682587 . etal.
• Kamboh MI, Williams ER, Law JC . Molecular basis of a unique African variant (A-IV 5) of human apolipoprotein A-IV and its significance in lipid metabolism. . Genet. Epidemiol. . 9 . 6 . 379–88 . 1993 . 1487136 . 10.1002/gepi.1370090602 . 40107026 . etal.
• Lohse P, Kindt MR, Rader DJ, Brewer HB . Three genetic variants of human plasma apolipoprotein A-IV. apoA-IV-1(Thr347----Ser), apoA-IV-0(Lys167----Glu,Gln360----His), and apoA-IV-3(Glu165----Lys). . J. Biol. Chem. . 266 . 21 . 13513–8 . 1991 . 10.1016/S0021-9258(18)92728-6 . 1677358 . free .
• Tenkanen H, Koskinen P, Metso J . A novel polymorphism of apolipoprotein A-IV is the result of an asparagine to serine substitution at residue 127. . Biochim. Biophys. Acta . 1138 . 1 . 27–33 . 1992 . 1737067 . 10.1016/0925-4439(92)90147-f. etal.
• Lohse P, Kindt MR, Rader DJ, Brewer HB . Human plasma apolipoproteins A-IV-0 and A-IV-3. Molecular basis for two rare variants of apolipoprotein A-IV-1. . J. Biol. Chem. . 265 . 21 . 12734–9 . 1990 . 10.1016/S0021-9258(19)38406-6 . 1973689 . free .
• Tenkanen H, Lukka M, Jauhiainen M . The mutation causing the common apolipoprotein A-IV polymorphism is a glutamine to histidine substitution of amino acid 360. . Arterioscler. Thromb. . 11 . 4 . 851–6 . 1991 . 2065039 . 10.1161/01.atv.11.4.851. etal. free .
• de Temmerman P, Visvikis S, Boerwinkle E, Siest G . Study of the sequence tagged site (STS) in the beginning of human apo A4 gene region. . Nucleic Acids Res. . 18 . 18 . 5576 . 1990 . 2216752 . 10.1093/nar/18.18.5576 . 332267 .
• Wei S, Rocchi M, Archidiacono N . Physical mapping of the human chromosome 11q23 region containing the ataxia-telangiectasia locus. . Cancer Genet. Cytogenet. . 46 . 1 . 1–8 . 1990 . 2331673 . 10.1016/0165-4608(90)90002-R . etal.
• Lohse P, Kindt MR, Rader DJ, Brewer HB . Genetic polymorphism of human plasma apolipoprotein A-IV is due to nucleotide substitutions in the apolipoprotein A-IV gene. . J. Biol. Chem. . 265 . 17 . 10061–4 . 1990 . 10.1016/S0021-9258(19)38779-4 . 2351649 . free .
• Yang CY, Gu ZW, Chong IS . The primary structure of human apolipoprotein A-IV. . Biochim. Biophys. Acta . 1002 . 2 . 231–7 . 1989 . 2930771 . 10.1016/0005-2760(89)90292-0 . etal.
• Elshourbagy NA, Walker DW, Boguski MS . The nucleotide and derived amino acid sequence of human apolipoprotein A-IV mRNA and the close linkage of its gene to the genes of apolipoproteins A-I and C-III. . J. Biol. Chem. . 261 . 5 . 1998–2002 . 1986 . 10.1016/S0021-9258(17)35888-X . 3080432 . etal. free .
• Bisgaier CL, Sachdev OP, Lee ES . Effect of lecithin:cholesterol acyltransferase on distribution of apolipoprotein A-IV among lipoproteins of human plasma. . J. Lipid Res. . 28 . 6 . 693–703 . 1987 . 10.1016/S0022-2275(20)38666-1 . 3611972 . etal. free .
• Karathanasis SK, Yunis I, Zannis VI . Structure, evolution, and tissue-specific synthesis of human apolipoprotein AIV. . Biochemistry . 25 . 13 . 3962–70 . 1986 . 3755616 . 10.1021/bi00361a034 .
• Karathanasis SK . Apolipoprotein multigene family: tandem organization of human apolipoprotein AI, CIII, and AIV genes . Proceedings of the National Academy of Sciences of the United States of America . 82 . 19 . 6374–8 . 1985 . 3931073 . 10.1073/pnas.82.19.6374 . 390718 . 1985PNAS...82.6374K . free .
• Gordon JI, Bisgaier CL, Sims HF . Biosynthesis of human preapolipoprotein A-IV. . J. Biol. Chem. . 259 . 1 . 468–74 . 1984 . 10.1016/S0021-9258(17)43684-2 . 6706947 . etal. free .
• Menzel HJ, Dieplinger H, Sandholzer C . Apolipoprotein A-IV polymorphism in the Hungarian population: gene frequencies, effect on lipid levels, and sequence of two new variants. . Hum. Mutat. . 5 . 1 . 58–65 . 1995 . 7728150 . 10.1002/humu.1380050108 . 3063305 . etal. free .
• Duverger N, Tremp G, Caillaud JM . Protection against atherogenesis in mice mediated by human apolipoprotein A-IV . Science . 273 . 5277 . 966–8 . 1996 . 8688083 . 10.1126/science.273.5277.966 . etal. 1996Sci...273..966D . 30484255 .
• Deeb SS, Nevin DN, Iwasaki L, Brunzell JD . Two novel apolipoprotein A-IV variants in individuals with familial combined hyperlipidemia and diminished levels of lipoprotein lipase activity. . Hum. Mutat. . 8 . 4 . 319–25 . 1997 . 8956036 . 10.1002/(SICI)1098-1004(1996)8:4<319::AID-HUMU4>3.0.CO;2-2 . 19100488 .

Notes and References

1. Karathanasis SK, Oettgen P, Haddad IA, Antonarakis SE . Structure, evolution, and polymorphisms of the human apolipoprotein A4 gene (APOA4) . Proceedings of the National Academy of Sciences of the United States of America . 83 . 22 . 8457–61 . November 1986 . 3095836 . 386949 . 10.1073/pnas.83.22.8457. 1986PNAS...83.8457K . free .
2. Elshourbagy NA, Walker DW, Paik YK, Boguski MS, Freeman M, Gordon JI, Taylor JM . Structure and expression of the human apolipoprotein A-IV gene . J. Biol. Chem. . 262 . 17 . 7973–81 . June 1987 . 10.1016/S0021-9258(18)47513-8 . 3036793 . free .
3. Luo CC, Li WH, Moore MN, Chan L . Structure and evolution of the apolipoprotein multigene family . J. Mol. Biol. . 187 . 3 . 325–340 . February 1986 . 3084795 . 10.1016/0022-2836(86)90436-5.
4. Web site: Entrez Gene: APOA4 apolipoprotein A-IV.
5. Deeg . M A . Bierman E L . Cheung M C . March 2001 . GPI-specific phospholipase D associates with an apoA-I- and apoA-IV-containing complex . J. Lipid Res. . 42 . 3 . 442–51 . United States. 10.1016/S0022-2275(20)31669-2 . 0022-2275. 11254757 . free .