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Current Opinion in Lipidology Aug 2008We have examined the evidence from recent human studies examining the role of apolipoprotein A-V in triglyceride-rich lipoprotein metabolism and cardiovascular disease... (Review)
Review
PURPOSE OF REVIEW
We have examined the evidence from recent human studies examining the role of apolipoprotein A-V in triglyceride-rich lipoprotein metabolism and cardiovascular disease risk. Special emphasis was placed on the evidence emerging from the association between genetic variability at the apolipoprotein A5 locus, lipid phenotypes and disease outcomes. Moreover, we address recent reports evaluating apolipoprotein A5 gene-environment interactions in relation to cardiovascular disease and its common risk factors.
RECENT FINDINGS
Several genetic association studies have continued to strengthen the position of APOA5 as a major gene that is involved in triglyceride metabolism and modulated by dietary factors and pharmacological therapies. Moreover, genetic variants at this locus have been significantly associated with both coronary disease and stroke risks.
SUMMARY
Apolipoprotein A-V has an important role in lipid metabolism, specifically for triglyceride-rich lipoproteins. However, its mechanism of action is still poorly understood. Clinical significance at present comes largely from genetic studies showing a consistent association with plasma triglyceride concentrations. Moreover, the effects of common genetic variants on triglyceride concentrations and disease risk are further modulated by other factors such as diet, pharmacological interventions and BMI. Therefore, these genetic variants could be potentially used to predict cardiovascular disease risk and individualize therapeutic options to decrease cardiovascular disease risk.
Topics: Apolipoprotein A-V; Apolipoproteins A; Diabetes Complications; Endpoint Determination; Humans; Metabolic Syndrome; Polymorphism, Single Nucleotide; Triglycerides
PubMed: 18607181
DOI: 10.1097/MOL.0b013e328304b681 -
Journal of the American College of... May 2017
Topics: Aged; Aged, 80 and over; Amyloidosis; Apolipoproteins A; Biomarkers; Cardiomyopathies; Female; Humans; Male; Middle Aged
PubMed: 28449784
DOI: 10.1016/j.jacc.2017.02.047 -
Physiological Research 2009High plasma levels of triglycerides (TG) are an independent risk factor in the development of cardiovascular disease, with about 50 % of the final levels being... (Review)
Review
High plasma levels of triglycerides (TG) are an independent risk factor in the development of cardiovascular disease, with about 50 % of the final levels being determined genetically. Apolipoprotein A5 (APOA5) is the last discovered member of the apolipoprotein APOA1/C3/A4 gene cluster, found by comparative sequencing analysis. The importance of APOA5 gene for determination of plasma triglyceride levels has been suggested after development of transgenic and knock-out mice (transgenic mice displayed significantly reduced TG, whereas knock-out mice had high TG). In Czech population, alleles C-1131 and Trp19 are associated with elevated levels of plasma TG and higher risk of myocardial infarction development. These alleles also play some role in nutrigenetics and actigenetics of lifestyle interventions leading to the plasma cholesterol changes as well as in the pharmacogenetics of statin treatment. On the contrary, APOA5 mutations detected in Czech population did not show strict effect on plasma TG levels. Val153 --> Met variant exhibit the sex-specific effect of HDL-cholesterol levels. The suggested roles of APOA5 variants in determination of the plasma remnant particles, plasma concentrations of C-reactive protein or some anthropometrical parameters were excluded.
Topics: Animals; Apolipoprotein A-V; Apolipoproteins; Apolipoproteins A; Disease Models, Animal; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Hypercholesterolemia; Male; Mice; Mice, Knockout; Myocardial Infarction; Phenotype; Polymorphism, Genetic; Rats; Risk Assessment; Triglycerides
PubMed: 20131928
DOI: 10.33549/physiolres.931911 -
Molecules and Cells Jun 2015Apolipoprotein A-I and A-IV are protein constituents of high-density lipoproteins although their functional difference in lipoprotein metabolism is still unclear. To...
Apolipoprotein A-I and A-IV are protein constituents of high-density lipoproteins although their functional difference in lipoprotein metabolism is still unclear. To compare anti-atherogenic properties between apoA-I and apoA-4, we characterized both proteins in lipid-free and lipid-bound state. In lipid-free state, apoA4 showed two distinct bands, around 78 and 67 Å on native gel electrophoresis, while apoA-I showed scattered band pattern less than 71 Å. In reconstituted HDL (rHDL) state, apoA-4 showed three major bands around 101 Å and 113 Å, while apoA-I-rHDL showed almost single band around 98 Å size. Lipid-free apoA-I showed 2.9-fold higher phospholipid binding ability than apoA-4. In lipid-free state, BS3-crosslinking revealed that apoA-4 showed less multimerization tendency upto dimer, while apoA-I showed pentamerization. In rHDL state (95:1), apoA-4 was existed as dimer as like as apoA-I. With higher phospholipid content (255:1), five apoA-I and three apoA-4 were required to the bigger rHDL formation. Regardless of particle size, apoA-I-rHDL showed superior LCAT activation ability than apoA-4-rHDL. Uptake of acetylated LDL was inhibited by apoA-I in both lipid-free and lipid-bound state, while apoA-4 inhibited it only lipid-free state. ApoA-4 showed less anti-atherogenic activity with more sensitivity to glycation. In conclusion, apoA-4 showed inferior physiological functions in lipid-bound state, compared with those of apoA-I, to induce more pro-atherosclerotic properties.
Topics: Antioxidants; Apolipoprotein A-I; Apolipoproteins A; Atherosclerosis; Cell Line; Circular Dichroism; Humans; Lipoproteins, HDL; Male; Phospholipids; Structure-Activity Relationship
PubMed: 25997739
DOI: 10.14348/molcells.2015.0052 -
The Journal of Biological Chemistry Dec 1984We have isolated and characterised A-IV apolipoprotein (apo-A-IV) from human lymph and plasma by immunoabsorbance chromatography and two-dimensional electrophoresis. Two...
We have isolated and characterised A-IV apolipoprotein (apo-A-IV) from human lymph and plasma by immunoabsorbance chromatography and two-dimensional electrophoresis. Two different apo-A-IV-containing lipoproteins were isolated from four different sources, human lymph triglyceride-rich fraction (TRL), lymph lipoprotein-deficient fraction (LDF), plasma high-density lipoprotein (HDL), and plasma lipoprotein-deficient fraction (LDF). The lipoprotein complexes obtained from lymph TRL and plasma HDL were similar and contained apo-A-IV, apo-A-I, and small molecular weight peptides (apo-C or -A-II). The second lipoprotein complex was isolated from lymph LDF and plasma LDF, and contained apo-A-IV, apo-A-I, and a peptide of Mr = 59,000. The lipid composition of the lipoprotein complexes varied according to the source: triglyceride predominating in lymph TRL and phospholipid and cholesteryl ester from the other sources. Free cholesterol was conspicuously present in very small amounts. Using two-dimensional electrophoresis and immunoblotting techniques, eleven isoproteins of apo-A-IV were identified (pI-4.98, 5.06, 5.10, 5.15, 5.20, 5.22, 5.25, 5.30, 5.34, 5.42, and 5.48). The isoprotein pattern of lymph TRL and plasma HDL was similar, but that of lymph and plasma LDF were different patterns. These results suggest that apo-A-IV associated with d less than 1.21 lipoproteins and apo-A-IV present in LDF may be in metabolically separate lipoproteins and may have different physiological roles.
Topics: Amino Acids; Apolipoproteins A; Chromatography, Affinity; Electrophoresis, Polyacrylamide Gel; Humans; Lymph; Molecular Weight; Structure-Activity Relationship; Triglycerides
PubMed: 6501321
DOI: No ID Found -
The Journal of Biological Chemistry Dec 1990We prepared a spherical reconstituted high density lipoprotein (rHDL) particle in pure form and compared it with its homogeneous discoidal rHDL precursors, in terms of...
We prepared a spherical reconstituted high density lipoprotein (rHDL) particle in pure form and compared it with its homogeneous discoidal rHDL precursors, in terms of the structure and stability of the apolipoprotein A-I (apoA-I) component, the dynamics of the surface lipids, and the relative reactivity with lecithin-cholesterol acyltransferase. The apoA-I-structure was examined in the rHDL particles by circular dichroism and fluorescence spectroscopic methods, and the binding of monoclonal antibodies specific for apoA-I epitopes. The stability of apoA-I on the rHDL particles was assessed by the effects of guanidine hydrochloride on the wavelength of maximum intrinsic fluorescence of the apolipoprotein. Lipid dynamics in the acyl chain region and the polarity of the lipid-water interface were investigated by means of fluorescence probes. The conformation of apoA-I in the spherical 93-A rHDL particles was found to be very similar to that in the 96-A rHDL discs but distinct from the apoA-I structure in the 78-A rHDL discs. The stability of apoA-I to denaturation by guanidine hydrochloride was highest in the 93-A rHDL spheres. The experiments on the lipids indicate somewhat more ordered and motionally restricted acyl chains in the spheres, relative to the discs, but a similar surface polarity. These results suggest that the folding and organization of apoA-I on the three particles include protein domains consisting of interacting alpha-helical segments in the carboxyl-terminal region and a globular domain in the amino-terminal region of each apoA-I molecule. The reactivity with lecithin-cholesterol acyltransferase was highest for the 96-A rHDL disc, and 16- and 34-fold lower for the 78-A rHDL disc and the 93-A rHDL sphere, respectively, possibly as a result of differences in apoA-I structure and product inhibition in these particles.
Topics: Antibodies, Monoclonal; Apolipoprotein A-I; Apolipoproteins A; Cholesterol; Circular Dichroism; Humans; Kinetics; Lipoproteins, HDL; Liposomes; Phosphatidylcholines; Protein Conformation; Spectrometry, Fluorescence; Thermodynamics
PubMed: 2125044
DOI: No ID Found -
The Journal of Clinical Investigation Feb 1991Low HDL-cholesterol (HDL-C) levels may elevate atherosclerosis risk, and often associate with hypertriglyceridemia (HTG); however, the metabolic causes of low HDL-C...
Low HDL-cholesterol (HDL-C) levels may elevate atherosclerosis risk, and often associate with hypertriglyceridemia (HTG); however, the metabolic causes of low HDL-C levels with or without HTG are poorly understood. We studied the turnover of radioiodinated HDL apolipoproteins, apo A-I and apo A-II, in 15 human subjects with low HDL-C, six with normal plasma TG levels (group 1) and nine with high TG (group 2), and compared them to 13 control subjects with normal HDL-C and TG levels (group 3). The fractional catabolic rate (FCR) was equally elevated in groups 1 and 2 vs. group 3 for both apo A-I (0.313 +/- 0.052 and 0.323 +/- 0.063 vs. 0.245 +/- 0.043 pools/d, P = 0.003) and apo A-II (0.213 +/- 0.036 and 0.239 +/- 0.037 vs. 0.185 +/- 0.031 pools/d, P = 0.006). Thus, high FCR characterized low HDL-C regardless of the presence or absence of HTG. In contrast, transport rate (TR) of apo A-I did not differ significantly among the groups and the apo A-II TR differed only between groups 2 and 3 (2.15 +/- 0.57, 2.50 +/- 0.39, and 1.83 +/- 0.48 mg/kg per d for groups 1 to 3, respectively, P = 0.016). Several HDL-related factors were similar in groups 1 and 2 but differed in group 3, as with FCR, including the ratio of lipoprotein lipase to hepatic lipase activity (LPL/HL) in post-heparin plasma, the ratio of the HDL-C to apo A-I plus apo A-II levels, and the percent of tracer in the d greater than 1.21 fraction. In linear regression analysis HDL-C levels correlated inversely with the FCR of apo A-I and apo A-II (r = -0.74, P less than 0.0001 for both). Major correlates of FCR were HDL-C/apo A-I + apo A-II, LPL/HL, and plasma TG levels. We hypothesize that lipase activity and plasma TG affect HDL composition which modulates FCR, which in turn regulates HDL-C. Thus, HTG is only one of several factors which may contribute to elevated FCR and low HDL-C. Given the relationship of altered HDL composition with high FCR and low HDL-C levels, factors affecting HDL composition may increase atherosclerosis susceptibility.
Topics: Apolipoprotein A-I; Apolipoprotein A-II; Apolipoproteins A; Cholesterol, HDL; Female; Humans; Hypertriglyceridemia; Kinetics; Lipase; Lipoprotein Lipase; Liver; Male
PubMed: 1899429
DOI: 10.1172/JCI115028 -
The Journal of Biological Chemistry Jul 1990Human apolipoprotein (apo) A-IV is a polymorphic plasma protein controlled by two codominant alleles at a single genetic locus. Thus far, five different isoproteins... (Comparative Study)
Comparative Study
Human apolipoprotein (apo) A-IV is a polymorphic plasma protein controlled by two codominant alleles at a single genetic locus. Thus far, five different isoproteins (apoA-IV-0 to apoA-IV-4) have been described in Caucasians. We have recently identified the nucleotide and amino acid substitutions that are the basis for the most common isoproteins, apoA-IV-1 and apoA-IV-2. In this report, the mutations producing the two rare isoproteins apoA-IV-0 and apoA-IV-3 are described. Analysis of the apoA-IV-0 allele revealed an insertion of 12 nucleotides in a carboxyl-terminal region, which is highly conserved among human, rat, and mouse A-IV apolipoproteins. This in-frame insertion of the 4 amino acids Glu-Gln-Gln-Gln between residues 361 and 362 of the mature protein produces the 1 charge unit more acidic apoA-IV-0 isoprotein (pI 4.92). In the apoA-IV-3 allele we identified a single G to A substitution that converts the glutamic acid (GAG) at position 230 of the mature protein to a lysine (AAG), thus adding 2 positive charge units to the apoA-IV-1 isoprotein (pI 4.97) and forming the more basic apoA-IV-3 isoprotein (pI 5.08). Comparison with the mouse and rat A-IV apolipoproteins revealed that this residue, located at position 4 of the 10th/11th amphiphilic alpha-helical repeat, is also highly conserved in evolution.
Topics: Alleles; Amino Acid Sequence; Animals; Apolipoproteins A; Base Sequence; Blotting, Western; Humans; Isoelectric Point; Mice; Molecular Sequence Data; Oligonucleotides; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Protein Conformation; Rats
PubMed: 1973689
DOI: No ID Found -
Journal of Lipid Research Nov 2019HDL-bound ApoM and albumin are protein chaperones for the circulating bioactive lipid, sphingosine 1-phosphate (S1P); in this role, they support essential extracellular...
HDL-bound ApoM and albumin are protein chaperones for the circulating bioactive lipid, sphingosine 1-phosphate (S1P); in this role, they support essential extracellular S1P signaling functions in the vascular and immune systems. We previously showed that ApoM- and albumin-bound S1P exhibit differences in receptor activation and biological functions. Whether the physiological functions of S1P require chaperones is not clear. We examined ApoM-deficient, albumin-deficient, and double-KO (DKO) mice for circulatory S1P and its biological functions. In albumin-deficient mice, ApoM was upregulated, thus enabling S1P functions in embryonic development and postnatal adult life. The DKO mice reproduced, were viable, and exhibited largely normal vascular and immune functions, which suggested sufficient extracellular S1P signaling. However, DKO mice had reduced levels (∼25%) of plasma S1P, suggesting that novel S1P chaperones exist to mediate S1P functions. In this study, we report the identification of ApoA4 as a novel S1P binding protein. Recombinant ApoA4 bound to S1P, activated multiple S1P receptors, and promoted vascular endothelial barrier function, all reflective of its function as a S1P chaperone in the absence of ApoM and albumin. We suggest that multiple S1P chaperones evolved to support complex and essential extracellular signaling functions of this lysolipid mediator in a redundant manner.
Topics: Amino Acid Sequence; Animals; Apolipoproteins A; Apolipoproteins M; Gene Knockout Techniques; Lysophospholipids; Mice; Mice, Inbred C57BL; Serum Albumin; Sphingosine; Sphingosine-1-Phosphate Receptors
PubMed: 31462513
DOI: 10.1194/jlr.RA119000277 -
Structure (London, England : 1993) May 2012Apolipoproteins are key structural elements of lipoproteins and critical mediators of lipid metabolism. Their detergent-like properties allow them to emulsify lipid or...
Apolipoproteins are key structural elements of lipoproteins and critical mediators of lipid metabolism. Their detergent-like properties allow them to emulsify lipid or exist in a soluble lipid-free form in various states of self-association. Unfortunately, these traits have hampered high-resolution structural studies needed to understand the biogenesis of cardioprotective high-density lipoproteins (HDLs). We derived a crystal structure of the core domain of human apolipoprotein (apo)A-IV, an HDL component and important mediator of lipid absorption. The structure at 2.4 Å depicts two linearly connected 4-helix bundles participating in a helix swapping arrangement that offers a clear explanation for how the protein self-associates as well as clues to the structure of its monomeric form. This also provides a logical basis for antiparallel arrangements recently described for lipid-containing particles. Furthermore, we propose a "swinging door" model for apoA-IV lipid association.
Topics: Apolipoproteins A; Binding Sites; Crystallography, X-Ray; Dimerization; Humans; Lipid Metabolism; Models, Molecular; Protein Structure, Secondary
PubMed: 22579246
DOI: 10.1016/j.str.2012.02.020