Apolipoprotein A1
Encyclopedia
Apolipoprotein A-I is a protein
that in humans is encoded by the APOA1 gene
. It has a specific role in lipid metabolism
.
Apolipoprotein A-I is the major protein component of high density lipoprotein
(HDL) in plasma
. Chylomicrons secreted from the intestinal enterocyte also contain ApoA1 but it is quickly transferred to HDL in the bloodstream . The protein promotes cholesterol
efflux from tissues to the liver for excretion. It is a cofactor for [Lecithin-cholesterol acyltransferase|lecithin cholesterolacyltransferase]] (LCAT) which is responsible for the formation of most plasma cholesteryl esters. ApoA-I was also isolated as a prostacyclin
(PGI2) stabilizing factor, and thus may have an anticlotting effect. Defects in the gene encoding it are associated with HDL deficiencies, including Tangier disease
, and with systemic non-neuropathic amyloidosis
.
It has an approximate molecular weight 28 KDa.
from arteries. Five of nine men found to carry a mutation (E164X) who were at least 35 years of age had developed premature coronary artery disease. One of four mutants of ApoA-I is present in roughly 0.3% of the Japanese population, but is found 6% of those with low HDL cholesterol levels.
ApoA-1 Milano
is a naturally occurring mutant of ApoA-I, found in a family descended from a single couple of the 18th century. Described in 1980, it was the first known molecular abnormality of apolipoprotein
s. Paradoxically, carriers of this mutation have very low HDL cholesterol levels, but no increase in the risk of heart disease. Biochemically, ApoA-I contains an extra cysteine
bridge, causing it to exist as a homodimer or as a heterodimer with ApoA-II. However, the enhanced cardioprotective activity of this mutant (which likely depends on cholesterol efflux) cannot easily be replicated by other cysteine mutants.
Recombinant Apo-I Milano dimers formulated into liposomes can reduce atheroma
s in animal models by up to 30%. ApoA-I Milano has also been shown in small clinical trials to have a statistically significant effect in reducing (reversing) plaque build-up on arterial walls.
In human trials the reversal of plaque build-up was measured over the course of five weeks.
in the promoter of the ApoA-I gene has been associated with the age at which patients presented with Alzheimer disease. Protection from Alzheimer disease by ApoA1 may rely on a synergistic interaction with alpha-tocopherol
.
Amyloid
deposited in the knee following surgery consists largely of ApoA-I secreted from chondrocytes (cartilage
cells). A wide variety of amyloidosis
symptoms are associated with rare ApoA-I mutants.
ApoA-I binds to lipopolysaccharide
or endotoxin
, and has a major role in the anti-endotoxin function of HDL.
In one study, a decrease in ApoA1 levels was detected in schizophrenia
patients' CSF
, brain and peripheral tissues.
, and increased by a drug that antagonizes it.
Exercise or statin
treatment may cause an increase in HDL-C levels by inducing ApoA-I production, but this depends on the G/A promoter polymorphism.
, has a predicted biochemical interaction with Carbohydrate Kinase Domain Containing Protein
. The relationship between these two proteins is substantiated by Cooccurance across genomes, Coexpression, and Rosetta Stone Analysis. The ortholog of CARKD in E. coli contains a domain not present in any eukaryotic ortholog. This domain has a high sequence identity to APOA1BP. CARKD is a protein of unknown function, and the biochemical basis for this interaction is unknown.
with ABCA1
, GPLD1
and PLTP
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the APOA1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. It has a specific role in lipid metabolism
Lipid metabolism
Lipid metabolism refers to the processes that involve the intercourse and degradation of lipids.The types of lipids involved include:* Bile salts* Cholesterols* Eicosanoids* Glycolipids* Ketone bodies* Fatty acids - see also fatty acid metabolism...
.
Apolipoprotein A-I is the major protein component of high density lipoprotein
High density lipoprotein
High-density lipoprotein is one of the five major groups of lipoproteins, which, in order of sizes, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, which enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream...
(HDL) in plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
. Chylomicrons secreted from the intestinal enterocyte also contain ApoA1 but it is quickly transferred to HDL in the bloodstream . The protein promotes cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
efflux from tissues to the liver for excretion. It is a cofactor for [Lecithin-cholesterol acyltransferase|lecithin cholesterolacyltransferase]] (LCAT) which is responsible for the formation of most plasma cholesteryl esters. ApoA-I was also isolated as a prostacyclin
Prostacyclin
Prostacyclin is a member of the family of lipid molecules known as eicosanoids.As a drug, it is also known as "epoprostenol". The terms are sometimes used interchangeably.-History:...
(PGI2) stabilizing factor, and thus may have an anticlotting effect. Defects in the gene encoding it are associated with HDL deficiencies, including Tangier disease
Tangier disease
Tangier disease is a rare inherited disorder characterized by a severe reduction in the amount of high density lipoprotein , often referred to as "good cholesterol," in the bloodstream.-Diagnosis:...
, and with systemic non-neuropathic amyloidosis
Amyloidosis
In medicine, amyloidosis refers to a variety of conditions whereby the body produces "bad proteins", denoted as amyloid proteins, which are abnormally deposited in organs and/or tissues and cause harm. A protein is described as being amyloid if, due to an alteration in its secondary structure, it...
.
It has an approximate molecular weight 28 KDa.
Activity associated with high HDL-C and protection from heart disease
As a major component of the high-density lipoprotein complex ("good cholesterol"), ApoA-I helps to clear cholesterolCholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
from arteries. Five of nine men found to carry a mutation (E164X) who were at least 35 years of age had developed premature coronary artery disease. One of four mutants of ApoA-I is present in roughly 0.3% of the Japanese population, but is found 6% of those with low HDL cholesterol levels.
ApoA-1 Milano
ApoA-1 Milano
ApoA-1 Milano is a naturally occurring mutated variant of the apolipoprotein A1 protein found in human HDL, the lipoprotein particle that carries cholesterol from tissues to the liver and is associated with protection against cardiovascular disease. ApoA1 Milano was first identified by Dr...
is a naturally occurring mutant of ApoA-I, found in a family descended from a single couple of the 18th century. Described in 1980, it was the first known molecular abnormality of apolipoprotein
Apolipoprotein
Apolipoproteins are proteins that bind lipids to form lipoproteins and transport the lipids through the lymphatic and circulatory systems....
s. Paradoxically, carriers of this mutation have very low HDL cholesterol levels, but no increase in the risk of heart disease. Biochemically, ApoA-I contains an extra cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
bridge, causing it to exist as a homodimer or as a heterodimer with ApoA-II. However, the enhanced cardioprotective activity of this mutant (which likely depends on cholesterol efflux) cannot easily be replicated by other cysteine mutants.
Recombinant Apo-I Milano dimers formulated into liposomes can reduce atheroma
Atheroma
In pathology, an atheroma is an accumulation and swelling in artery walls that is made up of macrophage cells, or debris, that contain lipids , calcium and a variable amount of fibrous connective tissue...
s in animal models by up to 30%. ApoA-I Milano has also been shown in small clinical trials to have a statistically significant effect in reducing (reversing) plaque build-up on arterial walls.
In human trials the reversal of plaque build-up was measured over the course of five weeks.
Novel Haplotypes within Apolipoprotein AI-CIII-AIV gene cluster
Lately, two novel susceptibility haplotypes i.e. P2-S2-X1 and P1-S2-X1 have been discovered in ApoAI-CIII-AIV gene cluster on chromosme 11q23, which confer approximately threefold higher risk of coronary heart disease in normal as well as in the patients having non-insulin diabetes mellitus.Role in other diseases
A G/A polymorphismPolymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
in the promoter of the ApoA-I gene has been associated with the age at which patients presented with Alzheimer disease. Protection from Alzheimer disease by ApoA1 may rely on a synergistic interaction with alpha-tocopherol
Alpha-tocopherol
α-Tocopherol is a type of tocopherol with formula C29H50O2. It has E number "E307".α-Tocopherol is a form of vitamin E that is preferentially absorbed and accumulated in humans...
.
Amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
deposited in the knee following surgery consists largely of ApoA-I secreted from chondrocytes (cartilage
Cartilage
Cartilage is a flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs...
cells). A wide variety of amyloidosis
Amyloidosis
In medicine, amyloidosis refers to a variety of conditions whereby the body produces "bad proteins", denoted as amyloid proteins, which are abnormally deposited in organs and/or tissues and cause harm. A protein is described as being amyloid if, due to an alteration in its secondary structure, it...
symptoms are associated with rare ApoA-I mutants.
ApoA-I binds to lipopolysaccharide
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
or endotoxin
Endotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...
, and has a major role in the anti-endotoxin function of HDL.
In one study, a decrease in ApoA1 levels was detected in schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
patients' CSF
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
, brain and peripheral tissues.
Epistatic impact of ApoA-I
Apolipoprotein A-I and APOE interact epistatically to modulate triglyceride levels in Coronary Heart Disease patients.Individually, neither ApoA-I nor ApoE was found to be associated with TG levels however, pairwise epistasis (additive x additive model) explored their significant synergistic contributions with raised TG levels (P<0.01).Factors affecting ApoA-I activity
ApoA-I production is decreased by calcitriolCalcitriol
Calcitriol , also called 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3, is the hormonally active form of vitamin D with three hydroxyl groups...
, and increased by a drug that antagonizes it.
Exercise or statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
treatment may cause an increase in HDL-C levels by inducing ApoA-I production, but this depends on the G/A promoter polymorphism.
Potential Binding Partners
Apolipoprotein A-1 binding precursor, a relative of APOA-1 abbreviated APOA1BPAPOA1BP
Apolipoprotein A-I-binding protein also known as APOA1BP is a protein that in humans is encoded by the APOA1BP gene.- Function :APOA1BP binds to APOA1, APOA2, and high-density lipoprotein . In addition, APOA1BP appears to play a role in sperm capacitation....
, has a predicted biochemical interaction with Carbohydrate Kinase Domain Containing Protein
CARKD
Carbohydrate kinase domain containing protein, also known as CARKD, is a human protein of unknown function. The protein is conserved throughout many species, and has predicted orthologs through eukaryotes, bacteria, and archea.- Gene :...
. The relationship between these two proteins is substantiated by Cooccurance across genomes, Coexpression, and Rosetta Stone Analysis. The ortholog of CARKD in E. coli contains a domain not present in any eukaryotic ortholog. This domain has a high sequence identity to APOA1BP. CARKD is a protein of unknown function, and the biochemical basis for this interaction is unknown.
Interactions
Apolipoprotein A1 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with ABCA1
ABCA1
ATP-binding cassette transporter ABCA1 , also known as the cholesterol efflux regulatory protein is a protein which in humans is encoded by the ABCA1 gene...
, GPLD1
GPLD1
Phosphatidylinositol-glycan-specific phospholipase D is an enzyme that in humans is encoded by the GPLD1 gene.-Interactions:GPLD1 has been shown to interact with Apolipoprotein A1 and APOA4.-Further reading:...
and PLTP
PLTP
Phospholipid transfer protein is a protein that in humans is encoded by the PLTP gene.- Function :The protein encoded by this gene is one of at least two lipid transfer proteins found in human plasma. The encoded protein transfers phospholipids from triglyceride-rich lipoproteins to high density...
.