Lipoprotein(a)
Encyclopedia
Lipoprotein (also called Lp(a)) is a lipoprotein
subclass. Studies have identified Lp(a) as a putative risk factor for atherosclerotic diseases such as coronary heart disease
and stroke
.
Lipoprotein(a) was discovered in 1963 by Kåre Berg
and the human gene
encoding this protein was cloned in 1987.
IV repeats in the LPA gene. This size variation at the gene level is expressed on the protein level as well, resulting in apo(a) proteins with 10 to > 50 kringle IV repeats (each of the variable kringle IV consists of 114 amino acids). These variable apo(a) sizes are known as "apo(a) isoforms". There is a general inverse correlation between the size of the apo(a) isoform and the Lp(a) plasma concentration which is caused by a variable rate of degradation before the apo(a) protein has matured for Lp(a) assembly. Apo(a) is expressed by liver cells (hepatocytes), and the assembly of apo(a) and LDL particles seems to take place at the outer hepatocyte surface. The half-life of Lp(a) in the circulation is about 3 to 4 days.
Other functions have been related to recruitment of inflammatory cells through interaction with Mac-1 integrin, angiogenesis, and wound healing.
However, individuals without Lp(a) or with very low Lp(a) levels seem to be healthy. Thus plasma Lp(a) is certainly not vital, at least under normal environmental conditions. Since apo(a)/Lp(a) derived rather recently in mammalian evolution - only old world monkeys and humans have been shown to harbour Lp(a) - its function might not be vital but just evolutionarily advantageous under certain environmental conditions, e.g. in case of exposure to certain infectious diseases.
Another possibility, suggested by Linus Pauling
, is that Lp(a) is a primate adaptation to L-gulonolactone oxidase
(GULO) deficiency, found only in certain lines of mammals. GULO is required for converting glucose
to ascorbic acid
(vitamin C), which is needed to repair arteries; following the loss of GULO, those primates that adopted diets less abundant in vitamin C may have used Lp(a) as an ascorbic-acid surrogate to repair arterial walls.
) and it competes with plasminogen for its binding site, leading to reduced fibrinolysis. Also because Lp(a) stimulates secretion of PAI-1 it leads to thrombogenesis. In addition, because of LDL cholesterol
content, Lp-a contributes to atherosclerosis
.
(CHD), cerebrovascular disease
(CVD), atherosclerosis
, thrombosis
, and stroke. Lp-a concentrations may be affected by disease states, but are only slightly affected by diet, exercise, and other environmental factors. Commonly prescribed lipid-reducing drugs have little or no effect on Lp(a) concentration. Niacin (nicotinic acid) and aspirin are two relatively safe, easily available and inexpensive drugs known to significantly reduce the levels of Lp(a) in some individuals with high Lp(a); they should be used under the supervision of a qualified physician.
High Lp(a) predicts risk of early atherosclerosis similar to high LDL, but in advanced atherosclerosis, Lp(a) is an independent risk factor not dependent on LDL. Lp(a) then indicates a coagulant risk of plaque thrombosis. Apo(a) contains domains that are very similar to plasminogen (PLG). Lp(a) accumulates in the vessel wall and inhibits binding of PLG to the cell surface, reducing plasmin generation which increases clotting. This inhibition of PLG by Lp(a) also promotes proliferation of smooth muscle cells. These unique features of Lp(a) suggest Lp(a) causes generation of clots and atherosclerosis.
Vegetarians have higher levels of Lp-a than fish eaters in one homogeneous tribal population of Tanzania raising the possibility that pharmacologic amounts of fish oil supplements may be helpful to lower the levels of Lp-a.
Some studies have shown that regular consumption of moderate amounts of alcohol leads to significant decline in plasma levels of Lp-a while other studies have not.
, although studies show an association of Lp(a) and cardiovascular disease
, which does not automatically mean a causal relation. While it might well be indicated to measure Lp(a) in high risk patients, the association of Lp(a) and cardiovascular disease
is rather complicated. Apart from the total Lp(a) plasma concentration, the apo(a) isoform might be an important risk parameter. Furthermore, the ethnic origin of an individual must be considered when evaluating its Lp(a) concentration in respect of the risk for cardiovascular events. E.g. the "conventional" risk threshold of 30 mg/dl would classify up to > 50% of the individuals in some African populations as being at risk. Furthermore, Lp(a) measurement is in urgent need of standardisation.
Thus the threshold values given below should be seen very critically. They are applicable only to individuals of European descent, if at all.
Lipoprotein(a) - Lp(a)
LP(a) appears with different isoforms (per kringle repeats) of apolipoprotein - 40% of the variation in Lp(a) levels when measured in mg/dl can be attributed to different isoforms. Lighter Lp(a) are also associated with disease. Thus a test in mg/dl is not preferred.
with Calnexin
, Fibronectin
and Fibrinogen beta chain
. Niacin
has shown to have some effect in reducing Lp(a).
Lipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
subclass. Studies have identified Lp(a) as a putative risk factor for atherosclerotic diseases such as coronary heart disease
Coronary heart disease
Coronary artery disease is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients. It is sometimes also called coronary heart disease...
and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
.
Lipoprotein(a) was discovered in 1963 by Kåre Berg
Kåre Berg
Kåre Ingmar Berg was a Norwegian MD, professor in medical genetics, physician-in-chief and well-cited researcher.-Education and positions:...
and the human 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...
encoding this protein was cloned in 1987.
Structure
Lipoprotein(a) [Lp(a)] consists of an LDL-like particle and the specific apolipoprotein(a) [apo(a)], which is covalently bound to the apoB of the LDL like particle. Lp(a) plasma concentrations are highly heritable and mainly controlled by the apolipoprotein(a) gene [LPA] located on chromosome 6q26-27. Apo(a) proteins vary in size due to a size polymorphism [KIV-2 VNTR], which is caused by a variable number of so called kringleKringle domain
Kringle Domains are autonomous protein domains that fold into large loops stabilized by 3 disulfide linkages. These are important in protein-protein interactions with blood coagulation factors...
IV repeats in the LPA gene. This size variation at the gene level is expressed on the protein level as well, resulting in apo(a) proteins with 10 to > 50 kringle IV repeats (each of the variable kringle IV consists of 114 amino acids). These variable apo(a) sizes are known as "apo(a) isoforms". There is a general inverse correlation between the size of the apo(a) isoform and the Lp(a) plasma concentration which is caused by a variable rate of degradation before the apo(a) protein has matured for Lp(a) assembly. Apo(a) is expressed by liver cells (hepatocytes), and the assembly of apo(a) and LDL particles seems to take place at the outer hepatocyte surface. The half-life of Lp(a) in the circulation is about 3 to 4 days.
Catabolism and clearance
The mechanism and sites of Lp(a) catabolism are largely unknown. Uptake via the LDL receptor is not a major pathway of Lp(a) metabolism. The kidney has been identified as playing a role in Lp(a) clearance from plasma.Populations
Lp(a) concentrations vary over one thousandfold between individuals, from < 0.2 to > 200 mg/dL. This range of concentrations is observed in all populations studied so far. The mean and median concentrations between different world populations show distinct particularities, the main being the two- to threefold higher Lp(a) plasma concentration of populations of African descent compared to Asian, Oceanic, or European populations. The general inverse correlation between apo(a) isoform size and Lp(a) plasma concentration is observed in all populations, however, mean Lp(a) associated with certain apo(a) isoforms varies between populations.Function
The physiological function of Lp(a)/apo(a) is still unknown. A function within the coagulation system seems plausible, given the aspect of the high homology between apo(a) and plasminogen. In fact, the LPA gene derives from a duplication of the plasminogen gene.Other functions have been related to recruitment of inflammatory cells through interaction with Mac-1 integrin, angiogenesis, and wound healing.
However, individuals without Lp(a) or with very low Lp(a) levels seem to be healthy. Thus plasma Lp(a) is certainly not vital, at least under normal environmental conditions. Since apo(a)/Lp(a) derived rather recently in mammalian evolution - only old world monkeys and humans have been shown to harbour Lp(a) - its function might not be vital but just evolutionarily advantageous under certain environmental conditions, e.g. in case of exposure to certain infectious diseases.
Another possibility, suggested by Linus Pauling
Linus Pauling
Linus Carl Pauling was an American chemist, biochemist, peace activist, author, and educator. He was one of the most influential chemists in history and ranks among the most important scientists of the 20th century...
, is that Lp(a) is a primate adaptation to L-gulonolactone oxidase
L-gulonolactone oxidase
L-gulonolactone oxidase is an enzyme that catalyzes the reaction of D-glucuronolactone with oxygen to L-xylo-hex-3-gulonolactone and hydrogen peroxide. It uses FAD as a cofactor...
(GULO) deficiency, found only in certain lines of mammals. GULO is required for converting glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
to ascorbic acid
Ascorbic acid
Ascorbic acid is a naturally occurring organic compound with antioxidant properties. It is a white solid, but impure samples can appear yellowish. It dissolves well in water to give mildly acidic solutions. Ascorbic acid is one form of vitamin C. The name is derived from a- and scorbutus , the...
(vitamin C), which is needed to repair arteries; following the loss of GULO, those primates that adopted diets less abundant in vitamin C may have used Lp(a) as an ascorbic-acid surrogate to repair arterial walls.
Pathology
Lipoprotein's structure is similar to plasminogen and tPA (tissue plasminogen activatorTissue plasminogen activator
Tissue plasminogen activator is a protein involved in the breakdown of blood clots. It is a serine protease found on endothelial cells, the cells that line the blood vessels. As an enzyme, it catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown...
) and it competes with plasminogen for its binding site, leading to reduced fibrinolysis. Also because Lp(a) stimulates secretion of PAI-1 it leads to thrombogenesis. In addition, because of LDL 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...
content, Lp-a contributes to atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
.
Lipoprotein(a) and Disease
High Lp(a) in blood is a risk factor for coronary heart diseaseCoronary heart disease
Coronary artery disease is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients. It is sometimes also called coronary heart disease...
(CHD), cerebrovascular disease
Cerebrovascular disease
Cerebrovascular disease is a group of brain dysfunctions related to disease of the blood vessels supplying the brain. Hypertension is the most important cause; it damages the blood vessel lining, endothelium, exposing the underlying collagen where platelets aggregate to initiate a repairing process...
(CVD), atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
, and stroke. Lp-a concentrations may be affected by disease states, but are only slightly affected by diet, exercise, and other environmental factors. Commonly prescribed lipid-reducing drugs have little or no effect on Lp(a) concentration. Niacin (nicotinic acid) and aspirin are two relatively safe, easily available and inexpensive drugs known to significantly reduce the levels of Lp(a) in some individuals with high Lp(a); they should be used under the supervision of a qualified physician.
High Lp(a) predicts risk of early atherosclerosis similar to high LDL, but in advanced atherosclerosis, Lp(a) is an independent risk factor not dependent on LDL. Lp(a) then indicates a coagulant risk of plaque thrombosis. Apo(a) contains domains that are very similar to plasminogen (PLG). Lp(a) accumulates in the vessel wall and inhibits binding of PLG to the cell surface, reducing plasmin generation which increases clotting. This inhibition of PLG by Lp(a) also promotes proliferation of smooth muscle cells. These unique features of Lp(a) suggest Lp(a) causes generation of clots and atherosclerosis.
Vegetarians have higher levels of Lp-a than fish eaters in one homogeneous tribal population of Tanzania raising the possibility that pharmacologic amounts of fish oil supplements may be helpful to lower the levels of Lp-a.
Some studies have shown that regular consumption of moderate amounts of alcohol leads to significant decline in plasma levels of Lp-a while other studies have not.
Cardiology diagnostic tests
Lp(a) cannot yet be regarded as a conventional, well established risk factor for cardiovascular diseaseCardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
, although studies show an association of Lp(a) and cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
, which does not automatically mean a causal relation. While it might well be indicated to measure Lp(a) in high risk patients, the association of Lp(a) and cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
is rather complicated. Apart from the total Lp(a) plasma concentration, the apo(a) isoform might be an important risk parameter. Furthermore, the ethnic origin of an individual must be considered when evaluating its Lp(a) concentration in respect of the risk for cardiovascular events. E.g. the "conventional" risk threshold of 30 mg/dl would classify up to > 50% of the individuals in some African populations as being at risk. Furthermore, Lp(a) measurement is in urgent need of standardisation.
Thus the threshold values given below should be seen very critically. They are applicable only to individuals of European descent, if at all.
Lipoprotein(a) - Lp(a)
- Desirable: < 14 mg/dL (< 35 nmol/l)
- Borderline risk: 14 - 30 mg/dL (35 - 75 nmol/l)
- High risk: 31 - 50 mg/dL (75 - 125 nmol/l)
- Very high risk: > 50 mg/dL (> 125 nmol/l)
LP(a) appears with different isoforms (per kringle repeats) of apolipoprotein - 40% of the variation in Lp(a) levels when measured in mg/dl can be attributed to different isoforms. Lighter Lp(a) are also associated with disease. Thus a test in mg/dl is not preferred.
Interactions
Lipoprotein(a) 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 Calnexin
Calnexin
Calnexin is a 90kDa integral protein of the endoplasmic reticulum . It consists of a large N-terminal calcium-binding lumenal domain, a single transmembrane helix and a short , acidic cytoplasmic tail....
, Fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
and Fibrinogen beta chain
Fibrinogen beta chain
Fibrinogen beta chain, also known as FGB, is a gene found in humans and most other vertebrates with a similar system of blood coagulation.-Interactions:Fibrinogen beta chain has been shown to interact with Lipoprotein.-Further reading:...
. Niacin
Niacin
"Niacin" redirects here. For the neo-fusion band, see Niacin .Niacin is an organic compound with the formula and, depending on the definition used, one of the forty to eighty essential human nutrients.Niacin is one of five vitamins associated with a pandemic deficiency disease: niacin deficiency...
has shown to have some effect in reducing Lp(a).
See also
- LipoproteinLipoproteinA lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
- ApolipoproteinApolipoproteinApolipoproteins are proteins that bind lipids to form lipoproteins and transport the lipids through the lymphatic and circulatory systems....
- Very low density lipoproteinVery low density lipoproteinVery-low-density lipoprotein is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins that enable fats and cholesterol to move within the water-based solution of the bloodstream...
- Low density lipoproteinLow density lipoproteinLow-density lipoprotein is one of the five major groups of lipoproteins, which in order of size, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, that enable transport of cholesterol within the water-based bloodstream...
- Combined hyperlipidemiaCombined hyperlipidemiaIn medicine, combined hyperlipidemia is a commonly occurring form of hypercholesterolemia characterised by increased LDL and triglyceride concentrations, often accompanied by decreased HDL...