Apolipoprotein C-III also known as apo-CIII, and apolipoprotein C3, is a protein that in humans is encoded by the APOC3 gene. Apo-CIII is secreted by the liver as well as the small intestine, and is found on triglyceride-rich lipoproteins such as chylomicrons, very low density lipoprotein (VLDL), and remnant cholesterol. [5]
| ApoC-III | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | ApoC-III | ||||||||
| Pfam | PF05778 | ||||||||
| InterPro | IPR008403 | ||||||||
| |||||||||
ApoC-III is a relatively small protein containing 79 amino acids that can be glycosylated at threonine-74. [6] The most abundant glycoforms are characterized by an O-linked disaccharide galactose linked to N-acetylgalactosamine (Gal–GalNAc), further modified with up to two sialic acid residues. Less abundant glycoforms are characterized by more complex and fucosylated glycan moieties. [7]
APOC3 inhibits lipoprotein lipase and hepatic lipase; it is thought to inhibit hepatic uptake [8] of triglyceride-rich particles. The APOA1 , APOC3 and APOA4 genes are closely linked in both rat and human genomes. The A-I and A-IV genes are transcribed from the same strand, while the A-1 and C-III genes are convergently transcribed. An increase in apoC-III levels induces the development of hypertriglyceridemia. Recent evidence suggests an intracellular role for Apo-CIII in promoting the assembly and secretion of triglyceride-rich VLDL particles from hepatic cells under lipid-rich conditions. [9] However, two naturally occurring point mutations in human apoC3 coding sequence, namely Ala23Thr and Lys58Glu have been shown to abolish the intracellular assembly and secretion of triglyceride-rich VLDL particles from hepatic cells. [10] [11]
Overexpression of Apo-CIII in humans contributes to atherosclerosis. [5] Two novel susceptibility haplotypes (specifically, P2-S2-X1 and P1-S2-X1) have been discovered in ApoAI-CIII-AIV gene cluster on chromosome 11q23; these confer approximately threefold higher risk of coronary heart disease in normal [12] as well as non-insulin diabetes mellitus. [13] In persons with type 2 diabetes, elevated plasma Apo-CIII is associated with higher plasma triglycerides and greater coronary artery calcification (a measure of subclinical atherosclerosis). [14]
Apo-CIII delays the catabolism of triglyceride rich particles. HDL cholesterol particles that bear Apo-CIII are associated with increased, rather than decreased, risk for coronary heart disease. [15]
Elevations of Apo-CIII associated with single-nucleotide polymorphisms found in genetic variation studies may predispose patients to non-alcoholic fatty liver disease, [16] although the association has been questioned [17] and may be specific to certain ethnicities [18] [19] or to people without central obesity. [20]
Antisense oligonucleotides that bind APOC3 mRNA and prevent its translation have been found to reduce episodes of acute pancreatitis in people with familial chylomicronemia syndrome and lower their triglyceride levels in blood. Adverse effects include thrombocytopenia, which may be prevented by targeting hepatocellular APOC3 expression with a chemically modified oligonucleotide. [21]
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
Apolipoprotein CIII is also found on HDL particles. Formation of APOCIII-containing HDL is not a matter of simple binding of APOCII to pre-existing HDL particles but requires the lipid transported ABCA1 in a fashion similar to APOA1-containing HDL. [22] Accumulation of APOCIII on HDL is important for the maintenance of plasma triglyceride homeostasis since it prevents excessive amount of APOCIII on VLDL and other triglyceride rich lipoproteins, thus preventing APOCIII-mediated inhibition of LpL and the subsequent hydrolysis of plasma triglycerides. This may explain the hypertriglyceridemia associated with ABCA1-deficiency in patients with Tangier's disease.
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL has been associated with the progression of atherosclerosis.
A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, surrounded by a phospholipid outer shell, with the hydrophilic portions oriented outward toward the surrounding water and lipophilic portions oriented inward toward the lipid center. A special kind of protein, called apolipoprotein, is embedded in the outer shell, both stabilising the complex and giving it a functional identity that determines its role.
Very-low-density lipoprotein (VLDL), density relative to extracellular water, 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. VLDL is assembled in the liver from triglycerides, cholesterol, and apolipoproteins. VLDL is converted in the bloodstream to low-density lipoprotein (LDL) and intermediate-density lipoprotein (IDL). VLDL particles have a diameter of 30–80 nanometers (nm). VLDL transports endogenous products, whereas chylomicrons transport exogenous (dietary) products. In the early 2010s both the lipid composition and protein composition of this lipoprotein were characterised in great detail.
Chylomicrons, also known as ultra low-density lipoproteins (ULDL), are lipoprotein particles that consist of triglycerides (85–92%), phospholipids (6–12%), cholesterol (1–3%), and proteins (1–2%). They transport dietary lipids, such as fats and cholesterol, from the intestines to other locations in the body, within the water-based solution of the bloodstream. ULDLs are one of the five major groups lipoproteins are divided into based on their density. A protein specific to chylomicrons is ApoB48.
Apolipoproteins are proteins that bind lipids to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph.
Hyperlipidemia is abnormally high levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.
Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene APOE.
Apolipoprotein B (ApoB) is a protein that in humans is encoded by the APOB gene. Its measurement is commonly used to detect risk of atherosclerotic cardiovascular disease.
Apolipoprotein C-II, or apolipoprotein C2 is a protein that in humans is encoded by the APOC2 gene.
Apolipoprotein C-I is a protein component of lipoproteins that in humans is encoded by the APOC1 gene.
Lecithin cholesterol acyltransferase deficiency is a disorder of lipoprotein metabolism. The disease has two forms: Familial LCAT deficiency, in which there is complete LCAT deficiency, and Fish-eye disease, in which there is a partial deficiency.
Apolipoprotein AI(Apo-AI) is a protein that in humans is encoded by the APOA1 gene. As the major component of HDL particles, it has a specific role in lipid metabolism.
Apolipoprotein C-IV, also known as apolipoprotein C4, is a protein that in humans is encoded by the APOC4 gene.
Apolipoprotein D (ApoD) is a protein that in humans is encoded by the APOD gene. Unlike other lipoproteins, which are mainly produced in the liver, apolipoprotein D is mainly produced in the brain and testes. It is a 29 kDa glycoprotein discovered in 1963 as a component of the high-density lipoprotein (HDL) fraction of human plasma. It is the major component of human mammary cyst fluid. The human gene encoding it was cloned in 1986 and the deduced protein sequence revealed that ApoD is a member of the lipocalin family, small hydrophobic molecule transporters. ApoD is 169 amino acids long, including a secretion peptide signal of 20 amino acids. It contains two glycosylation sites and the molecular weight of the mature protein varies from 20 to 32 kDa.
Hepatic lipase (HL), also called hepatic triglyceride lipase (HTGL) or LIPC (for "lipase, hepatic"), is a form of lipase, catalyzing the hydrolysis of triacylglyceride. Hepatic lipase is coded by chromosome 15 and its gene is also often referred to as HTGL or LIPC. Hepatic lipase is expressed mainly in liver cells, known as hepatocytes, and endothelial cells of the liver. The hepatic lipase can either remain attached to the liver or can unbind from the liver endothelial cells and is free to enter the body's circulation system. When bound on the endothelial cells of the liver, it is often found bound to heparan sulfate proteoglycans (HSPG), keeping HL inactive and unable to bind to HDL (high-density lipoprotein) or IDL (intermediate-density lipoprotein). When it is free in the bloodstream, however, it is found associated with HDL to maintain it inactive. This is because the triacylglycerides in HDL serve as a substrate, but the lipoprotein contains proteins around the triacylglycerides that can prevent the triacylglycerides from being broken down by HL.
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.
Apolipoprotein A-II is a protein that in humans is encoded by the APOA2 gene. It is the second most abundant protein of the high density lipoprotein particles. The protein is found in plasma as a monomer, homodimer, or heterodimer with apolipoprotein D. ApoA-II regulates many steps in HDL metabolism, and its role in coronary heart disease is unclear. Remarkably, defects in this gene may result in apolipoprotein A-II deficiency or hypercholesterolemia.
Apolipoprotein A-IV is plasma protein that is the product of the human gene APOA4.
Microsomal triglyceride transfer protein large subunit is a protein that in humans is encoded by the MTTP, also known as MTP, gene.
Apolipoprotein M is an apolipoprotein and member of the lipocalin protein family that in humans is encoded by the APOM gene. It is found associated with high density lipoproteins and to a lesser extent with low density lipoproteins and triglyceride-rich lipoproteins. The encoded protein is secreted through the plasma membrane but remains membrane-bound, where it is involved in lipid transport. Two transcript variants encoding two different isoforms have been found for this gene, but only one of them has been fully characterized. It lacks an external amphipathic motif and is uniquely secreted to plasma without cleavage of its terminal signal peptide. The average molecular weight is 21253 Da, and the monoisotopic molecular weight is 21239 Da.
Lipids: lipoprotein particle metabolism | ||
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| Lipoprotein particle classes and subclasses |
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| Apolipoproteins | ||
| Extracellular enzymes | ||
| Lipid transfer proteins | ||
| Cell surface receptors | ||
| ATP-binding cassette transporter | ||
