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Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext . South Dartmouth (MA): MDText.com, Inc.; 2000-.


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ABSTRACT

Cholesterol and also triglycerides space insoluble in water and therefore these lipids must be transported in association with proteins. Lipoproteins are complicated particles through a main core containing cholesterol esters and triglycerides surrounding by cost-free cholesterol, phospholipids, and also apolipoproteins, i beg your pardon facilitate lipoprotein formation and also function. Plasma lipoproteins deserve to be separated into 7 classes based on size, lipid composition, and also apolipoproteins (chylomicrons, chylomicron remnants, VLDL, IDL, LDL, HDL, and also Lp (a)). Chylomicron remnants, VLDL, IDL, LDL, and also Lp (a) are all pro-atherogenic while HDL is anti-atherogenic. Apolipoproteins have actually four major functions consisting of 1) serving a structural role, 2) acting as ligands for lipoprotein receptors, 3) guiding the formation of lipoproteins, and also 4) serving as activators or inhibitors of enzymes connected in the metabolism of lipoproteins. The exogenous lipoprotein pathway starts v the organization of diet lipids right into chylomicrons in the intestine. In the circulation, the triglycerides brought in chylomicrons are metabolized in muscle and also adipose organization by lipoprotein lipase releasing cost-free fatty acids, which are subsequently metabolized by muscle and also adipose tissue, and chylomicron remnants are formed. Chylomicron remnants room then taken increase by the liver. The endogenous lipoprotein pathway starts in the liver with the development of VLDL. The triglycerides carried in VLDL room metabolized in muscle and also adipose tissue by lipoprotein lipase releasing free fatty acids and also IDL are formed. The IDL are further metabolized come LDL, which space taken increase by the LDL receptor in numerous tissues including the liver, the primary site that uptake. Turning back cholesterol transport starts with the formation of nascent HDL by the liver and also intestine. These tiny HDL particles have the right to then gain cholesterol and phospholipids that are effluxed native cells, a procedure mediated by ABCA1 leading to the formation of maturation HDL. Tires HDL have the right to acquire addition cholesterol from cell via ABCG1, SR-B1, or passive diffusion. The HDL climate transports the cholesterol to the liver either directly by communicating with hepatic SR-B1 or indirect by transporting the cholesterol come VLDL or LDL, a process facilitated by CETP. Cholesterol efflux from macrophages come HDL plays critical role in protecting indigenous the development of atherosclerosis. For finish coverage of all related locations of Endocrinology, you re welcome visit our on-line free web-text, WWW.ENDOTEXT.ORG.


INTRODUCTION

Because lipids, such as cholesterol and triglycerides, are insoluble in water this lipids need to be transported in association with proteins (lipoproteins) in the circulation. Big quantities of fatty acids indigenous meals must be transported as triglycerides to protect against toxicity. This lipoproteins play a crucial role in the absorption and also transport of dietary lipids through the small intestine, in the transport of lipids from the liver to peripheral tissues, and the carry of lipids from peripheral tissues to the liver and intestine (reverse cholesterol transport). A secondary duty is to transfer toxic international hydrophobic and amphipathic compounds, such together bacterial endotoxin, from areas of invasion and also infection (1).


STRUCTURE the LIPOPROTEINS (2)

Lipoproteins are complicated particles that have actually a main hydrophobic main point of non-polar lipids, primarily cholesterol esters and also triglycerides. This hydrophobic main point is surrounding by a hydrophilic membrane consist of of phospholipids, free cholesterol, and apolipoproteins (Figure 1). Plasma lipoproteins are split into 7 classes based on size, lipid composition, and apolipoproteins (Table 1 and also Figure 2).


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LipoproteinDensity (g/ml)Size (nm)Major LipidsMajor Apoproteins
Chylomicrons<0.93075-1200TriglyceridesApo B-48, Apo C, Apo E, Apo A-I, A-II, A-IV
Chylomicron Remnants0.930- 1.00630-80Triglycerides CholesterolApo B-48, Apo E
VLDL0.930- 1.00630-80TriglyceridesApo B-100, Apo E, Apo C
IDL1.006- 1.01925-35Triglycerides CholesterolApo B-100, Apo E, Apo C
LDL1.019- 1.06318- 25CholesterolApo B-100
HDL1.063- 1.2105- 12Cholesterol PhospholipidsApo A-I, Apo A-II, Apo C, Apo E
Lp (a)1.055- 1.085~30CholesterolApo B-100, Apo (a)

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Chylomicrons

These are big triglyceride wealthy particles do by the intestine, i m sorry are associated in the deliver of diet triglycerides and also cholesterol to peripheral tissues and liver. This particles save on computer apolipoproteins A-I, A-II, A-IV, A-V, B-48, C-II, C-III, and E. Apo B-48 is the core structural protein and also each chylomicron particle has one Apo B-48 molecule. The size of chylomicrons varies depending on the amount of fat ingested. A high fat meal leads to the development of big chylomicron particles as result of the increased amount of triglyceride being transported conversely, in the fasting state the chylomicron corpuscle are small carrying diminished quantities the triglyceride.


Chylomicron Remnants

The remove of triglyceride from chylomicrons through peripheral tissues results in smaller sized particles referred to as chylomicron remnants. Compared to chylomicrons this particles are enriched in cholesterol and are pro-atherogenic.


Very Low-Density Lipoproteins (VLDL)

These corpuscle are developed by the liver and are triglyceride rich. Castle contain apolipoprotein B-100, C-I, C-II, C-III, and E. Apo B-100 is the main point structural protein and also each VLDL particle includes one Apo B-100 molecule. Comparable to chylomicrons the size of the VLDL particles have the right to vary depending on the amount of triglyceride brought in the particle. When triglyceride manufacturing in the liver is increased, the secreted VLDL particles space large. However, VLDL particles are smaller sized than chylomicrons.


Intermediate-Density Lipoproteins (IDL; VLDL Remnants)

The removal of triglycerides from VLDL by muscle and also adipose tissue results in the development of IDL corpuscle which space enriched in cholesterol. This particles save on computer apolipoprotein B-100 and also E. These IDL particles are pro-atherogenic.


Low-Density Lipoproteins (LDL)

These particles are acquired from VLDL and IDL particles and also they are even further enriched in cholesterol. LDL tote the bulk of the cholesterol that is in the circulation. The primary apolipoprotein is B-100 and also each LDL particle includes one Apo B-100 molecule. LDL consists of a spectrum of particles varying in size and also density. An abundance of tiny dense LDL particles are seen in association with hypertriglyceridemia, short HDL levels, obesity, form 2 diabetes (i.e. Patients through the metabolic syndrome) and also infectious and inflammatory states. These little dense LDL particles are considered to be an ext pro-atherogenic than large LDL particles for a number of reasons. Small dense LDL particles have actually a lessened affinity for the LDL receptor resulting in a prolonged retention time in the circulation. Additionally, they an ext easily go into the arterial wall and bind much more avidly to intra-arterial proteoglycans, which traps them in the arterial wall. Finally, tiny dense LDL particles are much more susceptible come oxidation, i m sorry could an outcome in an intensified uptake by macrophages.


High-Density Lipoproteins (HDL)

These particles play crucial role in reverse cholesterol move from peripheral organization to the liver, which is one potential mechanism through which HDL might be anti-atherogenic. In addition, HDL particles have actually anti-oxidant, anti-inflammatory, anti-thrombotic, and anti-apoptotic properties, i m sorry may likewise contribute to their ability to inhibit atherosclerosis. HDL particles space enriched in cholesterol and also phospholipids. Apolipoproteins A-I, A-II, A-IV, C-I, C-II, C-III, and E are linked with these particles. Apo A-I is the main point structural protein and each HDL particle might contain multiple Apo A-I molecules. HDL corpuscle are really heterogeneous and also can be classified based on density, size, charge, or apolipoprotein ingredient (Table 2).


Table 2.


Classification the HDL


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Method that classificationTypes the HDL
Density gradient ultracentrifugationHDL2, HDL3, really high-density HDL
Nuclear magnetic resonancelarge, medium, and also small
Gradient gel electrophoresisHDL 2a, 2b, 3a, 3b, 3c
2-dimensional gel electrophoresispre-beta 1 and 2, alpha 1, 2, 3, 4
Apolipoprotein compositionA-I particles, A-I: A-II particles, A-I: E particles

Lipoprotein (a) (Lp (a))

Lp (a) is an LDL fragment that has actually apolipoprotein (a) attached to Apo B-100 via a de defiders bond. This fragment is pro-atherogenic. The physiologic duty of this lipoprotein is unknown.


APOLIPOPROTEINS (3,4)

Apolipoproteins have four significant functions including 1) offer a structure role, 2) acting together ligands because that lipoprotein receptors, 3) guiding the development of lipoproteins, and 4) serving together activators or inhibitors that enzymes connected in the metabolism of lipoproteins (Table 3). Apolipoproteins hence play a an important role in lipoprotein metabolism.


Apolipoprotein A-I

Apo A-I is synthesized in the liver and also intestine and also is the significant structural protein that HDL audit for roughly 70% the HDL protein. It also plays a role in the communication of HDL through ATP-binding cassette protein A1 (ABCA1), ABCG1, and class B, form I scavenger receptor (SR-B1). Apo A-I is an activator the lecithin: cholesterol acyltransferase (LCAT), one enzyme the converts cost-free cholesterol right into cholesteryl ester. High levels of Apo A-I is connected with a lessened risk that atherosclerosis.


Apolipoprotein A-II

Apo A-II is synthesized in the liver and also is the 2nd most numerous protein top top HDL accountancy for roughly 20% that HDL protein. The role of Apo A-II in lipid management is unclear. Apo A-II is a strong predictor of danger for CVD.


Apolipoprotein A-IV (5)

Apo A-IV is synthesized in the intestine throughout fat absorption. Apo A-IV is associated with chylomicrons and also high-density lipoproteins, but is additionally found in the lipoprotein-free fraction. Its specific role in lipoprotein metabolism stays to it is in determined however studies have argued a role for Apo A-IV in regulation food intake.


Apolipoprotein A-V (6)

Apo A-V is synthesized in the liver and associates with triglyceride wealthy lipoproteins. The is an activator the LPL mediated lipolysis and thereby plays an important role in the metabolism of triglyceride well-off lipoproteins.


Apolipoprotein B-48

Apo B-48 is synthesized in the intestine and also is the significant structural protein of chylomicrons and chylomicron remnants. Over there is a solitary molecule that apo B-48 per chylomicron particle. There is a single apolipoprotein B gene the is to express in both the liver and intestine. The intestine expresses a protein the is about ½ the dimension of the liver due to mRNA editing. The apobec-1 editing complex is to express in the intestine and also edits a specific cytidine come an uracil in the apo B mRNA in the intestine creating a protect against codon that results in the cessation the protein translation and a much shorter Apo B (Apo B-48). Notably Apo B-48 is not recognized by the LDL receptor.


Apolipoprotein B-100

Apo B-100 is synthesized in the liver and also is the major structural ingredient of VLDL, IDL, and also LDL. There is a single molecule the Apo B-100 per VLDL, IDL, and also LDL particle. Apo B-100 is a ligand for the LDL receptor and also therefore plays vital role in the clearance of lipoprotein particles. High level of Apo B-100 is connected with an raised risk that atherosclerosis.


Apolipoprotein C (7,8)

The C apolipoproteins space synthesized generally in the liver and also freely exchange in between lipoprotein particles and also therefore are discovered in association through chylomicrons, VLDL, and also HDL.

Apo C-II is a co-factor because that lipoprotein lipase (LPL) and also thus stimulates triglyceride hydrolysis (7). Lose of role mutations in Apo C-II result in marked hypertriglyceridemia as result of a failure to metabolize triglyceride well-off lipoproteins.

Apo C-III is an inhibitor the LPL (9). Additionally, Apo C-III inhibits the interaction of triglyceride affluent lipoproteins v their receptors. Current studies have shown that ns of duty mutations in Apo C-III lead to decreases in serum triglyceride levels and a lessened risk of cardiovascular disease. Interestingly, inhibition the Apo C-III expression outcomes in a to decrease in serum triglyceride levels even in patient deficient in lipoprotein lipase indicating that the capability of Apo C-III to modulate serum triglyceride level is not dependent solely on regulating lipoprotein lipase activity.


Apolipoprotein E (10)

Apolipoprotein E is synthesized in plenty of tissues yet the liver and also intestine room the primary source of turn Apo E. Apo E exchanges between lipoprotein particles and also is connected with chylomicrons, chylomicron remnants, VLDL, IDL, and also a subgroup that HDL particles. There space three typical genetic variants that Apo E (Apo E2, E3, and E4). ApoE2 differs from the most typical isoform, Apo E3, through a single amino mountain substitution where cysteine substitutes for arginine at residue 158. Apo E4 different from Apo E3 in ~ residue 112, where arginine substitutes because that cysteine. Apo E3 and also E4 are ligands because that the LDL receptor when Apo E2 is poorly well-known by the LDL receptor. Patients who space homozygous for Apo E2 can develop familial dysbetalipoproteinemia. Apo E4 is connected with an boosted risk the Alzheimer’s condition and an enhanced risk that atherosclerosis.


Apolipoprotein (a) (11)

Apo (a) is synthesized in the liver. This protein is a homolog of plasminogen and its molecular load varies indigenous 300,000 come 800,000. That is attached to Apo B-100 via a de defiders bond. High levels of Apo (a) are connected with an enhanced risk of atherosclerosis. Apo (a) is an inhibitor that fibrinolysis and can additionally enhance the uptake of lipoproteins by macrophages, both the which might increase the danger of atherosclerosis. The physiologic role of Apo (a) is unknown. Interestingly this apolipoprotein is found in primates but not in various other species.


Table 3.


Apolipoproteins


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ApolipoproteinMWPrimary SourceLipoprotein AssociationFunction
Apo A-I28,000Liver, IntestineHDL, chylomicronsStructural protein because that HDL, Activates LCAT
Apo A-II17,000LiverHDL, chylomicronsStructural protein for HDL, Activates hepatic lipase
Apo A-IV45,000IntestineHDL, chylomicronsUnknown
Apo A-V39,000LiverVLDL, chylomicrons, HDLPromotes LPL mediated TG lipolysis
Apo B-48241,000IntestineChylomicronsStructural protein because that chylomicrons
Apo B-100512,000LiverVLDL, IDL, LDL, Lp (a)Structural protein, Ligand because that LDL receptor
Apo C-I6,600LiverChylomicrons, VLDL, HDLActivates LCAT
Apo C-II8,800LiverChylomicrons, VLDL, HDLCo-factor for LPL
Apo C-III8,800LiverChylomicrons, VLDL, HDLInhibits LPL and uptake the lipoproteins
Apo E34,000LiverChylomicron remnants, IDL, HDLLigand for LDL receptor
Apo (a)250,000- 800,00LiverLp (a)Inhibits plasminogen activation

LIPOPROTEIN RECEPTORS and also LIPID TRANSPORTERS

There are several receptors and transporters that play a crucial role in lipoprotein metabolism.

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LDL Receptor (12)

The LDL receptor is existing in the liver and most various other tissues. It recognizes Apo B-100 and Apo E and also hence mediates the uptake of LDL, chylomicron remnants, and also IDL, which occurs via endocytosis (Figure 3). After internalization, the lipoprotein particle is degraded in lysosomes and also the cholesterol is released. The delivery of cholesterol to the cell decreases the task of HMGCoA reductase, a vital enzyme in the biosynthesis that cholesterol, and also the expression of LDL receptors. LDL receptors in the liver play a significant role in determining plasma LDL levels (a low number of receptors is linked with high plasma LDL levels while a high variety of hepatic LDL receptors is linked with short plasma LDL levels). The variety of LDL receptors is regulated by the cholesterol content of the cell (13). As soon as cellular cholesterol level are reduced the transcription element SREBP is transported native the absorbent reticulum to the golgi whereby proteases cleave and activate SREBP, which climate migrates to the nucleus and also stimulates the expression of LDL receptors (Figure 4). Conversely, when cellular cholesterol levels are high SREBP stays in the endoplasmic reticulum in an inactive kind and the expression of LDL receptor is low. As questioned later PCSK9 regulates the rate of deterioration of LDL receptors.