Which lipoprotein has the highest protein content?

I know that HDLs have the highest protein/lipid ratio but know that the HDLs are very small molecules too and I couldn't find the exact answer for this question. I mean, by amounts which of these lipoproteins have the most protein?

LDL has the higher protein content than HDL. LDL consists of Apo B48 and Apo B100. These are proteins with higher molecular weights between 250 kDa to 550 kDa as compared to other apoproteins. And these apoproteins are not present in HDL.

And if lipoprotein (a) is included in comparison then it has highest protein content.


Lipoproteins: Definition, Structure, Functions, Classification & Composition

Lipoproteins are simple proteins and fats bonded together to facilitate transport of the non-soluble fats through blood. They are classified into five types according to their composition and density.

The lipoprotein structure consists of a core of lipids surrounded by a covering of proteins.

The functions of the lipoproteins can only be described as extremely crucial.

Too much of lipoproteins in the blood is to be avoided because then, they can cause complications that can be described as extremely dangerous.

Metabolic disorders: Sex and gender evidence in dyslipidemia, diabetes, and obesity

Connie B. Newman , . Savitha Subramanian , in How Sex and Gender Impact Clinical Practice , 2021

Lipoprotein (a)

Lipoprotein (a) [Lp (a)] is structurally an LDL-like particle in which apolipoprotein B is bound to apolipoprotein (a). Elevated levels of Lp (a), defined as 50 mg/dL or higher, are associated with enhanced risk for ASCVD. The effect of Lp (a) reduction on cardiovascular outcomes is not known. Limited data from small studies show that small elevations of Lp (a) are seen in menopausal women compared to pre- and perimenopausal women, with large elevations during pregnancy. In clinical practice Lp (a) is not measured routinely, but may be useful to further define cardiovascular risk if this would impact the treatment plan.

Basic Science

Plasma lipoprotein particles contain variable proportions of four major elements: cholesterol, triglycerides, phospholipids and specific proteins called apoproteins (Table 31.2). An alphabetical nomenclature (A, B, C, D, E.) is generally used to designate the apoproteins. The varying composition of these elements determines the density, size, and electrophoretic mobility of each particle. These factors in turn have been used for the clinical and biochemical classification of lipoprotein disorders. Schematically, lipoproteins have been described as globular or spherical units in which a nonpolar core lipid (consisting mainly of cholesterol esters and triglycerides) is surrounded by a layer containing phospholipids, apoproteins, and small amounts of unesterified cholesterol. Apoproteins, in addition to serving as carrier proteins, have other important functions such as being co-factors for enzymes involved in lipoprotein metabolism, acting as specific ligands for binding of the particles to cellular receptor sites, and intervening in the exchange of lipid constituents between lipoprotein particles.

Table 31.2

Characteristics and Percentage Content of the Various Lipoprotein Particles Relative to Total Weight.

The fact that all the cholesterol required by the body can be produced by biosynthesis points to the essential nature of this substance. As an estimated loss of 1.0 to 1.5 g of cholesterol occurs daily through desquamation and fecal loss, this amount must be replaced. Usually this replacement is obtained from dietary sources, but another portion is synthesized in multiple cells of the body. Triglycerides are also obtained from the diet as well as synthesized by the liver.

The origin of circulating lipoproteins is less understood than is their uptake, transport, and degradation. The lipid transport system in plasma has been described as involving two pathways: an exogenous route for the transport of cholesterol and triglycerides absorbed from dietary fat in the intestine, and an endogenous system through which cholesterol and triglycerides reach the plasma from the liver and other nonintestinal tissues (Figure 31.1).

Figure 31.1

Exogenous and endogenous fat-transport pathways are diagrammed. Dietary cholesterol is absorbed through the wall of the intestine and is packaged, along with triglyceride (glycerol ester-linked to three fatty acid chains), in chylomicrons. In the capillaries (more. )

Exogenous Pathway

The exogenous pathway starts with the intestinal absorption of triglycerides and cholesterol from dietary sources. Its end result is the transfer of triglycerides to adipose and muscle tissue and of cholesterol to the liver. After absorption, triglycerides and cholesterol are re-esterified in the intestinal mucosal cells and then coupled with various apoproteins, phospholipids, and unesterified cholesterol into lipoprotein particles called chylomicrons. The chylomicrons in turn are secreted into intestinal lymph, enter the bloodstream through the thoracic: duct, and bind to the wall of capillaries in adipose and skeletal muscle tissue. At these binding sites the chylomicrons interact with the enzyme lipoprotein lipase, which causes hydrolysis of the triglyceride core and liberation of free fatty acids. These fatty acids then pass through the capillary endothelial cells and reach the adipocytes and skeletal muscle cells for storage or oxidation, respectively.

After removal of the triglyceride core, remnant chylomicron particles are formed. These are high in cholesterol esters and characterized by the presence of apoproteins B, CIII, and E. These remnants are cleared from the circulation by binding of their E apoprotein to a receptor present only on the surface of hepatic cells. Subsequently, the bound remnants are taken to the inside of hepatic cells by endocytosis and then catabolized by lysosomes. This process liberates cholesterol, which is then either converted into bile acids, excreted in bile, or incorporated into lipoproteins originated in the liver (VLDL).

Under normal physiologic conditions, chylomicrons are present in plasma for 1 to 5 hours after a meal and may give it a milky appearance. They are usually cleared from the circulation after a 12-hour fast.

Endogenous Pathway

The liver constantly synthesizes triglycerides by utilizing as substrates free fatty acids and carbohydrates these endogenous triglycerides are secreted into the circulation in the core of very-low-density lipoprotein particles (VLDL). The synthesis and secretion of VLDL at cellular level occur in a process similar to that of chylomicrons, except that a different B apoprotein (B-100 instead of B-48) together with apoproteins C and E intervene in their secretion. Subsequent interaction of the VLDL particles with lipoprotein lipase in tissue capillaries leads to hydrolysis of the core triglycerides and production of smaller remnant VLDL particles rich in cholesterol esters (intermediate-density lipoproteins, IDL) and liberation of free fatty acids. Around half of these remnant particles are removed from the circulation in 2 to 6 hours as they bind tightly to hepatic cells. The rest undergo modifications with detachment of the remaining triglycerides and its substitution by cholesterol esters and removal of all the apoproteins except apoprotein B. This process results in transformation of the remnant VLDL particles into low-density lipoprotein particles (LDL) rich in cholesterol. In fact, these last particles contain around three-fourths of the total cholesterol in human plasma, although they constitute only some 7% of the total cholesterol pool. Their predominant function is to supply cholesterol to cells with LDL receptors, like those in the adrenal glands, skeletal muscle, lymphocytes, gonads, and kidneys. The quantity of cholesterol freed from LDL is said to control cholesterol metabolism in the cell through the following mechanisms: (1) increased LDL cholesterol in the cell decreases synthesis of the enzyme 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase, which modulates the intracellular synthesis of cholesterol (2) increased LDL cholesterol may enhance the storage of cholesterol within the cell by activation of another enzyme and (3) increased cholesterol within the cell diminishes the synthesis of LDL receptors through a negative feedback process.

Besides the above described route for LDL degradation in extrahepatic sites, a so-called scavenger cell pathway has been described. This consists of cells in the reticuloendothelial system which, by phagocytosis, dispose of the excess concentrations of this lipoprotein in plasma.

Transport of High-Density Lipoprotein Cholesterol

High-density lipoproteins are a heterogeneous group of macromolecules with different physical properties and chemical components two subclasses of HDL have been identified (HDL2 and HDL3) within which several subspecies have also been demonstrated. The predomination function of HDL seems to be the reverse transport of cholesterol from different tissues into the liver, where it is eventually removed. Subclass HDL2 has been reported to have a better correlation with coronary artery disease protection than total HDL cholesterol.

The serum concentration of HDL and its components derives from various complex intravascular and cellular metabolic events. These events include secretion of precursor HDL particles from the liver and small intestine, interaction of these particles with lipids and proteins released during the catabolism of triglyceride-rich lipoproteins, and production of cholesteryl esters (the core substance in HDL) from the action of lecithin𠄼holesterol acyltransferase (LCAT), an enzyme that originates in the liver. This enzyme acts on unesterified cholesterol released into plasma from cellular turnover. The cholesterol esters formed in this reaction are in turn transferred to VLDL and subsequently appear in LDL. The end result is a system that allows the transfer of cholesterol through LDL to peripheral cells and its return to the liver through HDL, and that prevents excessive accumulation of cholesterol in the body.

4 Major Classes of Conjugated Proteins

Conjugated proteins are proteins that contain non-pro­tein constituents or prosthetic groups. The pros­thetic groups are permanently associated with the molecule, usually through covalent and/or non-covalent linkages with the side chains of certain amino acids.

Conjugated proteins can be divided into three major classes:

1. Chromo proteins:

The chromo proteins are a heterogeneous group of conjugated proteins related to each other only in that they all possess color. The hemoglobin’s, myoglobin’s, and other heme-containing proteins such as the cyto­chromes and hemerythrins belong to this group. The prosthetic groups of the chromo proteins, such as the heme groups of hemoglobin and the cytochromes, are bound to the polypeptide portion of the molecule through a combination of covalent and non covalent bonds.

2. Glycoproteins:

Glycoproteins are proteins that contain various amounts of carbohydrate. A number of very important proteins fall in this class, including many of the blood plasma proteins and a large number of en­zymes and hormones.

The surfaces (i.e., plasma mem­branes) of most cells also contain quantities of glyco­proteins, and these molecules serve there as antigenic determinants and as receptor sites. Virtually all of the carbohydrate that is present in red blood cells occurs as membrane glycoproteins. Although more than 100 different sugars (or mono-saccharides) are known, only about nine occur as regular constituents of glyco­proteins (Table 4-5).

The amount of carbohydrate present in glycopro­teins varies from less than 1% of the molecule’s total molecular weight to more than 85% (Table 4-6). For example, in egg white ovalbumin (molecular weight 45,000), there is only one monosaccharide per protein molecule, whereas in mucin (a secretion of the sali­vary glands having a molecular weight of about 1 mil­lion), about 800 mono-saccharides are present.

The carbohydrate moieties of glycoproteins are usually bound to the protein through covalent bonds with either asparagine, threonine, hydroxylysine, serine, or hydroxyproline (see Fig. 4-26). The carbohydrate bonded at each site of the protein may consist of a sin­gle monosaccharide unit (as in Fig. 4-26) or a linear or branched chain of several mono saccharides (called an oligosaccharide), as depicted in Figure 4-27.

Lipid-containing proteins are called lipoproteins. This class includes some of the blood plasma proteins’ and also a large number of membrane proteins. The lipid content of lipoproteins is often very high, ac­counting for as much as 40 to 90% of the total molecu­lar weight of the complex.

In lipoproteins, the amount of lipid present markedly affects the density of the molecule, and this property is often used as the basis for lipoprotein classification. Whereas un-complexed proteins have a density in water of about 1.35, lipopro­teins vary in density down to 0.9 (i.e., a lipoprotein may be less dense than water).

The interactions between the lipid and protein por­tions of a lipoprotein usually involve similar functional groups. For example, the hydrophobic portions of fatty acids, glycerides, sterols, and the like (see Chap­ter 6) form van der Waals interactions with the hydro­phobic side chains of the nonpolar amino acids. Cova­lent bonds are believed to occur between the phosphate moieties of certain phospholipids and the hydroxyl-containing side chains of amino acids like serine.

4. Nucleoproteins:

In eukaryotic cells, specific proteins called nucleopro­teins are found intimately associated with nuclear DNA. Also, in prokaryotes as well as eukaryotes, ribo- nucleoprotein complexes (i.e., protein complexed with RNA) occur. These proteins are not usually classified with the conjugated proteins, because the nucleic acids involved cannot be regarded as prosthetic groups.

Two types of proteins have been identified in nucleoproteins, the histones and non-histones. His- tones have a rather restricted amino acid composition (containing about 25% arginine and lysine) and are quite similar in all plant and animal cells.

Their highly basic nature accounts for the close associations they form with the nucleic acids and lends credence to the notion that they are involved in the tight packing of DNA molecules during the condensation of chromatin (i.e., chromosomes) that precedes mitosis.

The non-histones are considerably more heterogeneous in amino acid composition and have acidic properties. There is much evidence to suggest that by selectively combin­ing with certain stretches of nuclear DNA, the non-his­tones are involved in the regulation of gene expres­sion.

Lipoprotein Receptor Biology Laboratory

An increased level of low-density lipoprotein (LDL) cholesterol, the so-called “bad cholesterol”, in the circulation is a primary risk factor for the development of cardiovascular heart disease. Our lab’s primary research interests are cellular and molecular mechanisms that regulate cholesterol homeostasis in the body and ultimately blood LDL-cholesterol levels.

Clearance of LDL from the circulation requires the LDL receptor, a protein on the cell surface that binds to LDL particles with high affinity and mediates their uptake into cells, mainly in the liver. Since the liver is the primary means for LDL clearance, increased liver LDLR protein expression is a highly desirable goal for therapies aimed at lowering cardiovascular disease risk. Indeed, the efficacy of the widely prescribed statin drugs is ascribed to their ability to increase liver LDL receptors at the gene transcriptional level. However, many patients undergoing statin therapy do not reach therapeutic goals for cholesterol lowering or suffer unacceptable secondary effects, highlighting the need for improved and/or alternate means for increasing liver LDL receptor function.

The removal of LDL from the circulation occurs mainly in liver via the LDL receptor (LDLR), a cell surface glycoprotein that binds to LDL particles with high affinity and mediates their endocytosis. Internalized LDL particles are degraded in lysosomes and liberated cholesterol is then used for the synthesis of membranes, steroid hormones, lipoproteins and bile acids.

This process is subject to a negative feedback mechanism that maintains tight control of cellular cholesterol levels. Cholesterol influx results in transcriptional suppression of genes encoding cholesterol biosynthetic enzymes and LDLR, thus preventing potentially toxic cholesterol over-accumulation. Conversely, when cholesterol levels are depleted the expression of these same genes is stimulated.

Cholesterol-lowering statin drugs modulate this regulatory circuit by directly inhibiting the rate-controlling enzyme in the cholesterol biosynthetic pathway, resulting in increased LDLR expression, increased LDL uptake by the liver, and lowered plasma LDL levels. Thus, negative feedback control in the liver ultimately dictates plasma LDL-cholesterol levels and associated cardiovascular heart disease risk. We are studying mechanisms that affect cholesterol uptake and trafficking in cells with an emphasis on how these processes affect negative feedback control of cholesterol metabolism.

Studies of PCSK9-Mediated LDL Receptor Degradation

An aspect of negative feedback control of cholesterol metabolism is the co-regulation of genes encoding the LDLR and PCSK9 (proprotein convertase subtilisin/kexin type-9), a secreted protease that promotes LDLR degradation in liver. Importantly, loss-of-function mutations in PCSK9 have been identified in the human population and are associated with lowered plasma LDL levels and greatly decreased incidence of cardiovascular disease. This exciting finding validates PCSK9 as a therapeutic target for LDL lowering.

In previous work we have shown that secreted PCSK9 is active in the circulation, and that PCSK9 binds directly to LDLRs on the surface of hepatic cells leading to LDLR degradation in the endosomal/lysosomal compartment. Surprisingly, PCSK9&rsquos protease activity is not required for LDLR degradation - instead it acts as a molecular chaperone to interfere with LDLR recycling. We have recently identified the pertinent regions on both LDLR and PCSK9 involved in direct binding between these proteins.

Our future goals are to identify and characterize regulatory mechanisms that affect both the initial PCSK9:LDLR interaction as well as the downstream cellular degradative pathway utilizing cell-based approaches as well as protein-protein interaction studies with purified protein components.

Mechanisms of intracellular cholesterol trafficking

The protein machinery that ultimately regulates negative feedback control of cholesterol metabolism is located in the endoplasmic reticulum (ER) and is regulated by cholesterol content in this organelle. Cholesterol trafficking pathways that deliver LDL-derived free cholesterol from lysosomes to the ER play a critical role in this process, yet these pathways remain poorly understood.

Phosphatidylcholine (PC), the most abundant phospholipid in cell membranes, can positively influence the incorporation and bilateral movement of cholesterol in membrane bilayers. Within cells, PC and cholesterol content in membranes are maintained within narrow ratios. Using Chinese hamster ovary (CHO) cell lines harbouring altered cholesterol and/or PC metabolic genes we are studying how altered cholesterol/PC ratios in the cell influence the trafficking of LDL-derived free cholesterol from the lysosomal compartment to other membrane sites, including the plasma membrane and the ER.

Protein Purification and Analysis Core Equipment

Left to right: AKTA Purifier FPLC (GE Healthcare), Profinia Protein Purification (Bio-Rad), Licor Odyssey Infrared Imager (Licor Biosciences)

Available to Heart Institute investigators. Contact Tom Lagace for information.

See current publications list at PubMed.

1. Thomas A. Lagace (2009) PCSK9 and heart disease: quieting an outdated metabolic moderator. Clin. Lipidology 4(4), pp. 407-410.

2. Markey C. McNutt, Hyock Joo Kwon, Chiyuan Chen, Justin R. Chen, Jay D. Horton and Thomas A. Lagace (2009) Antagonism of Secreted PCSK9 Increases Low-Density Lipoprotein Receptor Expression in HepG2 Cells. J. Biol. Chem. 284, pp. 10561-10570.

3. Hyock Joo Kwon, Thomas A. Lagace, Markey C. McNutt, Jay D. Horton, and Johann Deisenhofer (2008) Molecular basis for LDL receptor recognition by PCSK9. Proc. Nat. Acad. Sci. 105, pp.1820-1825.

4. Markey C. McNutt, Thomas A. Lagace, and Jay D. Horton (2007) Catalytic Activity is Not Required for Secreted PCSK9 to Reduce LDL Receptors in HepG2 Cells. J. Biol. Chem. 282, pp. 20799-20803.

5. Thomas A. Lagace, David E. Curtis, Rita Garuti, Markey C. McNutt, Sahng Wook Park, Heidi B. Prather, Norma N. Anderson, Y. K. Ho, Robert E. Hammer, and Jay D. Horton (2006) Secreted PCSK9 Decreases LDL Receptors in Hepatocytes and in Livers of Parabiotic Mice. J. Clin. Invest. 116(11) pp. 2995-3005.

6. Thomas A. Lagace and Neale D. Ridgway (2005) The Rate-limiting Enzyme in Phosphatidylcholine Synthesis Regulates Proliferation of the Nucleoplasmic Reticulum. Mol. Biol. Cell 16(3) pp.1120-1130.

Lab Director

Tom Lagace, PhD

Research Assistant

Tanja Francetic, MSc

Graduate Student

Samantha Sarkar, BSc

Cholesterol Ratio: Range for men and women

Women, in general, have higher HDL levels as compared to men. This implies that their cholesterol ratio is naturally lower. The recommended cholesterol ratio for women is 3.3. Meanwhile, a ratio greater 4.4 could imply a risk of cardiovascular diseases. This risk doubles when this ratio goes up to 7.

On the other hand, the recommended cholesterol ratio for men is 3.4. Meanwhile, a ratio greater 5 could imply a risk of cardiovascular diseases. This risk doubles when this ratio goes up to 9.6.

Peer review information Nature Structural & Molecular Biology thanks Alessandra Polissi and Markus Seeger for their contribution to the peer review of this work. Florian Ullrich and Anke Sparmann were the primary editors on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Over the past 60 years, egg yolk (EY) has been routinely used in both liquid semen extenders and those used to cryopreserve sperm. However, the mechanism by which EY protects sperm during liquid storage or from freezing damage is unknown. Bovine seminal plasma contains a family of proteins designated BSP-A1/-A2, BSP-A3, and BSP-30-kDa (collectively called BSP proteins). These proteins are secretory products of seminal vesicles that are acquired by sperm at ejaculation, modifying the sperm membrane by inducing cholesterol efflux. Because cholesterol efflux is time and concentration dependent, continuous exposure to seminal plasma (SP) that contains BSP proteins may be detrimental to the sperm membrane, which may adversely affect the ability of sperm to be preserved. In this article, we show that the BSP proteins bind to the low-density fraction (LDF), a lipoprotein component of the EY extender. The binding is rapid, specific, saturable, and stable even after freeze-thawing of semen. Furthermore, LDF has a very high capacity for BSP protein binding. The binding of BSP proteins to LDF may prevent their detrimental effect on sperm membrane, and this may be crucial for sperm storage. Thus, we propose that the sequestration of BSP proteins of SP by LDF may represent the major mechanism of sperm protection by EY.

Very low-density lipoproteins (VLDL)

VLDL is a lipoprotein class synthesized by the liver that is analogous to the chylomicrons secreted by the intestine. Its purpose is also to deliver triglycerides, cholesteryl esters, and cholesterol to peripheral tissues. VLDL is largely depleted of its triglyceride content in these tissues and gives rise to an intermediate-density lipoprotein (IDL) remnant, which is returned to the liver in the bloodstream. As might be expected (see table), the same proteins are present in both VLDL and IDL.