Low density lipoprotein physiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Rim Halaby, M.D. [3]
Overview
Low-density lipoprotein (LDL) belongs to the lipoprotein particle family. Its size is approximately 22 nm but since LDL particles contain a changing number of fatty acids they actually have a mass and size distribution. Each native LDL particle contains a single apolipoprotein B-100 molecule (Apo B-100, a protein with 4536 amino acid residues) that surrounds the fatty acids keeping them soluble in the aqueous environment.[1] The average composition of LDL is approximately 20% protein, 20% phospholipids, 40% cholesteryl esters, 10% unesterified cholesterol, and 5% triglycerides.[2]
Physiology
Structure
Low-density lipoprotein (LDL) belongs to the lipoprotein particle family. It has a discoid shape with an average diameter of approximately 20 nm.[3] However, LDL is considered a heterogeneous molecule due to fluctuating density, size, and flotation rate.
The LDL particle can be structurally divided into 3 layers according to molecular orientational behavior:
- Outer surface layer with tangential orientation: It forms a shell composed of phospholipid monolayer to cover the core. The phospholipid monolayer is organized in a way that hydrophilic residues with polar head groups interact with the outer aqueous solvent; while the inner hydrophobic residues face the lipid interior.
- Interfacial layer with radial orientation
- A polar lipid core with random orientation: It contains cholesteryl esters and triglycerides.[2][4]
Each native LDL particle contains a single apolipoprotein B-100 (Apo-100) molecule. Apo B-100 is a protein with 4536 amino acid residues. It encircles the fatty acids keeping them soluble in the aqueous environment.[3]
ApoB-100 covers the surface layer of LDL in a heterogeneous fashion, covering one hemisphere of LDL, while keeping other surfaces uncovered with exposed lipids.[2]
Shown below is a table depicting the biochemistry characteristics of LDL.
| Lipoprotein | Density | Size | % Protein | % Phospholipids | % Free cholesterol | % Cholesterol ester | % Triglyceride | Apolipoprotein[5] |
| LDL | 1.019–1.063 | 21.6 | 22% | 22% | 8 | 42 | 6 | B 100 |
For more information about the biochemistry of all lipoproteins, click here.
LDL Subtype Patterns
LDL particles actually vary in size and density, and studies have shown that a pattern that has more small dense LDL particles ("Pattern B") equates to a higher risk factor for coronary heart disease (CHD) than does a pattern with more of the larger and less dense LDL particles ("Pattern A"). This is because the smaller particles are more easily able to penetrate the endothelium. "Pattern I", meaning "intermediate", indicates that most LDL particles are very close in size to the normal gaps in the endothelium (26 nm).
The correspondence between Pattern B and coronary heart disease has been suggested by some in the medical community to be stronger than the correspondence between the LDL number measured in the standard lipid profile test. Tests to measure these LDL subtype patterns have been more expensive and not widely available, so the common lipid profile test has been used more commonly.
Role
LDL’s main role is mediating metabolism and transport of cholesterol. LDL transports cholesterol and triglycerides from the liver to peripheral tissues. LDL transports approximately 70% of circulating cholesterol.[6] It is formed in the circulation from VLDL by the action of lipoprotein lipase (LPL). LDL receptors, located at specific coat pits on plasma membrane of specific target cells mediate the selective uptake of molecules into cells by endocytosis. The coat pits contain clathrin protein on the cytoplasmic end of the plasma membrane to promote endocytosis. LDL receptors are glycoproteins that have negatively charged domains capable of interacting with positively charged arginine and lysine residues of apo B-100. Inside the cell, LDL migrates within a vesicle and is targeted to be degraded within the lysosome that contains hydrolases capable of digesting components of LDL. LDL degradation produces cholesterol, amino acids, glycerol and fatty acids.[7]
Not only does LDL transport cholesterol, but also this activity is key to control cholesterol homeostasis.[8] Cholesterol derived from LDL following degradation within the lysosome contributes to the feedback inhibition of cholesterol synthesis by directly suppressing the rate-limiting step catalyzed by HMG-CoA reductase enzyme.[7] LDL also has the ability to suppress the transcription of LDL receptor genes, preventing accumulation of cholesterol and keeping cholesterol amounts within membranes constant despite varying cholesterol supply and demand.[9][10]
References
- ↑ Segrest, J. P.; et al. (September 2001). "Structure of apolipoprotein B-100 in low density lipoproteins". Journal of Lipid Research. 42: 1346–1367.
- ↑ 2.0 2.1 2.2 Hevonoja T, Pentikäinen MO, Hyvönen MT, Kovanen PT, Ala-Korpela M (2000). "Structure of low density lipoprotein (LDL) particles: basis for understanding molecular changes in modified LDL". Biochim Biophys Acta. 1488 (3): 189–210. PMID 11082530.
- ↑ 3.0 3.1 Segrest JP, Jones MK, De Loof H, Dashti N (2001). "Structure of apolipoprotein B-100 in low density lipoproteins". J Lipid Res. 42 (9): 1346–67. PMID 11518754.
- ↑ Prassl R (2011). "Human low density lipoprotein: the mystery of core lipid packing". J Lipid Res. 52 (2): 187–8. doi:10.1194/jlr.E013417. PMC 3023539. PMID 21131533.
- ↑ Ballantyne, Christie M. (2009). Clinical lipidology : a companion to Braunwald's heart diseas. Philadelphia, PA: Saunders/Elsevier. ISBN 1-4160-5469-3.
- ↑ Rader DJ, Cohen J, Hobbs HH (2003). "Monogenic hypercholesterolemia: new insights in pathogenesis and treatment". J Clin Invest. 111 (12): 1795–803. doi:10.1172/JCI18925. PMC 161432. PMID 12813012.
- ↑ 7.0 7.1 Goldstein JL, Brown MS (1973). "Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol". Proc Natl Acad Sci U S A. 70 (10): 2804–8. PMC 427113. PMID 4355366.
- ↑ Murtola T, Vuorela TA, Hyvonen MT et al. Low density lipoprotein: Structure, dynamics, and interactions of apoB-100 with lipids. Soft Matter. 2011;7:8136-8141
- ↑ Brown MS, Goldstein JL (1975). "Regulation of the activity of the low density lipoprotein receptor in human fibroblasts". Cell. 6 (3): 307–16. PMID 212203.
- ↑ Brown MS, Goldstein JL (1999). "A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood". Proc Natl Acad Sci U S A. 96 (20): 11041–8. PMC 34238. PMID 10500120.