Low-density lipoprotein

Low-density lipoprotein (LDL) is a type of lipoprotein that transports cholesterol and triglycerides from the liver to peripheral tissues. LDL is one of the five major groups of lipoproteins; these groups include chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein, and high-density lipoprotein (HDL). Like all lipoproteins, LDL enables fats and cholesterol to move within the water based solution of the blood stream. LDL also regulates cholesterol synthesis at these sites. It commonly appears in the medical setting as part of a cholesterol blood test, and since high levels of LDL cholesterol can signal medical problems like cardiovascular disease, it is sometimes called "bad cholesterol" (as opposed to HDL, the "good cholesterol"). [ [http://www.americanheart.org/presenter.jhtml?identifier=180 LDL and HDL Cholesterol: What's Bad and What's Good?] ]

Biochemistry

tructure

Each native LDL particle contains a single apolipoprotein B-100 molecule (Apo B-100, a protein with 4536 amino acid residues) that circulates the fatty acids, keeping them soluble in the aqueous environment. In addition, LDL has a highly-hydrophobic core consisting of polyunsaturated fatty acid known as "linoleate" and about 1500 esterified cholesterol molecules. This core is surrounded by a shell of phospholipids and unesterified cholesterol as well as a single copy of B-100 large protein (514 kD). LDL particles are approximately 22 nm in diameter and have a mass of about 3 million daltons, but since LDL particles contain a changing number of fatty acids, they actually have a mass and size distribution. [cite journal|journal=Journal of Lipid Research|author=Segrest, J. P. "et al"|date=September 2001ture of apolipoprotein B-100 in low density lipoproteins|volume=42|pages=1346–1367]

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—called "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 CHD 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.

There has also been noted a correspondence between higher triglyceride levels and higher levels of smaller, denser LDL particles and alternately lower triglyceride levels and higher levels of the larger, less dense LDL.cite journal |author=Superko HR, Nejedly M, Garrett B |title=Small LDL and its clinical importance as a new CAD risk factor: a female case study |journal=Prog Cardiovasc Nurs |volume=17 |issue=4 |pages=167–73 |year=2002 |pmid=12417832|url=http://www.lejacq.com/articleDetail.cfm?pid=ProgCardiovascNurs_17;4:167
doi= |accessdate=2007-12-04]

With continued research, decreasing cost, greater availability and wider acceptance of other "lipoprotein subclass analysis" assay methods, including NMR spectroscopy, research studies have continued to show a stronger correlation between human clinically obvious cardiovascular event and quantitatively-measured particle concentrations.

Transport into the cell

When a cell requires cholesterol, it synthesizes the necessary LDL receptors, and inserts them into the plasma membrane. The LDL receptors diffuse freely until they associate with clathrin-coated pits. LDL particles in the blood stream bind to these extracellular LDL receptors. The clathrin-coated pits then form vesicles that are endocytosed into the cell.

After the clathrin coat is shed, the vesicles deliver the LDL and their receptors to early endosomes, onto late endosomes to lysosomes. Here the cholesterol esters in the LDL are hydrolysed. The LDL receptors are recycled back to the plasma membrane.

Medical relevance

Because LDLs transport cholesterol to the arteries and can be retained there by arterial proteoglycans starting the formation of plaques, increased levels are associated with atherosclerosis, and thus heart attack, stroke, and peripheral vascular disease. For this reason, cholesterol inside LDL lipoproteins is often called "bad" cholesterol. This is a misnomer. The cholesterol transported on LDL is the same as cholesterol transported on other lipoprotein particles. The cholesterol itself is not "bad"; rather, it is "how" and "where" the cholesterol is being transported, and in what amounts over time, that causes adverse effects. Fact|date=June 2008

Increasing evidence has revealed that the concentration and size of the LDL particles more powerfully relates to the degree of atherosclerosis progression than the concentration of cholesterol contained within all the LDL particles. [ [http://www.npr.org/templates/story/story.php?storyId=15886898 Not All Calories Are Created Equal, Author Says] . Talk of the Nation discussion of the book "Good Calories, Bad Calories", by Gary Taubes. National Public Radio, 2 Nov 2007.] The healthiest pattern, though relatively rare, is to have small numbers of large LDL particles and no small particles. Having small LDL particles, though common, is an unhealthy pattern; high concentrations of small LDL particles (even though potentially carrying the same total cholesterol content as a low concentration of large particles) correlates with much faster growth of atheroma, progression of atherosclerosis and earlier and more severe cardiovascular disease events and death.

LDL is formed as VLDL lipoproteins lose triglyceride through the action of lipoprotein lipase (LPL) and become smaller and denser, containing a higher proportion of cholesterol.

A hereditary form of high LDL is familial hypercholesterolemia (FH). Increased LDL is termed hyperlipoproteinemia type II (after the dated Fredrickson classification).

LDL poses a risk for cardiovascular disease when it invades the endothelium and becomes oxidized, since the oxidized form is more easily retained by the proteoglycans. A complex set of biochemical reactions regulates the oxidation of LDL, chiefly stimulated by presence of free radicals in the endothelium. Nitric oxide down-regulates this oxidation process catalyzed by L-arginine. In a corresponding manner, when there are high levels of asymmetric dimethylarginine in the endothelium, production of nitric oxide is inhibited and more LDL oxidation occurs.Facts|date=June 2008

Lowering LDL

The mevalonate pathway serves as the basis for the biosynthesis of many molecules, including cholesterol. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) is an essential component in the pathway.

Pharmaceutical
The use of statins (HMG-CoA reductase inhibitors) is effective against high levels of LDL cholesterol. Statins inhibit the enzyme HMG-CoA reductase in the liver, which stimulates LDL receptors, resulting in an increased clearance of LDL.

Clofibrate is effective at lowering cholesterol levels, but has been associated with significantly increased cancer and stroke mortality, despite lowered cholesterol levels. [ [http://www.ncbi.nlm.nih.gov/pubmed/6147641] PMID:6147641]

Torcetrapib was a drug developed to treat high cholesterol levels, but its development was halted when studies showed a 60% increase in deaths when used in conjunction with atorvastatin versus the statin alone [cite news
author = Theresa Agovino (Associated Press) | title = Pfizer ends cholesterol drug development
url = http://news.yahoo.com/s/ap/20061203/ap_on_he_me/pfizer_cholesterol_drug_5&printer=1
publisher = Yahoo! News | date = December 3 2006 | accessdate = 2006-12-03 "Each study arm (torcetrapib + atorvastatin vs. atorvastatin alone) had 7500 patients enrolled; 51 deaths were observed in the atorvastatin alone arm, while 82 deaths occurred in the torcetrapib + atorvastatin arm." (Link dead as of 15 January 2007)] .

Niacin (B₃), lowers LDL by selectively inhibiting hepatic diacyglycerol acyltransferase 2, reducing triglyceride synthesis and VLDL secretion through a receptor HM74 [ [http://www.ncbi.nlm.nih.gov/pubmed/15529025] PMID:15529025] and HM74A or GPR109A [ [http://www.ncbi.nlm.nih.gov/pubmed/17238156] PMID:17238156] .

Dietary
Insulin induces HMG-CoA reductase activity, whereas glucagon downregulates it. [ [http://web.indstate.edu/thcme/mwking/cholesterol.html#regulation Regulation of Cholesterol Synthesis ] ] While glucagon production is stimulated by dietary protein ingestion, insulin production is stimulated by dietary carbohydrate. The rise of insulin is, in general, determined by the unfolding of carbohydrates into glucose during the process of digestion. Glucagon levels are very low when insulin levels are high.

A ketogenic diet may have similar response to taking niacin (lowered LDL and increased HDL) through beta-hydroxybutyrate, a ketone body, coupling the niacin receptor (HM74A) [ [http://www.ncbi.nlm.nih.gov/pubmed/17238156] PMID:17238156] .

Lowering the blood lipid concentration of triglycerides helps lower the amount of LDL, because VLDL gets converted in the bloodstream into LDL.

Fructose, a component of sucrose as well as high-fructose corn syrup, upregulates hepatic VLDL synthesis. [ [http://www.nutritionandmetabolism.com/content/2/1/5 Fructose, insulin resistance, and metabolic dyslipidemia] ]

Importance of antioxidants

Because LDL appears to be harmless until oxidized by free radicals, [ [http://grande.nal.usda.gov/ibids/index.php?mode2=detail&origin=ibids_references&therow=404450 Inhibition of in vitro human LDL oxidation by phenolic antioxidants from grapes and wines. Teissedre, P.L. : Frankel, E.N. : Waterhouse, A.L. : Peleg, H. : German, J.B.] J-sci-food-agric. Sussex : John Wiley : & : Sons Limited. Jan 1996. v. 70 (1) p. 55-61. ] it is postulated that ingesting antioxidants and minimizing free radical exposure may reduce LDL's contribution to atherosclerosis, though results are not conclusive. [ [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=1756027&dopt=Citation Effect of antioxidants on oxidative modification of LDL. Esterbauer H, Puhl H, Dieber-Rotheneder M, Waeg G, Rabl H.] Ann Med. 1991;23(5):573-81.]

Measurement of LDL

Chemical measures of lipid concentration have long been the most-used clinical measurement, not because they have the best correlation with individual outcome, but because these lab methods are less expensive and more widely available. However, there is increasing evidence and recognition of the value of more sophisticated measurements. To be specific, LDL particle number (concentration), and to a lesser extent size, have shown much tighter correlation with atherosclerotic progression and cardiovascular events than is obtained using chemical measures of total LDL concentration contained within the particles. LDL cholesterol concentration can be low, yet LDL particle number high and cardiovascular events rates are high. Also, LDL cholesterol concentration can be relatively high, yet LDL particle number low and cardiovascular events are also low. If LDL particle concentration is tracked against event rates, many other statistical correlates of cardiovascular events, such as diabetes mellitus, obesity, and smoking, lose much of their additional predictive power.Fact|date=June 2008

The lipid profile does not measure LDL level directly but instead estimates it via the Friedewald equation cite journal |author=Friedewald WT, Levy RI, Fredrickson DS |title=Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge |journal=Clin. Chem. |volume=18 |issue=6 |pages=499–502 |year=1972 |pmid=4337382 |doi= |url=http://www.clinchem.org/cgi/pmidlookup?view=long&pmid=4337382 |accessdate=2007-12-02] cite web |url=http://www.clinchem.org/cgi/content/abstract/36/1/15
author=Warnick et al|volume=36 (1): 15 |journal=Clinical Chemistry |title=Estimating low-density lipoprotein cholesterol by the Friedewald equation is adequate for classifying patients on the basis of nationally recommended cutpoints |accessdate=2007-12-04 |format= |work=] using levels of other cholesterol such as HDL::$extit\{LDL-C\}\; approx\; extit\{Total\; cholesterol\}\; -\; extit\{HDL-C\}\; -\; 0.20\; *\; extit\{Total\; triglycerides\}$:In mg/dl: LDL cholesterol = total cholesterol – HDL cholesterol – (0.20 × triglycerides):In mmol/l: LDL cholesterol = total cholesterol – HDL cholesterol – (0.45 × triglycerides)There are limitations to this method, most notably that samples must be obtained after a 12 to 14 h fast and that LDL-C cannot be calculated if plasma triglyceride is >4.52 mmol/L (400 mg/dL). Even at LDL-C levels 2.5 to 4.5 mmol/L, this formula is considered to be inaccurate.cite journal |author=Sniderman AD, Blank D, Zakarian R, Bergeron J, Frohlich J |title=Triglycerides and small dense LDL: the twin Achilles heels of the Friedewald formula |journal=Clin. Biochem. |volume=36 |issue=7 |pages=499–504 |year=2003 |pmid=14563441 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0009912003001176 |accessdate=2007-12-04] If both total cholesterol and triglyceride levels are elevated then a modified formula may be used:In mg/dl: LDL-C = Total-C – HDL-C – (0.16 × Trig)This formula provides an approximation with fair accuracy for most people, assuming the blood was drawn after fasting for about 14 hours or longer. (However, the concentration of LDL particles, and to a lesser extent their size, has far tighter correlation with clinical outcome than the content of cholesterol with the LDL particles, even if the LDL-C estimation is about correct.)

Normal ranges

In the USA, the American Heart Association, NIH, and NCEP provide a set of guidelines for fasting LDL-Cholesterol levels, estimated or measured, and risk for heart disease. As of 2003, these guidelines were:

These guidelines were based on a goal of presumably decreasing death rates from cardiovascular disease to less than 2% to 3% per year or less than 20% to 30% every 10 years. Note that 100 is not considered optimal; less than 100 is optimal, though it is unspecified how much less.

Over time, with more clinical research, these recommended levels keep being reduced because LDL reduction, including to abnormally low levels, has been the most effective strategy for reducing cardiovascular death rates in large double blind, randomized clinical trials;cite journal |author=Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ | title= Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group|journal=N Engl J Med. |volume=333 |issue=30 |pages=1301–1307 |year=1995 |pmid=7566020 |url= http://content.nejm.org/cgi/content/abstract/333/20/1301 | doi= 10.1056/NEJM199511163332001 ] far more effective than coronary angioplasty/stenting or bypass surgery.

For instance, for people with known atherosclerosis diseases, the 2004 updated American Heart Association, NIH and NCEP recommendations are for LDL levels to be lowered to less than 70 mg/dL, unspecified how much lower. It has been estimated from the results of multiple human pharmacologic LDL lowering trialsFact|date=October 2007 that LDL should be lowered to about 50 to reduce cardiovascular event rates to near zero. For reference, from longitudinal population studies following progression of atherosclerosis-related behaviors from early childhood into adulthoodFact|date=October 2007, it has been discovered that the usual LDL in childhood, before the development of fatty streaks, is about 35 mg/dL. However, all the above values refer to chemical measures of lipid/cholesterol concentration within LDL, not LDLipoprotein concentrations, probably not the better approach.

Footnotes

References

* [http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm Adult Treatment Panel III Full Report]
* [http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3upd04.htm ATP III Update 2004]
*cite journal | author=Cromwell WC, Otvos JD | title=Low-density lipoprotein particle number and risk for cardiovascular disease | journal=Curr Atheroscler Rep | year=2004 | pages=381–7 | volume=6 | issue=5 | pmid=15296705 | doi = 10.1007/s11883-004-0050-5
*cite journal | author=O'Keefe JH Jr, Cordain L, Harris LH, Moe RM, Vogel R | title=Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal | journal=J Am Coll Cardiol | year=2004 | pages=2142–6 | volume=43 | issue=11 | pmid=15172426 | doi=10.1016/j.jacc.2004.03.046

See also

* Cholesterol
* High density lipoprotein
* Triglyceride
* LDL receptor
* Lipoprotein(a)
* Lipoprotein-X
* Melatonin
* Saturated fat
*
* Vitamin C
* Vitamin E
* Vitamin A
* Glutathione
* Coenzyme Q10
* Polyphenol
* Flavonoid
* Catechin
* Potential effects of tea on health
* Stanol ester
* Sterol ester