Low-density lipoprotein 51521 225734217 2008-07-15T03:43:18Z Metagraph 6738192 Reverted edits by [[Special:Contributions/24.12.12.65|24.12.12.65]] to last version by Elektron (using [[WP:HG|Huggle]]) {{otheruses4|Low-density lipoprotein|the educational technique LdL|Learning by teaching}} '''Low-density lipoprotein''' ('''LDL''') is a [[lipoprotein]] that transports [[cholesterol]] and [[triglyceride]]s from the [[liver]] to peripheral tissues. 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 [[High-density lipoprotein|HDL]], the "good cholesterol").<ref>[http://www.americanheart.org/presenter.jhtml?identifier=180 LDL and HDL Cholesterol: What's Bad and What's Good?]</ref> ==Biochemistry== ===Structure=== 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 [[Atomic mass unit|daltons]], but since LDL particles contain a changing number of fatty acids, they actually have a mass and size distribution.<ref>{{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}}</ref> ===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&mdash;called "Pattern B"&mdash;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.<ref name="pmid12417832">{{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}}</ref><ref name="Warnick"/> 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]]-[[Caveolae|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 [[artery|arteries]] and can be retained there by arterial [[proteoglycan]]s starting the formation of plaques, increased levels are associated with [[atherosclerosis]], and thus [[myocardial infarction|heart attack]], [[cerebrovascular accident|stroke]], and [[peripheral artery occlusive disease|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.<ref>[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.</ref> 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 [[oxidize]]d, 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 [[statin]]s (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 receptor]]s, resulting in an increased clearance of LDL. '''Dietary''' [[Insulin]] induces HMG-CoA reductase activity, whereas glucagon downregulates it.<ref>[http://web.indstate.edu/thcme/mwking/cholesterol.html#regulation Regulation of Cholesterol Synthesis ]</ref> 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. 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.<ref>[http://www.nutritionandmetabolism.com/content/2/1/5 Fructose, insulin resistance, and metabolic dyslipidemia]</ref> [[Niacin]] (B<sub>3</sub>), which blocks breakdown of fats, also lowers VLDL and, as a consequence, LDL. It comes with the added benefit of increasing [[high-density lipoprotein]], HDL, the so-called 'good' cholesterol.{{Fact|date=November 2007}} === Importance of antioxidants === Because LDL appears to be harmless until oxidized by free radicals,<ref> [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. </ref> it is postulated that ingesting [[antioxidants]] and minimizing free radical exposure may reduce LDL's contribution to atherosclerosis, though results are not conclusive.<ref> [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.</ref> == 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''' <ref name="pmid4337382">{{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}}</ref><ref name="Warnick">{{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=}}</ref> using levels of other cholesterol such as [[High density lipoprotein|HDL]]: :<math>\textit{LDL-C} \approx \textit{Total\ cholesterol} - \textit{HDL-C} - 0.20 * \textit{Total\ triglycerides} </math> :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 LDC-L levels 2.5 to 4.5 mmol/L, this formula is considered to be inaccurate.<ref name="Sniderman">{{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}}</ref> If both total cholesterol and triglyceride levels are elevated then a modified formula may be used :In mg/dl: LDL-C = Total-C &ndash; HDL-C &ndash; (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]], [[National Institutes of Health|NIH]], and [[National Cholesterol Education Program|NCEP]] provide a set of guidelines for fasting LDL-Cholesterol levels, estimated or measured, and risk for [[Coronary heart disease|heart disease]]. As of 2003, these guidelines were: {| class="wikitable" ! Level [[kilogram|mg]]/[[litre|dL]] ! Level [[Mole (unit)|mmol]]/L ! Interpretation |- | <100 | <2.6 | Optimal LDL cholesterol, corresponding to reduced, but not zero, risk for heart disease |- | 100 to 129 | 2.6 to 3.3 | Near optimal LDL level |- | 130 to 159 | 3.3 to 4.1 | Borderline high LDL level |- | 160 to 189 | 4.1 to 4.9 | High LDL level |- | >190 | >4.9 | Very high LDL level, corresponding to highest increased risk of heart disease |} 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;<ref name="pmid7566020 ">{{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 }}</ref> 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 trials{{Fact|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 adulthood{{Fact|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== {{reflist}} ==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 <!--Retrieved from CrossRef by DOI bot-->}} *{{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 == <div style="-moz-column-count:3; column-count:3;"> * [[Cholesterol]] * [[High density lipoprotein]] * [[Triglyceride]] * [[LDL receptor]] * [[Lipoprotein(a)]] * [[Lipoprotein-X]] * [[Melatonin]] * [[Saturated fat]] * [[:Category:Low density lipoprotein receptor gene family]] * [[Vitamin C]] * [[Vitamin E]] * [[Vitamin A]] * [[Glutathione]] * [[Coenzyme Q10]] * [[Polyphenol]] * [[Flavonoid]] * [[Catechin]] * [[Potential effects of tea on health]] * [[Stanol ester]] * [[Sterol ester]] </div> {{Lipoproteins}} [[Category:Cardiology]] [[Category:Lipid disorders]] [[Category:Health risks|Low density lipoprotein]] [[Category:Lipoproteins]] [[de:Low Density Lipoprotein]] [[es:Lipoproteína de baja densidad (LDL)]] [[fr:Lipoprotéine de basse densité]] [[ko:저밀도지질단백질]] [[it:Low Density Lipoprotein]] [[he:LDL]] [[pl:LDL]] [[pt:Lipoproteína de baixa densidade]] [[ru:Липопротеины низкой плотности]] [[fi:LDL]] [[zh:低密度脂蛋白]]