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| {{SI}} | | {{LDL}} |
| | {{CMG}}; {{AE}} {{CZ}}; {{Rim}} |
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| {{CMG}}; '''Associate Editor-In-Chief:''' {{CZ}} | | {{SK}} Low density lipoprotein-cholesterol, Low density lipoprotein-C |
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| ==Overview== | | == [[Low density lipoprotein overview|Overview]] == |
| '''Low-density lipoprotein''' ('''LDL''') belongs to the [[lipoprotein]] particle family. Its size is approx. 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 circles the fatty acids keeping them soluble in the aqueous environment.<ref>{{cite journal|journal=Journal of Lipid Research|author=Segrest, J. P. ''et al''|date=September 2001|title=Structure of apolipoprotein B-100 in low density lipoproteins|volume=42|pages=1346-1367}}</ref>.
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| ==Physiology== | | == [[Low density lipoprotein historical perspective|Historical Perspective]] == |
| ===Structure===
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| * Low-density lipoprotein (LDL) belongs to the [[lipoprotein]] particle family. It has a discoid shape with an average diameter of approximately 20 nm.<ref name="pmid11518754">{{cite journal| author=Segrest JP, Jones MK, De Loof H, Dashti N| title=Structure of apolipoprotein B-100 in low density lipoproteins. | journal=J Lipid Res | year= 2001 | volume= 42 | issue= 9 | pages= 1346-67 | pmid=11518754 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11518754 }} </ref> However, LDL is considered a heterogeneous molecule due to fluctuating density, size, and flotation rate.
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| * The average composition of LDL is 20% [[protein]], 20% [[phospholipids]], 40% cholesteryl esters, 10% unesterified [[cholesterol]], and 5% [[triglycerides]].<ref name="pmid11082530">{{cite journal| author=Hevonoja T, Pentikäinen MO, Hyvönen MT, Kovanen PT, Ala-Korpela M| title=Structure of low density lipoprotein (LDL) particles: basis for understanding molecular changes in modified LDL. | journal=Biochim Biophys Acta | year= 2000 | volume= 1488 | issue= 3 | pages= 189-210 | pmid=11082530 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11082530 }} </ref>
| | == [[Low density lipoprotein classification|Classification]] == |
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| * The LDL particle can be structurally divided into 3 layers according to molecular orientational behavior:
| | == [[Low density lipoprotein physiology|Physiology]] == |
| ** 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.
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| ** Interfacial layer with radial orientation
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| ** Apolar lipid core with random orientation: It contains cholesteryl esters and triglycerides.<ref name="pmid11082530">{{cite journal| author=Hevonoja T, Pentikäinen MO, Hyvönen MT, Kovanen PT, Ala-Korpela M| title=Structure of low density lipoprotein (LDL) particles: basis for understanding molecular changes in modified LDL. | journal=Biochim Biophys Acta | year= 2000 | volume= 1488 | issue= 3 | pages= 189-210 | pmid=11082530 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11082530 }} </ref><ref name="pmid21131533">{{cite journal| author=Prassl R| title=Human low density lipoprotein: the mystery of core lipid packing. | journal=J Lipid Res | year= 2011 | volume= 52 | issue= 2 | pages= 187-8 | pmid=21131533 | doi=10.1194/jlr.E013417 | pmc=PMC3023539 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21131533 }} </ref>
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| * 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.<ref name="pmid11518754">{{cite journal| author=Segrest JP, Jones MK, De Loof H, Dashti N| title=Structure of apolipoprotein B-100 in low density lipoproteins. | journal=J Lipid Res | year= 2001 | volume= 42 | issue= 9 | pages= 1346-67 | pmid=11518754 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11518754 }} </ref>
| | ==[[High LDL pathophysiology|Pathophysiology]]== |
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| * 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.<ref name="pmid11082530">{{cite journal| author=Hevonoja T, Pentikäinen MO, Hyvönen MT, Kovanen PT, Ala-Korpela M| title=Structure of low density lipoprotein (LDL) particles: basis for understanding molecular changes in modified LDL. | journal=Biochim Biophys Acta | year= 2000 | volume= 1488 | issue= 3 | pages= 189-210 | pmid=11082530 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11082530 }} </ref>
| | == [[Low density lipoprotein causes|Causes]] == |
| | [[Low LDL causes|Low LDL]] | [[High LDL causes|High LDL]] |
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| ===Function=== | | ==[[Low density lipoprotein epidemiology and demographics|Epidemiology and Demographics]]== |
| * In 1973, Myant first hypothesized the role of LDL in the metabolism of [[cholesterol]].<ref name="pmid4354844">{{cite journal| author=Myant NB| title=Cholesterol metabolism. | journal=J Clin Pathol Suppl (Assoc Clin Pathol) | year= 1973 | volume= 5 | issue= | pages= 1-4 | pmid=4354844 | doi= | pmc=PMC1436101 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4354844 }} </ref> 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]].<ref name="pmid12813012">{{cite journal| author=Rader DJ, Cohen J, Hobbs HH| title=Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. | journal=J Clin Invest | year= 2003 | volume= 111 | issue= 12 | pages= 1795-803 | pmid=12813012 | doi=10.1172/JCI18925 | pmc=PMC161432 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12813012 }} </ref> It is formed in the circulation from VLDL by the action of [[lipoprotein lipase]] (LPL).
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| * 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.
| | ==[[High LDL risk factors|Risk Factors]]== |
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| * 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.<ref name="pmid4355366">{{cite journal| author=Goldstein JL, Brown MS| title=Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol. | journal=Proc Natl Acad Sci U S A | year= 1973 | volume= 70 | issue= 10 | pages= 2804-8 | pmid=4355366 | doi= | pmc=PMC427113 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4355366 }} </ref>
| | == [[Low density lipoprotein screening|Screening]] == |
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| * Not only does LDL transport cholesterol, but also this activity is key to control cholesterol homeostasis.<ref>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
| | ==[[High LDL prognosis and complications|Prognosis and Complications]]== |
| </ref> 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.<ref name="pmid4355366">{{cite journal| author=Goldstein JL, Brown MS| title=Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol. | journal=Proc Natl Acad Sci U S A | year= 1973 | volume= 70 | issue= 10 | pages= 2804-8 | pmid=4355366 | doi= | pmc=PMC427113 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4355366 }} </ref>
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| * 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.<ref name="pmid212203">{{cite journal| author=Brown MS, Goldstein JL| title=Regulation of the activity of the low density lipoprotein receptor in human fibroblasts. | journal=Cell | year= 1975 | volume= 6 | issue= 3 | pages= 307-16 | pmid=212203 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=212203 }} </ref><ref name="pmid10500120">{{cite journal| author=Brown MS, Goldstein JL| title=A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. | journal=Proc Natl Acad Sci U S A | year= 1999 | volume= 96 | issue= 20 | pages= 11041-8 | pmid=10500120 | doi= | pmc=PMC34238 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10500120 }} </ref>
| | ==Diagnosis== |
| | [[Low density lipoprotein laboratory findings|Laboratory Findings]] |
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| ==Clinical Significance== | | == Treatment == |
| * There is a direct association between cardiovascular death and plasma levels of LDL-cholesterol (LDL-C) and duration of elevated plasma LDL-C levels. In most cases, elevated LDL is a contribution of both polygenic factors and environmental influences.<ref name="pmid12813012">{{cite journal| author=Rader DJ, Cohen J, Hobbs HH| title=Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. | journal=J Clin Invest | year= 2003 | volume= 111 | issue= 12 | pages= 1795-803 | pmid=12813012 | doi=10.1172/JCI18925 | pmc=PMC161432 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12813012 }} </ref>
| | [[Low density lipoprotein medical therapy|Medical Therapy]] | [[Low density lipoprotein landmark trials|Landmark Trials]] | [[Low density lipoprotein future or investigational therapies|Future or Investigational Therapies]] |
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| * According to Qebec Cardiovascular study in 2001 increased density, and reduced size < 25.6 nm carry significant unfavorable clinical implications. However, LDL diameter remains a controversial predictor of outcome based on conflicting data in the literature.<ref name="pmid11521128">{{cite journal| author=Lamarche B, St-Pierre AC, Ruel IL, Cantin B, Dagenais GR, Després JP| title=A prospective, population-based study of low density lipoprotein particle size as a risk factor for ischemic heart disease in men. | journal=Can J Cardiol | year= 2001 | volume= 17 | issue= 8 | pages= 859-65 | pmid=11521128 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11521128 }} </ref>
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| * Stampfer and colleagues (1996) also revealed in a nested case-control study that elevated triglyceride component within LDL has independent association with [[myocardial infarction]] (MI). Clinically, the study revealed that non-fasting [[triglyceride]] levels is an independent predictor of MI, especially when combined with elevation of total [[cholesterol]].
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| * However, the occurrence of isolated small dense LDL phenotype is quite uncommon. It is usually part of multiple metabolic disturbances, including low [[HDL]], elevated [[triglyceride]] levels, increased waist-to-hip ratio, and [[insulin]] resistance.
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| * The decreased affinity of small dense LDL particles for LDL receptors has been postulated to be the cause of atherogenic properties of small dense LDL. They are more prone to oxidation,<ref name="pmid1590824">{{cite journal| author=Tribble DL, Holl LG, Wood PD, Krauss RM| title=Variations in oxidative susceptibility among six low density lipoprotein subfractions of differing density and particle size. | journal=Atherosclerosis | year= 1992 | volume= 93 | issue= 3 | pages= 189-99 | pmid=1590824 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1590824 }} </ref> have higher affinity to vascular proteoglycans,<ref name="pmid9519339">{{cite journal| author=Chapman MJ, Guérin M, Bruckert E| title=Atherogenic, dense low-density lipoproteins. Pathophysiology and new therapeutic approaches. | journal=Eur Heart J | year= 1998 | volume= 19 Suppl A | issue= | pages= A24-30 | pmid=9519339 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9519339 }} </ref> and are preferentially taken up by [[macrophage]]s via scanvenger proteins that promote [[atherosclerosis]].<ref name="pmid16357786">{{cite journal| author=Vergès B| title=New insight into the pathophysiology of lipid abnormalities in type 2 diabetes. | journal=Diabetes Metab | year= 2005 | volume= 31 | issue= 5 | pages= 429-39 | pmid=16357786 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16357786 }} </ref>
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| ===Atherosclerosis===
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| * The term atherosclerosis was first introduced by Marchand to describe the association between fatty degeneration and medium to large-sized arterial sub-intimal thickening. Since the early 1980s, it has been emphasized that LDL oxidation is important for the development of atherosclerosis and coronary heart disease (CHD).<ref name="pmid6587396">{{cite journal| author=Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D| title=Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. | journal=Proc Natl Acad Sci U S A | year= 1984 | volume= 81 | issue= 12 | pages= 3883-7 | pmid=6587396 | doi= | pmc=PMC345326 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6587396 }} </ref> Atherosclerosis is considered the end-product and the most feared outcome of nearly all diseases that accompany an elevated LDL.
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| * LDL undergoes oxidative modification in vivo by mechanisms that are still poorly understood. In-vitro studies have hypothesized the role of several enzymes in LDL oxidation, including 15-lipoxygenase, [[myeloperoxidase]], [[xanthine oxidase]], among several others.<ref name="pmid11518754">{{cite journal| author=Segrest JP, Jones MK, De Loof H, Dashti N| title=Structure of apolipoprotein B-100 in low density lipoproteins. | journal=J Lipid Res | year= 2001 | volume= 42 | issue= 9 | pages= 1346-67 | pmid=11518754 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11518754 }} </ref> It is believed that LDL oxidative modification accelerates accumulation of cholesterol within [[macrophage]]s ([[foam cells]]) and initiate atherosclerotic lesions, called [[fatty streak]]s. Fatty streaks predispose to vascular disease and perturbation in [[endothelial]] function.
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| * As a result, adhesive proteins such as ICAM-1 are overactivated allowing leukocytic and monocytic accumulation.<ref name="pmid16357786">{{cite journal| author=Vergès B| title=New insight into the pathophysiology of lipid abnormalities in type 2 diabetes. | journal=Diabetes Metab | year= 2005 | volume= 31 | issue= 5 | pages= 429-39 | pmid=16357786 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16357786 }} </ref> The latter plays a central role in the activation of inflammatory cascade and proliferation of smooth muscle cell and [[monocyte]]s, further enhancing the inflammatory process and contributing to LDL oxidation and uptake by macrophages. Fatty streaks then evolve gradually into fibrous plaques, and subsequent lipid accumulation by LDL activity from the [[blood]] to the vessel wall leads to [[plaque]] instability and rupture resulting finally in thrombotic occlusion of the arterial bed. Oxidized LDL is considered significantly atherogenic and chemotactic for macrophages.
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| * Once LDL moves from the blood to the vessel media, one of three outcomes will occur:
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| # LDL returns to [[blood]] causing regression of the lesion.
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| # LDL undergoes [[oxidation]] due to [[leukocyte]]s and [[free radical]]s.
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| # LDL are taken up by scavenger receptors of macrophages that become foam cells. Scavenger receptors have particular recognition to LDL in oxidized form only.
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| ===Familial Hypercholersterolemia===
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| * Contrary to other polygenic etiologies of elevated LDL, familial hypercholesterolemia (FH), also known as hyperlipidemia type II-A according to Fredrickson's classification, is a monogenic hypercholesterolemia due to deficiency of [[LDL receptor]]s caused by a mutation of LDLR gene on chromosome 19. The disorder follows an autosomal co-dominant segregation pattern.<ref name="pmid12813012">{{cite journal| author=Rader DJ, Cohen J, Hobbs HH| title=Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. | journal=J Clin Invest | year= 2003 | volume= 111 | issue= 12 | pages= 1795-803 | pmid=12813012 | doi=10.1172/JCI18925 | pmc=PMC161432 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12813012 }} </ref>
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| * Homozygous FH is a rare disorder; where individuals have extremely high levels of LDL, often > 1000 mg/dl in the presence of family history and cardiac or cutaneous symptoms, irrespective of other environmental factors, like diet, medications, or exercise.<ref name="pmid20846238">{{cite journal| author=Maiorana A, Nobili V, Calandra S, Francalanci P, Bernabei S, El Hachem M et al.| title=Preemptive liver transplantation in a child with familial hypercholesterolemia. | journal=Pediatr Transplant | year= 2011 | volume= 15 | issue= 2 | pages= E25-9 | pmid=20846238 | doi=10.1111/j.1399-3046.2010.01383.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20846238 }} </ref>
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| * Patients with homozygous FH are very susceptible to early-onset cardiovascular disease along with cutaneous manifestations of abnormal lipid metabolism, such as eruptive [[xanthoma]]s.
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| * Goldstein and Brown described three cardinal features of FH:<ref name="pmid4355366">{{cite journal| author=Goldstein JL, Brown MS| title=Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol. | journal=Proc Natl Acad Sci U S A | year= 1973 | volume= 70 | issue= 10 | pages= 2804-8 | pmid=4355366 | doi= | pmc=PMC427113 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4355366 }} </ref>
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| ** Selective elevation of LDL
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| ** Selective deposition of LDL-derived [[cholesterol]] into [[macrophages]] throughout the body but not in parenchyma
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| ** Inheritance as autosomal dominant trait with gene dosage effect
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| * On the other hand, heterozygous FH, where only one mutated allele is present, has an incidence of 1 out of 500.<ref name="pmid21191428">{{cite journal| author=Nemati MH, Astaneh B| title=Optimal management of familial hypercholesterolemia: treatment and management strategies. | journal=Vasc Health Risk Manag | year= 2010 | volume= 6 | issue= | pages= 1079-88 | pmid=21191428 | doi=10.2147/VHRM.S8283 | pmc=PMC3004511 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21191428 }} </ref> It is defined as any of the following:
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| ** LDL-C levels > 200 mg/dL + coronary heart disease/risk equivalents
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| ** LDL-C levels > 300 mg/dL regardless of disease or risk equivalents
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| * Heterogeneous FH responds better to anti-lipidemics than the homogeneous counterpart.<ref name="pmid12813012">{{cite journal| author=Rader DJ, Cohen J, Hobbs HH| title=Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. | journal=J Clin Invest | year= 2003 | volume= 111 | issue= 12 | pages= 1795-803 | pmid=12813012 | doi=10.1172/JCI18925 | pmc=PMC161432 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12813012 }} </ref>
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| ===Diabetes Mellitus===
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| * Although plasma LDL concentration may be normal in patients with [[diabetes mellitus|type II diabetes mellitus]], several qualitative modifications aid in promoting [[atherosclerosis]] in this particular population.<ref name="pmid16357786">{{cite journal| author=Vergès B| title=New insight into the pathophysiology of lipid abnormalities in type 2 diabetes. | journal=Diabetes Metab | year= 2005 | volume= 31 | issue= 5 | pages= 429-39 | pmid=16357786 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16357786 }} </ref> The quantity of small dense triglyceride-rich LDL particles seem to be more abundant in patients with type II diabetes.<ref name="pmid1450181">{{cite journal| author=Feingold KR, Grunfeld C, Pang M, Doerrler W, Krauss RM| title=LDL subclass phenotypes and triglyceride metabolism in non-insulin-dependent diabetes. | journal=Arterioscler Thromb | year= 1992 | volume= 12 | issue= 12 | pages= 1496-502 | pmid=1450181 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1450181 }} </ref>
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| * Furthermore, patients with [[diabetes]] have increased LDL plasma residence time that contributes to increased arterial deposition of [[cholesterol]] and [[atherosclerosis]].<ref name="pmid16357786">{{cite journal| author=Vergès B| title=New insight into the pathophysiology of lipid abnormalities in type 2 diabetes. | journal=Diabetes Metab | year= 2005 | volume= 31 | issue= 5 | pages= 429-39 | pmid=16357786 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16357786 }} </ref> Altered residence time is attributed to reduced LDL catabolism and decreased turnover,<ref name="pmid16357786">{{cite journal| author=Vergès B| title=New insight into the pathophysiology of lipid abnormalities in type 2 diabetes. | journal=Diabetes Metab | year= 2005 | volume= 31 | issue= 5 | pages= 429-39 | pmid=16357786 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16357786 }} </ref> probably due to decreased expression of LDL receptors.<ref name="pmid12716819">{{cite journal| author=Duvillard L, Florentin E, Lizard G, Petit JM, Galland F, Monier S et al.| title=Cell surface expression of LDL receptor is decreased in type 2 diabetic patients and is normalized by insulin therapy. | journal=Diabetes Care | year= 2003 | volume= 26 | issue= 5 | pages= 1540-4 | pmid=12716819 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12716819 }} </ref> The modification in LDL receptor have been attributed to diabetes that causes increased glycation of Apo-B within LDL altering adequate LDL receptor affinity and even worsening LDL oxidation.<ref name="pmid1526339">{{cite journal| author=Lyons TJ| title=Lipoprotein glycation and its metabolic consequences. | journal=Diabetes | year= 1992 | volume= 41 Suppl 2 | issue= | pages= 67-73 | pmid=1526339 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1526339 }} </ref>
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| * However, it is notable that [[insulin]] therapy targeting diabetes and anti-lipidemic treatment with statins have profound beneficial effects on the unfavorable LDL modifications present in diabetics. By inhibiting HMG-CoA reductase, [[statin]] therapy indirectly increases the expression of LDL receptors thus improving the abnormal affinity.<ref name="pmid16357786">{{cite journal| author=Vergès B| title=New insight into the pathophysiology of lipid abnormalities in type 2 diabetes. | journal=Diabetes Metab | year= 2005 | volume= 31 | issue= 5 | pages= 429-39 | pmid=16357786 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16357786 }} </ref>
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| ===Renal Disease===
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| * [[Renal disease]] causes a specific form of secondary dyslipidemia only when heavy [[proteinuria]] is present. Heavy proteinuria is required to exhibit decreased LDL receptor gene expression in hepatocytes, and alter gene expression of 2 key enzymes for LDL and [[cholesterol]] homeostasis: Increased activity of HMG-CoA reductase, the rate limiting enzyme for cholesterol synthesis, and reduced activity of 7α-hydroxylase, the rate limiting enzyme for cholesterol metabolism and [[bile acid]] synthesis.<ref name="pmid9249773">{{cite journal| author=Liang K, Vaziri ND| title=Gene expression of LDL receptor, HMG-CoA reductase, and cholesterol-7 alpha-hydroxylase in chronic renal failure. | journal=Nephrol Dial Transplant | year= 1997 | volume= 12 | issue= 7 | pages= 1381-6 | pmid=9249773 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9249773 }} </ref>
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|
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| * Similar to the pathogenesis observed in diabetic patients, nephrotic dyslipidemia also demonstrates changes in Apo-B that reduce LDL affinity to its receptor. The proportion of atherogenic small dense LDL particles is also increased.
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|
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| * Individuals undergoing [[dialysis]] also have abnormal LDL profiles. Patients on hemodialysis generally have normal LDL cholesterol but more concentrated small dense particules.<ref name="pmid12694323">{{cite journal| author=Kronenberg F, Lingenhel A, Neyer U, Lhotta K, König P, Auinger M et al.| title=Prevalence of dyslipidemic risk factors in hemodialysis and CAPD patients. | journal=Kidney Int Suppl | year= 2003 | volume= | issue= 84 | pages= S113-6 | pmid=12694323 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12694323 }} </ref> Specifically, patients on [[peritoneal dialysis]] generally have higher [[LDL]] and total [[cholesterol]] due to the considerable protein loss into the peritoneal dialysate that stimulates hepatic protein synthesis, including LDL and other [[lipoproteins]].<ref name="pmid8914053">{{cite journal| author=Wheeler DC| title=Abnormalities of lipoprotein metabolism in CAPD patients. | journal=Kidney Int Suppl | year= 1996 | volume= 56 | issue= | pages= S41-6 | pmid=8914053 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8914053 }} </ref>
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|
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| ===Liver Disease===
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| * [[Non-alcoholic fatty liver disease]] (NAFLD) eventually contributes to the overproduction of LDL, among other [[lipoproteins]]. A two-hit hypothesis has been proposed by Day and James in 1998.<ref name="pmid9547102">{{cite journal| author=Day CP, James OF| title=Steatohepatitis: a tale of two "hits"? | journal=Gastroenterology | year= 1998 | volume= 114 | issue= 4 | pages= 842-5 | pmid=9547102 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9547102 }} </ref> Initially, lipid accumulates in [[hepatocytes]] following insulin resistance. Second, [[oxidative stress]] leads to [[NASH|non-alcoholic steatohepatitis]] (NASH). Irregular metabolism of [[fatty acid]]s causes hypertriglyceridemia due to overproduction of [[VLDL]] that is eventually metabolized into LDL through CETP-mediated exchange of cholesteryl esters and triglycerides between the two lipoproteins.
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|
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| * Similar to other disease entities, [[hepatocellular damage]] yields small dense triglyceride-rich lipoproteins that have low LDL receptor affinity, carry more residence time, and are more susceptible to [[oxidation]] and [[atherosclerosis]].<ref name="pmid21773052">{{cite journal| author=Fon Tacer K, Rozman D| title=Nonalcoholic Fatty liver disease: focus on lipoprotein and lipid deregulation. | journal=J Lipids | year= 2011 | volume= 2011 | issue= | pages= 783976 | pmid=21773052 | doi=10.1155/2011/783976 | pmc=PMC3136146 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21773052 }} </ref>
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|
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| * Cholestatic liver disease is associated with marked hyperlipidemia and elevated LDL. It is hypothesized that because [[HDL]] is also elevated in these patients and is believed to play a protective role, cardiovascular disease does not seem to be increased in patients with cholestatic liver disease. Such outcomes, however, remain controversial.<ref name="pmid11469968">{{cite journal| author=Longo M, Crosignani A, Podda M| title=Hyperlipidemia in Chronic Cholestatic Liver Disease. | journal=Curr Treat Options Gastroenterol | year= 2001 | volume= 4 | issue= 2 | pages= 111-114 | pmid=11469968 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11469968 }} </ref>
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|
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| ===Thyroid Disease===
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| * [[Hypothyroidism]] is associated with marked elevations of LDL due to reduced LDL receptors that decrease LDL clearance. Since [[hypothyroidism]] also reduces oxygen consumption of cardiac [[myocytes]], cardiac contractility is reduced and vascular resistance is increased.
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| * Both vascular changes and LDL accumulation seen in [[hypothyroidism]] promote [[atherosclerosis]].<ref name="pmid12034052">{{cite journal| author=Duntas LH| title=Thyroid disease and lipids. | journal=Thyroid | year= 2002 | volume= 12 | issue= 4 | pages= 287-93 | pmid=12034052 | doi=10.1089/10507250252949405 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12034052 }} </ref>
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|
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| ===Obstructive Sleep Apnea===
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|
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| ==Recommended range; changing targets==
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| 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:
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|
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| {| class="wikitable"
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| ! Level mg/dL
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| ! Level mmol/L
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| ! Interpretation
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| |-
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| | <100
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| | <2.6
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| | Optimal LDL cholesterol, corresponding to reduced, but not zero, risk for heart disease
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| |-
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| | 100 to 129
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| | 2.6 to 3.3
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| | Near optimal LDL level
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| |-
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| | 130 to 159
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| | 3.3 to 4.1
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| | Borderline high LDL level
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| |-
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| | 160 to 189
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| | 4.1 to 4.9
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| | High LDL level
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| |-
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| | >190
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| | >4.9
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| | Very high LDL level, corresponding to highest increased risk of heart disease
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| |}
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|
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| These guidelines were based on a goal of presumably decreasing death rates from cardiovascular disease to less than 2 to 3%/year or less than 20 to 30%/10 years. Note that 100 is not considered optimal; less than 100 is optimal, though it is unspecified how much less.
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|
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| 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; far more effective than coronary angioplasty/stenting or bypass surgery.
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|
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| 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 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, 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.
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|
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| ==Measurement methods==
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| 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. Specifically, 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. Alternatively, 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 additive predictive power.
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|
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| ==LDL subtype patterns==
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| 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).
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|
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| 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.
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|
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| The lipid profile does not measure LDL level directly but instead estimates it via the Friedewald equation using levels of other cholesterol such as [[High density lipoprotein|HDL]]:
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| :<math>\textit{LDL-C} \approx \textit{Total\ cholesterol} - \textit{HDL-C} - 0.20 * \textit{Total\ triglycerides} </math>
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|
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| In mg/dl: LDL cholesterol = total cholesterol – HDL cholesterol – (0.2 × triglycerides)<br />
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| In mmol/l: LDL cholesterol = total cholesterol – HDL cholesterol – (0.45 × triglycerides)
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|
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| 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 (see Sniderman et al., <ref> [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=14563441&query_hl=15&itool=pubmed_ExternalLink]).
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| </ref>
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| If both total cholesterol and triglyceride levels are elevated then a modified formulat may be used
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|
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| LDL-C = Total-C HDL-C (0.16 x Trig)
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|
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| 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.)
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|
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| 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> [http://www.medscape.com/viewarticle/447166_print] </ref> <ref> [http://www.clinchem.org/cgi/content/abstract/36/1/15] </ref>
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|
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| However, cholesterol and lipid assays, as outlined above were never promoted because they worked the best to identify those more likely to have problems, but simply because they used to be far less expensive, by about 50 fold, than measured lipoprotein particle concentrations and subclass analysis. 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.
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|
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| == Differential Diagnosis of Causes of LDL Changes ==
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| === Decreased ===
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| * Abetalipoproteinemia
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| * Advanced liver disease
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| * Malnutrition
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| === Increased ===
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| * Acute myocardial infarction
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| * [[Diabetes Mellitus]]
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| * Drugs
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| * High fat diet
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| * [[Ddx:Hypothyroidism|Hypothyroidism]]
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| * [[Nephrotic Syndrome]]
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| * Obstructive liver disease
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| * Primary hyperlipoproteinemia
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|
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| ==Lowering LDL==
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|
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| The [[mevalonate pathway]] serves as the basis for the biosynthesis of many molecules, including cholesterol. 3-hydroxy-3-methylglutaryl coenzyme A reductase ([[HMG CoA reductase]]) is an essential component in the pathway.
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|
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| ===Pharmaceutical===
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|
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| 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.
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|
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| ===Dietary===
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|
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| [[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 generally determined by the unfolding of [[carbohydrates]] into [[glucose]] during the process of [[digestion]]. Glucagon levels are very low when insulin levels are high.
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|
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| Lowering the blood lipid concentration of [[triglycerides]] otherwise known as [[very low density lipoprotein]] (VLDL) helps lower the amount of LDL, because VLDL gets converted in the bloodstream into LDL.
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|
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| [[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>.
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|
| |
| [[Niacin]] (B<sub>3</sub>) which blocks breakdown of fats also lowers VLDL and consequently LDL. It comes with the added benefit of increasing [[High density lipoprotein]], HDL, the so-called 'good' cholesterol.
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|
| |
| ==References==
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| {{Reflist|2}}
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|
| |
| ==Additional Resources==
| |
| *[http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm Adult Treatment Panel III Full Report]
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| *[http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3upd04.htm ATP III Update 2004]
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|
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| == See also ==
| |
| <div style="-moz-column-count:3; column-count:3;">
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| * [[Cholesterol]]
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| * [[High density lipoprotein]]
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| * [[Triglyceride]]
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| * [[LDL receptor]]
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| * [[Lipoprotein(a)]]
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| * [[Lipoprotein-X]]
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| * [[Melatonin]]
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| * [[Saturated fat]]
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| * [[:Category:Low density lipoprotein receptor gene family]]
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| * [[Vitamin C]]
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| * [[Vitamin E]]
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| * [[Vitamin A]]
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| * [[Glutathione]]
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| * [[Coenzyme Q10]]
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| * [[Polyphenol]]
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| * [[Flavonoid]]
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| * [[Catechin]]
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| * [[Potential effects of tea on health]]
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| * [[Stanol ester]]
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| * [[Sterol ester]]
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| </div>
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|
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| <br>
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| {{Lipoproteins}} | | {{Lipoproteins}} |
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| [[Category:Health risks|Low density lipoprotein]] | | [[Category:Health risks|Low density lipoprotein]] |
| [[Category:Lipoproteins]] | | [[Category:Lipoproteins]] |
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| [[de:LDL (Medizin)]]
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| [[es:Lipoproteína de baja densidad (LDL)]]
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| [[fr:Lipoprotéine de basse densité]]
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| [[ko:저밀도지질단백질]]
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| [[it:Low Density Lipoprotein]]
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| [[he:LDL]]
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| [[pl:LDL]]
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| [[pt:Lipoproteína de baixa densidade]]
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| [[ru:Липопротеины низкой плотности]]
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| [[fi:LDL]]
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| [[zh:低密度脂蛋白]]
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