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リポタンパク質（リポたんぱくしつ、英語: Lipoprotein）は、脂質が血漿中に存在する様態で、脂質とアポタンパク質が結合したものである[1]。
脂肪酸のような分極した分子を除き（遊離脂肪酸）、脂質を血漿中に安定に存在させるには、タンパク質（アポタンパク質と呼ぶ）と結合させる必要がある。リポタンパク質は、トリアシルグリセロール（トリグリセリド、中性脂肪）および、細胞の生命維持に不可欠なコレステロールを多く含む球状粒子である。カイロミクロン（キロミクロン）、超低密度リポタンパク質（英語版） (VLDL)、中間密度リポタンパク質（英語版） (IDL)、低密度リポタンパク質（英語版） (LDL) 、高密度リポタンパク質（英語版） (HDL) の各種類があり、比重が大きいほどアポリポタンパク質の割合が高く、逆に脂質の割合が低い。
目次
- 1 概要
- 2 種類
- 2.1 カイロミクロン
- 2.2 超低密度リポタンパク質（VLDL）
- 2.3 中間密度リポタンパク質（IDL）
- 2.4 低密度リポタンパク質（LDL）
- 2.5 高密度リポタンパク質（HDL）
- 3 出典
- 4 関連項目
- 5 外部リンク
概要
リポタンパク質は、電気泳動法または超遠心にて分類される。通常見られるリポタンパク質は次のようなものである。
- 電気泳動法(アガロース法)では、陰極に近い方から
- カイロミクロン
- βリポタンパク
- pre-βリポタンパク
- αリポタンパク
- 電気泳動法(ポリアクリルアミドゲルディスク法、PAG法)では、陰極に近い方から
- カイロミクロン
- VLDL
- IDL
- LDL
- small-LDL
- HDL
- 超遠心では、比重の軽い方から
- カイロミクロン
- VLDL
- LDL
- HDL
3者の違いは、アガロース法はリポタンパク質を荷電で分析し、ポリアクリルアミドゲルディスク法では、主にリポタンパク質の粒子サイズの順に分析され、超遠心法はリポタンパク質の粒子の密度(体積あたりの重量)で分析される。 3者の間にはおよそ次の対応関係があるが正確ではない。
- βリポタンパク - LDL
- pre-βリポタンパク - VLDL
- αリポタンパク - HDL
カイロミクロンを構成するアポタンパク質はアポB48で外因性リポタンパク質と呼ばれ、VLDL、LDL、HDLを構成するアポタンパク質はアポB100で、内因性リポタンパク質と呼ばれる。 VLDLがトリグリセリドを失い小型化したリポタンパク質を、IDLと称する。またLDL粒子がトリグリセリドを失い小型化したリポタンパク質を、small dense LDLと言い、ともに動脈硬化の原因物質といわれている。 ディスク電気泳動法では、IDLはミッドバンドと呼ばれている。
種類
カイロミクロン
詳細は「カイロミクロン」を参照
0.94 g/mL 未満のリポタンパク質で、直径は 180 - 500 nm 程度[2]。
カイロミクロン中には約1:10の割合でコレステロールとトリアシルグリセロールが含まれる。腸管から吸収された脂質が腸管粘膜でリポタンパク質に再構成されリンパ管を通り中枢である肝臓に運ばれる。その役割を果たすのがカイロミクロンである。構成するアポリポタンパク質としてApoB48などがある。
リポタンパク質リパーゼ欠損症（英語版）では著しい高カイロミクロン血症をしめす。一方で、リポタンパク質を合成するのに必要なMTP（ミクロソームトリグリセリド輸送タンパク）を欠損する場合無βリポタンパク血症になり、脂溶性ビタミンが運ばれなくなるのでビタミンAやビタミンEの欠乏症に似た夜盲症や末梢神経麻痺などの症状をきたす。
超低密度リポタンパク質（VLDL）
1.006 g/mL 未満のリポタンパク質[2]。
肝臓で生成されて血中に放出される。約1:5の割合でコレステロールとトリアシルグリセロールが含まれ、末梢組織にトリアシルグリセロールを供給する。構成するアポリポタンパク質としてアポリポプロテインB-100（apo B-100）、アポリポプロテインC-II（apo C-II）、アポリポプロテインE（apo E）がある。
ApoB短縮症ではVLDLやLDLに乏しい低βリポ蛋白血症をきたす。
中間密度リポタンパク質（IDL）
1.006 - 1.019 g/mL のリポタンパク質[2]。
リパーゼの一種であるリポタンパク質リパーゼ（英語版）（LPL）によりVLDLやカイロミクロンが加水分解されトリアシルグリセロールを失う過程のリポタンパク質。レムナント（英語でremnant。remainと同系の単語）とも称される。
通常は速やかに代謝されるが、インスリン抵抗性を背景としたメタボリックシンドロームの患者ではLPL活性が低下しており、apo E変異症のIII型高脂血症の患者ではLDL受容体、VLDL受容体、LRP受容体への結合が進まず、レムナントが血中に鬱滞する。
PAG法電気泳動ではmidbandとして定性的・半定量的に測定可能である。また、抗ApoAI抗体と抗ApoB100抗体を使ったRLP-C測定キットでレムナントの多寡が定量的に評価できる。最近ではapo B48定量による評価も検討されている。
低密度リポタンパク質（LDL）
1.019 - 1.063 g/mL のリポタンパク質で、直径は 22 nm 程度[2]。
リポタンパク質の中でコレステロール含有量が最も多く、末梢組織にコレステロールを供給する。そのため、悪玉コレステロールとも呼ばれる。apo B-100やapo Eを認識するLDL受容体を介して主に肝臓に取り込まれ異化される。
LDL受容体欠損症は家族性高コレステロール血症(FH:familial hypercholesterolemia)とよばれ、特にホモ欠損症では総コレステロール値が600mg以上にもなり思春期にも虚血性心疾患など重篤な動脈硬化症に至る。
LDLが酸化・変性・糖化することによってLDL受容体への親和性を失う（酸化LDL）。その場合、スカベンジャー受容体などを経てマクロファージに取り込まれ、マクロファージの機能を変化させることにより動脈硬化症を発症すると考えられている。
最近ではスモールデンス（sd-LDL）と呼ばれるLDL受容体への親和性を失い、小粒子ゆえに血管壁に浸透しやすい種類のLDLが虚血性心疾患に関与していることもわかってきた。粒子径は25.5nm以下である。比重で分画した場合1.040 - 1.063のLDLに相当する。
高密度リポタンパク質（HDL）
1.063 - 1.21 g/mL のリポタンパク質[2]。
血管内皮など末梢組織に蓄積したコレステロールを肝臓に運ぶ働きがある。結果として動脈硬化を抑える働きをするので、善玉コレステロールと呼ばれることもある。構成するアポリポタンパク質としてアポリポプロテインA-I（apo A-I）やアポリポプロテインA-II（apo A-II）などがある。
LDLやVLDLとの間でHDLのトリアシルグリセロールとLDLやVLDLのコレステロールをコレステリルエステル転送タンパク質（英語版）（CETP）を用いて交換し、コレステロールはLDL受容体を介し肝臓に逆転送しやすくしている。
出典
- ^ IUPAC Gold Book - lipoproteins
- ^ a b c d e 『ストライヤー生化学』 東京化学同人、2004年、第5版、732頁。ISBN 978-4807905812。
関連項目
- 脂質異常症
- メタボリックシンドローム
- 高リポタンパク血症（英: w:Hyperlipidemia）
外部リンク
- 家族性高コレステロール血症について（家族性高脂血症） 金沢大学馬渕教授
"LDL" redirects here. For other uses, see LDL (disambiguation).
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein. These groups, from least dense (largest particles) to most dense (smallest particles), are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein and high-density lipoprotein (HDL).
Lipoproteins transfer lipids (fats) around the body in the extracellular fluid thereby facilitating fats to be available and taken up by the cells body wide via receptor-mediated endocytosis.[1][2] Lipoproteins are complex particles composed of multiple proteins, typically 80-100 proteins/particle (organized by a single apolipoprotein B for LDL and the larger particles). A single LDL particle is about 220-275 angstroms in diameter[3] typically transporting 3,000 to 6,000 fat molecules/particle, varying in size according to the number and mix of fat molecules contained within. The lipids carried include all fat molecules with cholesterol, phospholipids, and triglycerides dominant; amounts of each varying considerably. Lipoproteins can be sampled from blood for evaluation of atherosclerosis driving factors.
LDL particles pose a risk for cardiovascular disease when they invade the endothelium and become oxidized, since the oxidized forms are more easily retained by the proteoglycans. A complex set of biochemical reactions regulates the oxidation of LDL particles, chiefly stimulated by presence of necrotic cell debris and free radicals in the endothelium.[4] Increasing concentrations of LDL particles are strongly associated with increasing rates of accumulation of atherosclerosis within the walls of arteries over time, eventually resulting in sudden plaque ruptures, decades later, and triggering clots within the artery opening; these debris & clots narrowing or closing off the opening locally (more commonly microscopic branches distal to plaque rupture locations), i.e. cardiovascular disease, stroke, and other vascular disease complications.[5]
LDL particles (though far different from cholesterol per se) are sometimes referred to as bad cholesterol because they can transport their content of lipid molecules into artery walls, attract macrophages, and thus drive atherosclerosis. In contrast, HDL particles (though far different from cholesterol per se) are often called good cholesterol or healthy cholesterol because they can remove lipid molecules from macrophages in the wall of arteries.[6]
A hereditary form of high LDL is familial hypercholesterolemia (FH). High LDL is termed hyperlipoproteinemia type II (after the dated Fredrickson classification).
Contents
- 1 Biochemistry
- 2 Physiology
- 2.1 Transport into the cell
- 2.2 Role in the innate immune system
- 2.3 LDL subtype patterns
- 3 Testing
- 3.1 Estimation of LDL particles via cholesterol content
- 3.2 Direct measurement of LDL particle concentrations
- 4 Lowering LDL-cholesterol
- 4.1 Pharmaceutical
- 4.2 Lifestyle
- 4.3 Antioxidants
- 5 See also
- 6 Notes and references
- 7 External links
Biochemistry
Structure
Each native LDL particle enables emulsification, i.e. surrounding/packaging all fatty acids being carried, enabling these fats to move around the body within the water outside cells. Each particle contains a single apolipoprotein B-100 molecule (Apo B-100, a protein that has 4536 amino acid residues and a mass of 514 kDa), along with 80 to 100 additional ancillary proteins. Each LDL has a highly hydrophobic core consisting of polyunsaturated fatty acid known as linoleate and hundreds to thousands (about 1500 commonly cited as an average) esterified and unesterified cholesterol molecules. This core also carries varying numbers of triglycerides and other fats and is surrounded by a shell of phospholipids and unesterified cholesterol, as well as the single copy of Apo B-100. LDL particles are approximately 22 nm (0.00000087 in.) to 27.5 nm in diameter and have a mass of about 3 million daltons.[7] Since LDL particles contain a variable and changing number of fatty acid molecules, there is a distribution of LDL particle mass and size.[3] Determining the structure of LDL has been a tough task because of its heterogeneous structure. The structure of LDL at human body temperature in native condition, with a resolution of about 16 Angstroms using cryo-electron microscopy, has been recently described.[8]
Physiology
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LDL particles are formed as VLDL lipoproteins lose triglyceride through the action of lipoprotein lipase (LPL) and they become smaller and denser (i.e. fewer fat molecules with same protein transport shell), containing a higher proportion of cholesterol esters.[4]
Transport into the cell
When a cell requires additional cholesterol (beyond its current internal HMGCoA production pathway), it synthesizes the necessary LDL receptors as well as PCSK9, a proprotein convertase that marks the LDL receptor for degradation.[9] LDL receptors are inserted into the plasma membrane and diffuse freely until they associate with clathrin-coated pits. When LDL receptors bind LDL particles in the bloodstream, the clathrin-coated pits are endocytosed into the cell.
Vesicles containing LDL receptors bound to LDL are delivered to the endosome. In the presence of low pH, such as that found in the endosome, LDL receptors undergo a conformation change, releasing LDL. LDL is then shipped to the lysosome, where cholesterol esters in the LDL are hydrolysed. LDL receptors are typically returned to the plasma membrane, where they repeat this cycle. If LDL receptors bind to PCSK9, however, transport of LDL receptors is redirected to the lysosome, where they are degraded.
Role in the innate immune system
LDL interfere with the quorum sensing system that upregulates genes required for invasive Staphylococcus aureus infection. The mechanism of antagonism entails binding Apolipoprotein B to a S. aureus autoinducer pheromone, preventing signaling through its receptor. Mice deficient in apolipoprotein B are more susceptible to invasive bacterial infection.[10]
LDL subtype patterns
LDL particles 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 thought to be because the smaller particles are more easily able to penetrate the endothelium. Pattern I, for intermediate, indicates that most LDL particles are very close in size to the normal gaps in the endothelium (26 nm). According to one study, sizes 19.0–20.5 nm were designated as pattern B and LDL sizes 20.6–22 nm were designated as pattern A.[11]
Some in the medical community have suggested the correspondence between Pattern B and CHD is 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 is used more often.
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 (a.k.a. "buoyant") LDL.[12][13]
With continued research, decreasing cost, greater availability and wider acceptance of other lipoprotein subclass analysis assay methods, including NMR spectroscopy,[14] research studies have continued to show a stronger correlation between human clinically obvious cardiovascular events and quantitatively measured particle concentrations.[citation needed]
Testing
Blood tests commonly report LDL-C: the amount of cholesterol which is estimated to be contained with LDL particles, on average, using a formula, the Friedewald equation. In clinical context, mathematically calculated estimates of LDL-C are commonly used as an estimate of how much low density lipoproteins are driving progression of atherosclerosis. The problem with this approach is that LDL-C values are commonly discordant with both direct measurements of LDL-particles and actual rates of atherosclerosis progression.
Direct LDL measurements are also available and better reveal individual issues but are less often promoted or done due to slightly higher costs and being available from only a couple of laboratories in the United States. In 2008, the ADA and ACC recognized direct LDL particle measurement by NMR as superior for assessing individual risk of cardiovascular events.[15]
Estimation of LDL particles via cholesterol content
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.
The lipid profile does not measure LDL particles. It only estimates them using the Friedewald equation[13][16] by subtracting the amount of cholesterol associated with other particles, such as HDL and VLDL, assuming a prolonged fasting state, etc.:
- where H is HDL cholesterol, L is LDL cholesterol, C is total cholesterol, T are triglycerides, and k is 0.20 if the quantities are measured in mg/dl and 0.45 if in mmol/l.
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 triglyceride levels 2.5 to 4.5 mmol/L, this formula is considered inaccurate.[17] If both total cholesterol and triglyceride levels are elevated then a modified formula, with quantities in mg/dl, may be used
This formula provides an approximation with fair accuracy for most people, assuming the blood was drawn after fasting for about 14 hours or longer, but does not reveal the actual LDL particle concentration because the percentage of fat molecules within the LDL particles which are cholesterol varies, as much as 8:1 variation.
However, the concentration of LDL particles, and to a lesser extent their size, has a stronger and consistent correlation with individual clinical outcome than the amount of cholesterol within LDL particles, even if the LDL-C estimation is approximately correct. There is increasing evidence and recognition of the value of more targeted and accurate measurements of LDL particles. Specifically, LDL particle number (concentration), and to a lesser extent size, have shown slightly stronger correlations with atherosclerotic progression and cardiovascular events than obtained using chemical measures of the amount of cholesterol carried by the LDL particles.[18] It is possible that the LDL cholesterol concentration can be low, yet LDL particle number high and cardiovascular events rates are high. Correspondingly, it is possible that LDL cholesterol concentration can be relatively high, yet LDL particle number low and cardiovascular events are also low. If LDL particle concentration is used to predict cardiovascular events, many other correlates of these clinical outcomes, such as diabetes mellitus, obesity and smoking, lose most of their predictive accuracy.
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 about 2005, these guidelines were:[19][20][21]
| Level mg/dL |
Level mmol/L |
Interpretation |
| 25 to <50 |
<1.3 |
Optimal LDL cholesterol, levels in healthy young children before onset of atherosclerotic plaque in heart artery walls |
| <70 |
<1.8 |
Optimal LDL cholesterol, corresponding to lower rates of progression, promoted as a target option for those known to clearly have advanced symptomatic cardiovascular disease |
| <100 |
<2.6 |
Optimal LDL cholesterol, corresponding to lower, but not zero, rates for symptomatic cardiovascular disease events |
| 100 to 129 |
2.6 to 3.3 |
Near optimal LDL level, corresponding to higher rates for developing symptomatic cardiovascular disease events |
| 130 to 159 |
3.3 to 4.1 |
Borderline high LDL level, corresponding to even higher rates for developing symptomatic cardiovascular disease events |
| 160 to 199 |
4.1 to 4.9 |
High LDL level, corresponding to much higher rates for developing symptomatic cardiovascular disease events |
| >200 |
>4.9 |
Very high LDL level, corresponding to highest increased rates of symptomatic cardiovascular disease events |
Over time, with more clinical research, these recommended levels keep being reduced because LDL reduction, including to abnormally low levels, was the most effective strategy for reducing cardiovascular death rates in one large double blind, randomized clinical trial of men with hypercholesterolemia;[22] far more effective than coronary angioplasty/stenting or bypass surgery[23]
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. This low level of less than 70 mg/dL (higher than Tim Russert's value shortly prior to his heart attack) was recommended for primary prevention of 'very-high risk patients' and in secondary prevention as a 'reasonable further reduction'. Lack of evidence for such a recommendation is discussed in an article in the Annals of internal medicine.[24] It should also be noted that statin drugs involved in such clinical trials have numerous physiological effects beyond simply the reduction of LDL levels.
It has been estimated from the results of multiple human pharmacologic LDL lowering trials[25] that LDL should be lowered to below 30 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,[26] 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 measured low-density lipoprotein concentrations, the accurate approach.
The feasibility of these figures has been questioned by sceptics, claiming that many members of the AHA and NIH are heavily associated with pharmaceutical companies giving them bias towards lowering cholesterol levels and such guidelines giving rise to increased use of cholesterol lowering medicine such as statins.[citation needed]
A study was conducted measuring the effects of guideline changes on LDL cholesterol reporting and control for diabetes visits in the US from 1995 to 2004. It was found that although LDL cholesterol reporting and control for diabetes and coronary heart disease visits improved continuously between 1995 and 2004, neither the 1998 ADA guidelines nor the 2001 ATP III guidelines increased LDL cholesterol control for diabetes relative to coronary heart disease.[27]
Moreover, there are publications regarding the risks of low-LDL cholesterol too.[28]
Direct measurement of LDL particle concentrations
There are several competing methods for measurement of lipoprotein particle concentrations and size. The evidence is that the NMR methodology (developed, automated & greatly reduced in costs while improving accuracy as pioneered by Jim Otvos and associates) results in a 22-25% reduction in cardiovascular events within one year,[29] contrary to the longstanding claims by many in the medical industry that the superiority over existing methods was weak, even by statements of some proponents.[30]
Since the later 1990s, because of the development of NMR measurements, it has been possible to clinically measure lipoprotein particles at lower cost [under $80 US (including shipping) & is decreasing; versus the previous costs of >$400 to >$5,000] and higher accuracy. There are two other assays for LDL-particles, however, like LDL-C, most only estimate LDL particle concentrations.
Direct LDL particle measurement by NMR was mentioned by the ADA and ACC, in a 28 March 2008 joint consensus statement,[31] as having advantages for predicting individual risk of atherosclerosis disease events, but the statement noted that the test is less widely available, is more expensive [about $13.00 US (2015 without insurance coverage) from some labs which use the Vantera Analyzer[32]]. Debate continues that it is "...unclear whether LDL particle size measurements add value to measurement of LDL-particle concentration", though outcomes have always tracked LDL-particle, not LDL-C, concentrations.
Using NMR, as pioneered by researcher Jim Otvos and the North Carolina State University academic research spin-off company LipoScience, the total LDL particle concentrations, in nmol/L plasma, are typically subdivided by percentiles referenced to the 5,382 men and women, not on any lipid medications, who are participating in the MESA trial.[33]
Optimal ranges
The LDL particle concentrations are typically categorized by percentiles, <20%, 20–50%, 50th–80th%, 80th–95% and >95% groups of the people participating and being tracked in the MESA trial, a medical research study sponsored by the United States National Heart, Lung, and Blood Institute.
| MESA Percentile |
LDL particles nmol/L |
Interpretation |
| 0–20% |
<1,000 |
Those with lowest rate of cardiovascular disease events & low (optimal) LDL particle concentration |
| 20–50% |
1,000–1,299 |
Those with moderate rate of cardiovascular disease events & moderate LDL particle concentration |
| 50–80% |
1,300–1,599 |
Those with Borderline-High rate of cardiovascular disease events & higher LDL particle concentration |
| 89–95% |
1,600–2,000 |
Those with High rate of cardiovascular disease events and even higher LDL particle concentration |
| >95% |
>2,000 |
Those with very high rate of cardiovascular disease events and highest LDL particle concentration |
The lowest incidence of atherosclerotic events over time occurs within the <20% group, with increased rates for the higher groups. Multiple other measures, including particle sizes, small LDL particle concentrations, large total and HDL particle concentrations, along with estimations of insulin resistance pattern and standard cholesterol lipid measurements (for comparison of the plasma data with the estimation methods discussed above) are also routinely provided.
Lowering LDL-cholesterol
| Markers indicating a need for LDL-C Reduction
(Per 2004 United States Government Minimum Guidelines[34][35])
|
| If the patient's cardiac risk is... |
then the patient should consider LDL-C reduction if the count in mg/dL is over... |
and LDL-C reduction is indicated if the count in mg/dL is over... |
| High, meaning a 20% or greater risk of heart attack within 10 years, or an extreme risk factor |
70[36] |
100[36] |
| moderately high, meaning a 10-20% risk of heart attack within 10 years and more than 2 heart attack risk factors |
100[36] |
130[36] |
| moderate, meaning a 10% risk of heart attack within 10 years and more than 2 heart attack risk factors |
130[36] |
160[36] |
| low, meaning less than 10% risk of heart attack within 10 years and 1 or 0 heart attack risk factors |
160[36] |
190[36] |
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 and performs the first of 37 steps within the cholesterol production pathway, and present in every animal cell.
Keep in mind that LDL-C is not a measurement of actual LDL particles; LDL-C is only an estimate (not measured from the individual's blood sample) of how much cholesterol is being transported by all LDL particles; either a smaller concentration of large particles or a high concentration of small particles. Also keep in mind that LDL particles carry many fat molecules (typically 3,000 to 6,000 fat molecules per LDL particle); this includes cholesterol, triglycerides, phospholipids and others. Thus even if the hundreds to thousands of cholesterol molecules within an average LDL particle were measured, this does not reflect the other fat molecules or even the number of LDL particles.
Pharmaceutical
- PCSK9 inhibitors, in clinical trials, by several companies, are more effective for LDL reduction than the statins, including statins alone at high dose (though not necessarily the combination of statins plus ezetimibe).
- Statins reduce high levels of LDL particles by inhibiting the enzyme HMG-CoA reductase in cells, the rate-limiting step of cholesterol synthesis. To compensate for the decreased cholesterol availability, synthesis of LDL receptors (including hepatic) is increased, resulting in an increased clearance of LDL particles from the extracellular water, including of the blood.
- Ezetimibe reduces intestinal absorption of cholesterol, thus can reduce LDL particle concentrations when combined with statins.[37]
- Niacin (B3), lowers LDL by selectively inhibiting hepatic diacylglycerol acyltransferase 2, reducing triglyceride synthesis and VLDL secretion through a receptor HM74[38] and HM74A or GPR109A.[39]
- Several CETP inhibitors have been researched to improve HDL concentrations, but so far, despite dramatically increasing HDL-C, have not had a consistent track record in reducing atherosclerosis disease events. Some have increased mortality rates compared with placebo.
- Clofibrate is effective at lowering cholesterol levels, but has been associated with significantly increased cancer and stroke mortality, despite lowered cholesterol levels.[40] Other, more recently developed and tested fibrates, e.g. fenofibric acid[41] have had a better track record and are primarily promoted for lowering VLDL particles (triglycerides), not LDL particles, yet can help some in combination with other strategies.
- Some Tocotrienols, especially delta- and gamma-tocotrienols, are being promoted as statin alternative non-prescription agents to treat high cholesterol, having been shown in vitro to have an effect. In particular, gamma-tocotrienol appears to be another HMG-CoA reductase inhibitor, and can reduce cholesterol production.[42] As with statins, this decrease in intra-hepatic (liver) LDL levels may induce hepatic LDL receptor up-regulation, also decreasing plasma LDL levels. As always, a key issue is how benefits and complications of such agents compare with statins—molecular tools that have been analyzed in large numbers of human research and clinical trials since the mid-1970s.
- Phytosterols are widely recognized as having a proven LDL cholesterol lowering efficacy.[43] Current supplemental guidelines recommend doses of phytosterols in the 1.6-3.0 grams per day range (Health Canada, EFSA, ATP III,FDA) with a recent meta-analysis demonstrating an 8.8% reduction in LDL-cholesterol at a mean dose of 2.15 gram per day.[44] However, plant sterols and stanols, if absorbed (intestinal cells generally block), greatly accelerate progression of atherosclerosis more than cholesterol delivered into the arterial walls by lipoprotein particles.[citation needed]
- Insulin induces HMG-CoA reductase activity, whereas glucagon diminishes HMG-CoA reductase activity.[45] While glucagon production is stimulated by dietary protein ingestion, insulin production is stimulated by dietary carbohydrate.[citation needed] The rise of insulin is, in general, determined by the digestion of carbohydrates into glucose and subsequent increase in serum glucose levels. In non-diabetics, glucagon levels are very low when insulin levels are high; however, those who have become diabetic no longer suppress glucagon output after eating.
- 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).[39]
- Lowering the blood lipid concentration of triglycerides helps lower the concentration of small LDL particles, because fatty-acid rich VLDL particles convert in the bloodstream into small dense LDL particles.[vague]
Lifestyle
- The most effective approach has been minimizing fat stores located inside the abdominal cavity (visceral body fat) in addition to minimizing total body fat.[46] Visceral fat, which is more metabolically active than subcutaneous fat, has been found to produce many enzymatic signals, e.g. resistin, which increase insulin resistance and circulating VLDL particle concentrations, thus both increasing LDL particle concentrations and accelerating the development of diabetes mellitus.
Antioxidants
Because LDL particles appear harmless until they are within the blood vessel walls and oxidized by free radicals,[47] it has been postulated that ingesting antioxidants and minimizing free radical exposure may reduce LDL's contribution to atherosclerosis, though results are not conclusive.[48][49]
See also
- Catechin
- Cholesterol
- Lysosomal acid lipase deficiency
- Cholesteryl ester storage disease
- Coenzyme Q10
- Flavonoid
- Glutathione
- Health effects of tea
- High density lipoprotein
- LDL receptor
- Lipid profile
- Lipoprotein(a)
- Lipoprotein-X
- Melatonin
- Polyphenol antioxidant
- Saturated fat
- Stanol ester
- Sterol ester
- Triglyceride
- Vitamin A
- Vitamin C
- Vitamin E
Notes and references
- ^ Dashti M, Kulik W, Hoek F, Veerman EC, Peppelenbosch MP, Rezaee F (2011). "A phospholipidomic analysis of all defined human plasma lipoproteins.". Sci Rep. 1 (139). doi:10.1038/srep00139. PMC 3216620. PMID 22355656.
- ^ Dashty M, Motazacker MM, Levels J, de Vries M, Mahmoudi M, Peppelenbosch MP, Rezaee F (2014). "Proteome of human plasma very low-density lipoprotein and low-density lipoprotein exhibits a link with coagulation and lipid metabolism.". Thromb Haemost. 111: 518–530. doi:10.1160/TH13-02-0178. PMID 24500811.
- ^ a b Segrest JP, Jones MK, De Loof H, Dashti N (September 2001). "Structure of apolipoprotein B-100 in low density lipoproteins". Journal of Lipid Research. 42 (9): 1346–67. PMID 11518754.
- ^ a b "Lipoproteins".
- ^ Glagov, Seymour; Weisenberg, Elliot; Zarins, Christopher K.; Stankunavicius, Regina; Kolettis, George J. (28 May 1987). "Compensatory Enlargement of Human Atherosclerotic Coronary Arteries". N. Engl. J. Med. 316 (22): 1371–1375. doi:10.1056/NEJM198705283162204. PMID 3574413 – via Taylor and Francis+NEJM.
- ^ "Good vs. Bad Cholesterol".
- ^ Campos, Hannia (1992). "LDL Particle Size Distribution". Arteriosclerosis, Thrombosis, and Vascular Biology. 12: 1410–1419. doi:10.1161/01.ATV.12.12.1410.
- ^ Kumar V, Butcher SJ, Katrina O, Engelhardt P, Heikkonen J, Kaski K, Ala-Korpela M, Kovanen PT (May 2011). "Three-Dimensional cryoEM Reconstruction of Native LDL Particles to 16Å Resolution at Physiological Body Temperature". PLoS ONE. 6 (5): e18841. doi:10.1371/journal.pone.0018841. PMC 3090388. PMID 21573056.
- ^ Zhang, Da-Wei; Garuti, Rita; Tang, Wan-Jin; Cohen, Jonathan C.; Hobbs, Helen H. (2008-09-02). "Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor". Proceedings of the National Academy of Sciences of the United States of America. 105 (35): 13045–13050. doi:10.1073/pnas.0806312105. ISSN 0027-8424. PMC 2526098. PMID 18753623.
- ^ Peterson MM, Mack JL, Hall PR, et al. (December 2008). "Apolipoprotein B Is an innate barrier against invasive Staphylococcus aureus infection". Cell Host & Microbe. 4 (6): 555–66. doi:10.1016/j.chom.2008.10.001. PMC 2639768. PMID 19064256.
- ^ Bhalodkar, Narendra C.; Blum, Steve; Rana, Thakor; Kitchappa, Radha; Bhalodkar, Ami N.; Enas, Enas A. (1 May 2005). "Comparison of high-density and low-density lipoprotein cholesterol subclasses and sizes in asian indian women with caucasian women from the framingham offspring study". Clin Cardiol. 28 (5): 247–251. doi:10.1002/clc.4960280510 – via Wiley Online Library.
- ^ Superko HR, Nejedly M, Garrett B (2002). "Small LDL and its clinical importance as a new CAD risk factor: a female case study". Progress in Cardiovascular Nursing. 17 (4): 167–73. doi:10.1111/j.0889-7204.2002.01453.x. PMID 12417832.
- ^ a b Warnick GR, Knopp RH, Fitzpatrick V, Branson L (January 1990). "Estimating low-density lipoprotein cholesterol by the Friedewald equation is adequate for classifying patients on the basis of nationally recommended cutpoints". Clinical Chemistry. 36 (1): 15–9. PMID 2297909.
- ^ Otvos J (June 1999). "Measurement of triglyceride-rich lipoproteins by nuclear magnetic resonance spectroscopy". Clin Cardiol. 22 (6 Suppl): II21–7. doi:10.1002/clc.4960221405. PMID 10376193.
- ^ John D. Brunzell, MD, FACP, Michael Davidson, MD, FACC, Curt D. Furberg, MD, PhD, Ronald B. Goldberg, MD, Barbara V. Howard, PhD, James H. Stein, MD, FACC, FACP and Joseph L. Witztum, MD Lipoprotein Management in Patients With Cardiometabolic Risk, J Am Coll Cardiol, 2008; 51:1512-1524. [1]
- ^ Friedewald WT, Levy RI, Fredrickson DS (June 1972). "Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge". Clinical Chemistry. 18 (6): 499–502. PMID 4337382.
- ^ Sniderman AD, Blank D, Zakarian R, Bergeron J, Frohlich J (October 2003). "Triglycerides and small dense LDL: the twin Achilles heels of the Friedewald formula". Clinical Biochemistry. 36 (7): 499–504. doi:10.1016/S0009-9120(03)00117-6. PMID 14563441.
- ^ http://www.liposcience.com/userfiles/content/files/weightofevidence.pdf
- ^ "Cholesterol Levels". American Heart Association. Retrieved 2009-11-14.
- ^ "What Do My Cholesterol Levels Mean?" (PDF). American Heart Association. September 2007. Retrieved 2009-11-14.
- ^ "Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Executive Summary" (PDF). National Heart, Lung, and Blood Institute (NHLBI). National Institutes of Health. May 2001.
- ^ Shepherd J, Cobbe SM, Ford I, et al. (November 1995). "Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group". The New England Journal of Medicine. 333 (20): 1301–7. doi:10.1056/NEJM199511163332001. PMID 7566020.
- ^ William E. Boden, M.D.; et al. (April 2007). "Optimal Medical Therapy with or without PCI for Stable Coronary Disease". The New England Journal of Medicine. 356 (15): 1503–1516. doi:10.1056/NEJMoa070829. PMID 17387127.
- ^ Hayward, Rodney A. (3 October 2006). "Narrative Review: Lack of Evidence for Recommended Low-Density Lipoprotein Treatment Targets: A Solvable Problem". Ann Intern Med. 145 (7): 520–30. doi:10.7326/0003-4819-145-7-200610030-00010. PMID 17015870.
- ^ "The straight dope on cholesterol – Part VI - The Eating Academy - Peter Attia, M.D.". 30 May 2012.
- ^ "Google".
- ^ Wang, Y Richard; G Caleb Alexander; David O Meltzer (December 2005). "Lack of Effect of Guideline Changes on LDL Cholesterol Reporting and Control for Diabetes Visits in the U.S., 1995–2004". Diabetes Care. 28 (12): 2942–2944. doi:10.2337/diacare.28.12.2942. PMID 16306559. Retrieved 2011-11-11.
- ^ Shor, Renana; Wainstein, Julio; Oz, David; Boaz, Mona; Matas, Zipora; Fux, Asora; Halabe, Aaron (1 January 2007). "Low serum LDL cholesterol levels and the risk of fever, sepsis, and malignancy". Ann. Clin. Lab. Sci. 37 (4): 343–348. PMID 18000291.
- ^ Peter P. Toth; Michael Grabner; Rajeshwari S. Punekar; Ralph A. Quimbo; Mark J. Cziraky; Terry A. Jacobson (August 2014). "Cardiovascular risk in patients achieving low-density lipoprotein cholesterol and particle targets". Atherosclerosis. 235 (2): 585–591. doi:10.1016/j.atherosclerosis.2014.05.914.
- ^ Krauss RM (August 2010). "Lipoprotein subfractions and cardiovascular disease risk". Current Opinion in Lipidology. 21 (4): 305–11. doi:10.1097/MOL.0b013e32833b7756. PMID 20531184.
- ^ Brunzell, John D.; Davidson, Michael; Furberg, Curt D.; Goldberg, Ronald B.; Howard, Barbara V.; Stein, James H.; Witztum, Joseph L. (15 April 2008). "Lipoprotein Management in Patients With Cardiometabolic Risk". J Am Coll Cardiol. 51 (15): 1512–1524. doi:10.1016/j.jacc.2008.02.034.
- ^ "Google".
- ^ "MESA - Multi-Ethnic Study of Atherosclerosis".
- ^ http://www.nhlbi.nih.gov/health-pro/guidelines/current/cholesterol-guidelines/
- ^ https://www.acli.com/Events/Documents/Tue22812%20-%20Lipidology%20-%20Pamela%20Morris.pdf
- ^ a b c d e f g h Consumer Reports; Drug Effectiveness Review Project (March 2013), "Evaluating statin drugs to treat High Cholesterol and Heart Disease: Comparing Effectiveness, Safety, and Price" (PDF), Best Buy Drugs, Consumer Reports, p. 9, retrieved 27 March 2013 , which cites
- United States Department of Health and Human Services; National Heart, Lung, and Blood Institute; National Institutes of Health (June 2005). "NHLBI, High Blood Cholesterol: What You Need to Know". nhlbi.nih.gov. Retrieved 27 March 2013.
- ^ Research, Center for Drug Evaluation and. "Drug Safety Information for Heathcare [sic] Professionals - Follow-up to the January 25, 2008 Early Communication about an Ongoing Data Review for Ezetimibe/Simvastatin (marketed as Vytorin), Ezetimibe (marketed as Zetia), and Simvastatin (marketed as Zocor)".
- ^ Meyers CD, Kamanna VS, Kashyap ML (December 2004). "Niacin therapy in atherosclerosis". Current Opinion in Lipidology. 15 (6): 659–65. doi:10.1097/00041433-200412000-00006. PMID 15529025.
- ^ a b Soudijn W, van Wijngaarden I, Ijzerman AP (May 2007). "Nicotinic acid receptor subtypes and their ligands". Medicinal Research Reviews. 27 (3): 417–33. doi:10.1002/med.20102. PMID 17238156.
- ^ "WHO cooperative trial on primary prevention of ischemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Report of the Committee of Principal Investigators". Lancet. 2 (8403): 600–4. September 1984. doi:10.1016/s0140-6736(84)90595-6. PMID 6147641.
- ^ http://www.rxabbott.com/pdf/trilipix_pi.pdf
- ^ Song, B.L.; DeBose-Boyd, R.A. (2006). "Insig-Dependent Ubiquitination and Degradation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Stimulated by Delta- and Gamma-Tocotrienols". J. Biol. Chem. 281 (35): 25054–25601. doi:10.1074/jbc.M605575200. PMID 16831864.
- ^ European Food Safety Authority, Journal (2010). "Scientific opinion on the substantiation of health claims related to plant sterols and plant stanols and maintenance of normal blood cholesterol concentrations".
- ^ Demonty, I.; Ras, R.T.; van der Knaap, H.C.; Duchateau, G.S.; Meijer, L.; Zock, P.L.; Geleijnse, J.M.; Trautwein, E.A. (Feb 2009). "Continuous dose-response relationship of the LDL-cholesterol-lowering effect of phytosterol intake.". The Journal of Nutrition. 139 (2): 271–84. doi:10.3945/jn.108.095125. PMID 19091798.
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- ^ Zhang, Haifeng; Tong, Tom K.; Qiu, Weifeng; Zhang, Xu; Zhou, Shi; Liu, Yang; He, Yuxiu (2017-01-01). "Comparable Effects of High-Intensity Interval Training and Prolonged Continuous Exercise Training on Abdominal Visceral Fat Reduction in Obese Young Women". Journal of Diabetes Research. 2017: 5071740. doi:10.1155/2017/5071740. ISSN 2314-6753. PMC 5237463. PMID 28116314.
- ^ 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.
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External links
- Fat (LDL) Degradation: PMAP The Proteolysis Map-animation
- Adult Treatment Panel III Full Report
- ATP III Update 2004
- O'Keefe JH, Cordain L, Harris WH, Moe RM, Vogel R (June 2004). "Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal". Journal of the American College of Cardiology. 43 (11): 2142–6. doi:10.1016/j.jacc.2004.03.046. PMID 15172426.
|
Lipids: lipoprotein particle metabolism
|
|
| Lipoprotein particle classes and subclasses |
- delivery of TGs: Chylomicron
- VLDL
- delivery of C and CE: IDL
- LDL
- lb LDL
- sd LDL
- Lp(a)
- HDL
|
|
| Apolipoproteins |
- APOA
- APOB
- APOC
- APOD
- APOE
- APOH
- SAA
|
|
| Extracellular enzymes |
|
|
| Lipid transfer proteins |
|
|
| Cell surface receptors |
- IDL: LRP
- LRP1
- LRP1B
- LRP2
- LRP3
- LRP4
- LRP5
- LRP5L
- LRP6
- LRP8
- LRP10
- LRP11
- LRP12
- LDL: LDLR
- LRPAP1
|
|
| ATP-binding cassette transporter |
|
|
Cardiovascular disease (vessels) (I70–I99, 440–456)
|
|
Arteries, arterioles
and capillaries |
| Inflammation |
- Arteritis
- Buerger's disease
|
|
| Peripheral artery disease |
| Arteriosclerosis |
- Atherosclerosis
- Foam cell
- Fatty streak
- Atheroma
- Intermittent claudication
- Critical limb ischemia
- Monckeberg's arteriosclerosis
- Arteriolosclerosis
- Hyaline
- Hyperplastic
- Cholesterol
- LDL
- Oxycholesterol
- Trans fat
|
|
| Stenosis |
- Carotid artery stenosis
- Renal artery stenosis
|
|
| Other |
- Aortoiliac occlusive disease
- Degos disease
- Erythromelalgia
- Fibromuscular dysplasia
- Raynaud's phenomenon
|
|
|
Aneurysm / dissection /
pseudoaneurysm |
- torso: Aortic aneurysm
- Abdominal aortic aneurysm
- Thoracic aortic aneurysm
- Aneurysm of sinus of Valsalva
- Aortic dissection
- Coronary artery aneurysm
- head / neck
- Intracranial aneurysm
- Intracranial berry aneurysm
- Carotid artery dissection
- Vertebral artery dissection
- Familial aortic dissection
|
|
| Vascular malformation |
- Arteriovenous fistula
- Arteriovenous malformation
- Telangiectasia
- Hereditary hemorrhagic telangiectasia
|
|
| Vascular nevus |
- Cherry hemangioma
- Halo nevus
- Spider angioma
|
|
|
| Veins |
| Inflammation |
|
|
Venous thrombosis /
Thrombophlebitis |
- primarily lower limb
- abdomen
- Hepatic veno-occlusive disease
- Budd–Chiari syndrome
- May–Thurner syndrome
- Portal vein thrombosis
- Renal vein thrombosis
- upper limb / torso
- Mondor's disease
- Paget–Schroetter disease
- head
- Cerebral venous sinus thrombosis
- Post-thrombotic syndrome
|
|
| Varicose veins |
- Gastric varices
- Portacaval anastomosis
- Caput medusae
- Esophageal varices
- Hemorrhoid
- Varicocele
|
|
| Other |
- Chronic venous insufficiency
- Chronic cerebrospinal venous insufficiency
- Superior vena cava syndrome
- Inferior vena cava syndrome
- Venous ulcer
|
|
|
| Arteries or veins |
- Angiopathy
- Macroangiopathy
- Microangiopathy
- Embolism
- Pulmonary embolism
- Cholesterol embolism
- Paradoxical embolism
- Thrombosis
- Vasculitis
|
|
| Blood pressure |
| Hypertension |
- Hypertensive heart disease
- Hypertensive emergency
- Hypertensive nephropathy
- Essential hypertension
- Secondary hypertension
- Renovascular hypertension
- Benign hypertension
- Pulmonary hypertension
- Systolic hypertension
- White coat hypertension
|
|
| Hypotension |
|
|
ネフローゼの場合血中のタンパクはどんどん尿に漏出していく。そのためアルブミン、γグロブリンは割合が低下している。α2分画にはα2マクログロブリンが存在する。これは分子量が77万から82万という大きな分子であるので、ネフローゼで糸球体のサイズバリアが崩壊しているとしても尿中に排出されず残るため、相対的にα2分画が高くなる。
赤沈は第1相で赤血球同士が連銭形成し、第2相で沈んでいき、第3相では沈んできた赤血球の密度が上昇して沈降速度が鈍ってくる。赤沈が亢進するには、凝集が促進されるか、沈降の抵抗が少ないかである。赤血球の膜は負に帯電しており、正に帯電しているフィブリノゲン、γグロブリンが増加すると負の電荷同士で集まり合い凝集が促進される。逆に負に帯電しているアルブミンの量が減少すると、負同士の反発が軽減し凝集が容易になる。また貧血であると第3相で密度が低くなり沈降が早くなる。以上より、ネフローゼの場合アルブミンが尿中に排泄され血清アルブミンの濃度が低下、また、β分画のフィブリノゲンが上昇しているため赤沈は亢進する。
