Low density lipoprotein
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Rim Halaby, M.D. [3]
Synonyms and keywords: LDL-cholesterol, LDL-C
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.[1] There is a direct association between cardiovascular death and duration of elevated plasma LDL-cholesterol (LDL-C) levels. In most cases, elevated LDL is a contribution of both polygenic factors and environmental influences.[2] Not only does LDL transport cholesterol, but also this activity is key to control cholesterol homeostasis.[3] Several factors contribute to the elevation of the LDL levels, such as primary hyperlipoproteinemia, diabetes mellitus, hypothyroidism, high fat diet and drugs.
Physiology
Structure
- Low-density lipoprotein (LDL) belongs to the lipoprotein particle family. It has a discoid shape with an average diameter of approximately 20 nm.[4] However, LDL is considered a heterogeneous molecule due to fluctuating density, size, and flotation rate.
- The average composition of LDL is 20% protein, 20% phospholipids, 40% cholesteryl esters, 10% unesterified cholesterol, and 5% triglycerides.[5]
- The LDL particle can be structurally divided into 3 layers according to molecular orientational behavior:
- Outer surface layer with tangential orientation: It forms a shell composed of phospholipid monolayer to cover the core. The phospholipid monolayer is organized in a way that hydrophilic residues with polar head groups interact with the outer aqueous solvent; while the inner hydrophobic residues face the lipid interior.
- Interfacial layer with radial orientation
- Apolar lipid core with random orientation: It contains cholesteryl esters and triglycerides.[5][6]
- 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.[4]
- 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.[5]
Function
- In 1973, Myant first hypothesized the role of LDL in the metabolism of cholesterol.[7] 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.[2] It is formed in the circulation from VLDL by the action of lipoprotein lipase (LPL).
- LDL receptors, located at specific coat pits on plasma membrane of specific target cells mediate the selective uptake of molecules into cells by endocytosis. The coat pits contain clathrin protein on the cytoplasmic end of the plasma membrane to promote endocytosis. LDL receptors are glycoproteins that have negatively charged domains capable of interacting with positively charged arginine and lysine residues of apo B-100.
- Inside the cell, LDL migrates within a vesicle and is targeted to be degraded within the lysosome that contains hydrolases capable of digesting components of LDL. LDL degradation produces cholesterol, amino acids, glycerol and fatty acids.[8]
- Not only does LDL transport cholesterol, but also this activity is key to control cholesterol homeostasis.[9] 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.[8]
- 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.[10][11]
Clinical Significance
- There is a direct association between cardiovascular death and duration of elevated plasma LDL-cholesterol (LDL-C) levels. In most cases, elevated LDL is a contribution of both polygenic factors and environmental influences.[2]
- 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.[12]
- 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.
- 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.
- 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,[13] have higher affinity to vascular proteoglycans,[14] and are preferentially taken up by macrophages via scanvenger proteins that promote atherosclerosis.[15]
Atherosclerosis
- 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).[16] Atherosclerosis is considered the end-product and the most feared outcome of nearly all diseases that accompany an elevated LDL.
- 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.[4] It is believed that LDL oxidative modification accelerates accumulation of cholesterol within macrophages (foam cells) and initiate atherosclerotic lesions, called fatty streaks. Fatty streaks predispose to vascular disease and perturbation in endothelial function.
- As a result, adhesive proteins such as ICAM-1 are overactivated allowing leukocytic and monocytic accumulation.[15] The latter plays a central role in the activation of inflammatory cascade and proliferation of smooth muscle cell and monocytes, 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.
- Once LDL moves from the blood to the vessel media, one of three outcomes will occur:
- LDL returns to blood causing regression of the lesion.
- LDL undergoes oxidation due to leukocytes and free radicals.
- LDL are taken up by scavenger receptors of macrophages that become foam cells. Scavenger receptors have particular recognition to LDL in oxidized form only.
Familial Hypercholersterolemia
- 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 receptors caused by a mutation of LDLR gene on chromosome 19. The disorder follows an autosomal co-dominant segregation pattern.[2]
- 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.[17]
- Patients with homozygous FH are very susceptible to early-onset cardiovascular disease along with cutaneous manifestations of abnormal lipid metabolism, such as eruptive xanthomas.
- Goldstein and Brown described three cardinal features of FH:[8]
- Selective elevation of LDL
- Selective deposition of LDL-derived cholesterol into macrophages throughout the body but not in parenchyma
- Inheritance as autosomal dominant trait with gene dosage effect
- On the other hand, heterozygous FH, where only one mutated allele is present, has an incidence of 1 out of 500.[18] It is defined as any of the following:
- LDL-C levels > 200 mg/dL + coronary heart disease/risk equivalents
- LDL-C levels > 300 mg/dL regardless of disease or risk equivalents
- Heterogeneous FH responds better to anti-lipidemics than the homogeneous counterpart.[2]
Diabetes Mellitus
- Although plasma LDL concentration may be normal in patients with type II diabetes mellitus, several qualitative modifications aid in promoting atherosclerosis in this particular population.[15] The quantity of small dense triglyceride-rich LDL particles seem to be more abundant in patients with type II diabetes.[19]
- Furthermore, patients with diabetes have increased LDL plasma residence time that contributes to increased arterial deposition of cholesterol and atherosclerosis.[15] Altered residence time is attributed to reduced LDL catabolism and decreased turnover,[15] probably due to decreased expression of LDL receptors.[20] 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.[21]
- 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.[15]
Renal Disease
- 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.[22]
- 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.
- Individuals undergoing dialysis also have abnormal LDL profiles. Patients on hemodialysis generally have normal LDL cholesterol but more concentrated small dense particules.[23] 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.[24]
Liver Disease
- 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.[25] Initially, lipid accumulates in hepatocytes following insulin resistance. Second, oxidative stress leads to non-alcoholic steatohepatitis (NASH). Irregular metabolism of fatty acids 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.
- 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.[26]
- 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.[27]
Thyroid Disease
- 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.
- Both vascular changes and LDL accumulation seen in hypothyroidism promote atherosclerosis.[28]
Obstructive Sleep Apnea
Oxidized LDL measured in patients with obstructive sleep apnea syndrome (OSAS) shows significant increase when compared to control groups.[29] This was believed to be due to the hypoxemia experienced by these patients that cause lipid peroxidation and an imbalance between reactive oxygen species and counteracting antioxidant reserve.[30] However, newer research findings have not entirely supported this theory; thus the exact mechanism that associates OSAS and elevated LDL remains controversial. Elevated LDL normalizes following appropriate continuous positive airway pressure (CPAP) therapy for patients with OSAS.
Causes of Low LDL
- Abetalipoproteinemia
- Advanced liver disease
- Malnutrition
Causes of High LDL
- Acute myocardial infarction
- Diabetes Mellitus
- Drugs
- High fat diet
- Hypothyroidism
- Nephrotic Syndrome
- Obstructive liver disease
- Primary hyperlipoproteinemia
Measurement Methods
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.
LDL Subtype Patterns
LDL particles actually vary in size and density, and studies have shown that a pattern that has more small dense LDL particles ("Pattern B") equates to a higher risk factor for coronary heart disease (CHD) than does a pattern with more of the larger and less dense LDL particles ("Pattern A"). This is because the smaller particles are more easily able to penetrate the endothelium. "Pattern I", meaning "intermediate", indicates that most LDL particles are very close in size to the normal gaps in the endothelium (26 nm).
The correspondence between Pattern B and 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.
The lipid profile does not measure LDL level directly but instead estimates it via the Friedewald equation using levels of other cholesterol such as HDL:
In mg/dl: LDL cholesterol = total cholesterol – HDL cholesterol – (0.2 × triglycerides)
In mmol/l: LDL cholesterol = total cholesterol – HDL cholesterol – (0.45 × triglycerides)
There are limitations to this method, most notably that samples must be obtained after a 12 to 14 h fast and that LDL-C cannot be calculated if plasma triglyceride is >4.52 mmol/L (400 mg/dL). Even at LDC-L levels 2.5 to 4.5 mmol/L, this formula is considered to be inaccurate. If both total cholesterol and triglyceride levels are elevated then a modified formulat may be used
LDL-C = Total-C HDL-C (0.16 x TAG)
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.)
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.
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.
Treatment of High LDL
Available Guidelines
The National Cholesterol Education Program (NCEP) publishes the Adult Treatment Panel (ATP) guidelines for detection, evaluation, and treatment of hyperlipidemia in adults.
| Adult Treatment Panel | Release History |
| I | 1988 |
| II | 1993 |
| III | 2001 |
| III Addendum (update) | 2004 |
| IV | 2012 |
Other U.S. guidelines for the management of dyslipidemia are also present. LDL-C target ranges of the following guidelines are not different from the latest ATP guidelines:
- 2008: ADA/ACCF Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk
- 2011: AHA/ACC Guidelines for Secondary Prevention
- 2012: AACE Guidelines for the Management of Dyslipidemia and Prevention of Atherosclerosis
- 2013: ADA Standards of Medical Care in DM
Target Goal
- 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. According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III published in 2001, the target goal for LDL-cholesterol after 9- to 12- hour fast are as follows:[31]
| Level mg/dL | Level mmol/L | Interpretation |
|---|---|---|
| <100 | <2.6 | Optimal LDL cholesterol, corresponding to reduced, but not zero, risk for heart disease |
| 100 to 129 | 2.6 to 3.3 | Near optimal LDL level |
| 130 to 159 | 3.3 to 4.1 | Borderline high LDL level |
| 160 to 189 | 4.1 to 4.9 | High LDL level |
| >190 | >4.9 | Very high LDL level, corresponding to highest increased risk of heart disease |
- Nonetheless, ATP III guidelines emphasize on identification of clinical atherosclerotic disease and risk factors that predispose individuals to increased risk of coronary heart disease events. ATP III define clinical atherosclerotic disease as one of the following: [31]
- Clinical coronary heart disease
- Symptomatic carotid artery disease (Transient ischemic attack or stroke of carotid origin)
- Peripheral artery disease
- Abdominal aortic aneurysm[31]
- Categorization of risk and stratification of patients according to clinical atherosclerosis and risk factors play an integral part of ATP III guidelines. Accordingly, LDL-C target levels vary among various risk groups :[31]
| Risk Category (Number of Risk Factors) | 10 Year Risk | LDL-C Goal (mg/dL) |
| 0-1 | <10% | <160 |
| 2+ | ≦20% | <130 (ATP III in 2001) Optional: <100 (Updated ATP III in 2004) |
| CHD or CHD Risk Equivalents | >20% | <100 (ATP III in 2001) Optional: <70 (Updated ATP III in 200) |
- According to ATP III guidelines, the associated risk factors used to define LDL-C target include the following:
- Age ≥ 45 years for men and ≥ 55 years for women
- Smoking
- Hypertension
- HDL-C < 40 mg/dL
- Family history (first degree relative) of premature coronary heart disease at age < 55 years in males or 65 years in females)
2004 Addendum ATP III
- In July 2004, an addendum to the NCEP ATP III guidelines was published following the emergence of data from 5 major clinical trials that addressed new issues and demonstrated novel findings and outcomes.
- Following the addendum, ATP III currently emphasizes on achieving at least 30-40% LDL-C reduction in treating high and moderately high risk patients.[32]
- NCEP ATP IV Guidelines were expected to be published in 2009. However, ATP IV is still currently in the development process.
Significant Trials
- Heart Protection Study
- ALLHAT: Antihypertensive and Lipid-Lowering Treatment To Prevent Heart Attack Trial
- PROVE IT: Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis In Myocardial Infarction
- PROSPER: Prospective Study of Pravastatin in the Elderly at Risk
- ASCOT-LLA: Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm
LDL Cut Off Level to Initiate Therapy
| Risk Category | LDL Goal (mg/dL) |
LDL Level to Initiate TLC (mg/dL) |
LDL Level to Consider Drug Therapy (mg/dL) |
| CHD or CHD risk equivalents (10-year risk >20%) |
<100 | ≥100 | ≥130 |
| 2+ major risk factors (10-year risk ≤20%) |
<130 | ≥130 | 10-year risk 10-20% ≥130 10-year risk <10% ≥160 |
| 0-1 major risk factor | <160 | ≥160 | ≥190 |
Lifestyle Modifications
ATP III recommends the initiation of therapeutic lifestyle changes when LDL is above goal. ATP III recommends the following dietary lifestyle:
- Weight management
- Exercise
- Less than 7% of daily calories derived from saturated fat
- Daily cholesterol intake < 200 mg
- Daily intake of 10-25 g of soluble fiber intake and plant stanols/sterols intake of 2g
Pharmacotherapy
Shown below is a table that summarizes the mechanism of action, percent reduction of LDL and side effects of LDL-c lowering drugs.
| Drug Class | Mechanism of Action | % LDL Reduction | Side Effect |
| Statins | Inhibit HMG-CoA Reductase, rate limiting enzyme of cholesterol synthesis | 18-55 | Hepatotoxicity Myositis |
| Bile Acid Sequestrants | Bind bile inhibiting entero-hepatic circulation | 15-30 | GI distress Nausea Constipation Impaired absorption of fat soluble vitamins and other drugs |
| Niacin ( Vit B3) | Inhibits lipolysis in adipose tissue | 5-25 | Facial flushing Hyperglycemia Hyperuricemia Hepatotoxicity |
| Fibrates | Upregulate lipoprotein lipase | 5-20 | Myositis Hepatotoxicity Gallstones |
| Ezetimibe | Inhibit intestinal cholesterol absorption (synergistic effect with statin) | 17-20 | GI distress Headache Atrial fibrillation Myalgia Constipation |
References
- ↑ Segrest, J. P.; et al. (September 2001). "Structure of apolipoprotein B-100 in low density lipoproteins". Journal of Lipid Research. 42: 1346–1367.
- ↑ 2.0 2.1 2.2 2.3 2.4 Rader DJ, Cohen J, Hobbs HH (2003). "Monogenic hypercholesterolemia: new insights in pathogenesis and treatment". J Clin Invest. 111 (12): 1795–803. doi:10.1172/JCI18925. PMC 161432. PMID 12813012.
- ↑ 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
- ↑ 4.0 4.1 4.2 Segrest JP, Jones MK, De Loof H, Dashti N (2001). "Structure of apolipoprotein B-100 in low density lipoproteins". J Lipid Res. 42 (9): 1346–67. PMID 11518754.
- ↑ 5.0 5.1 5.2 Hevonoja T, Pentikäinen MO, Hyvönen MT, Kovanen PT, Ala-Korpela M (2000). "Structure of low density lipoprotein (LDL) particles: basis for understanding molecular changes in modified LDL". Biochim Biophys Acta. 1488 (3): 189–210. PMID 11082530.
- ↑ Prassl R (2011). "Human low density lipoprotein: the mystery of core lipid packing". J Lipid Res. 52 (2): 187–8. doi:10.1194/jlr.E013417. PMC 3023539. PMID 21131533.
- ↑ Myant NB (1973). "Cholesterol metabolism". J Clin Pathol Suppl (Assoc Clin Pathol). 5: 1–4. PMC 1436101. PMID 4354844.
- ↑ 8.0 8.1 8.2 Goldstein JL, Brown MS (1973). "Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol". Proc Natl Acad Sci U S A. 70 (10): 2804–8. PMC 427113. PMID 4355366.
- ↑ Murtola T, Vuorela TA, Hyvonen MT et al. Low density lipoprotein: Structure, dynamics, and interactions of apoB-100 with lipids. Soft Matter. 2011;7:8136-8141
- ↑ Brown MS, Goldstein JL (1975). "Regulation of the activity of the low density lipoprotein receptor in human fibroblasts". Cell. 6 (3): 307–16. PMID 212203.
- ↑ Brown MS, Goldstein JL (1999). "A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood". Proc Natl Acad Sci U S A. 96 (20): 11041–8. PMC 34238. PMID 10500120.
- ↑ Lamarche B, St-Pierre AC, Ruel IL, Cantin B, Dagenais GR, Després JP (2001). "A prospective, population-based study of low density lipoprotein particle size as a risk factor for ischemic heart disease in men". Can J Cardiol. 17 (8): 859–65. PMID 11521128.
- ↑ Tribble DL, Holl LG, Wood PD, Krauss RM (1992). "Variations in oxidative susceptibility among six low density lipoprotein subfractions of differing density and particle size". Atherosclerosis. 93 (3): 189–99. PMID 1590824.
- ↑ Chapman MJ, Guérin M, Bruckert E (1998). "Atherogenic, dense low-density lipoproteins. Pathophysiology and new therapeutic approaches". Eur Heart J. 19 Suppl A: A24–30. PMID 9519339.
- ↑ 15.0 15.1 15.2 15.3 15.4 15.5 Vergès B (2005). "New insight into the pathophysiology of lipid abnormalities in type 2 diabetes". Diabetes Metab. 31 (5): 429–39. PMID 16357786.
- ↑ Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D (1984). "Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids". Proc Natl Acad Sci U S A. 81 (12): 3883–7. PMC 345326. PMID 6587396.
- ↑ Maiorana A, Nobili V, Calandra S, Francalanci P, Bernabei S, El Hachem M; et al. (2011). "Preemptive liver transplantation in a child with familial hypercholesterolemia". Pediatr Transplant. 15 (2): E25–9. doi:10.1111/j.1399-3046.2010.01383.x. PMID 20846238.
- ↑ Nemati MH, Astaneh B (2010). "Optimal management of familial hypercholesterolemia: treatment and management strategies". Vasc Health Risk Manag. 6: 1079–88. doi:10.2147/VHRM.S8283. PMC 3004511. PMID 21191428.
- ↑ Feingold KR, Grunfeld C, Pang M, Doerrler W, Krauss RM (1992). "LDL subclass phenotypes and triglyceride metabolism in non-insulin-dependent diabetes". Arterioscler Thromb. 12 (12): 1496–502. PMID 1450181.
- ↑ Duvillard L, Florentin E, Lizard G, Petit JM, Galland F, Monier S; et al. (2003). "Cell surface expression of LDL receptor is decreased in type 2 diabetic patients and is normalized by insulin therapy". Diabetes Care. 26 (5): 1540–4. PMID 12716819.
- ↑ Lyons TJ (1992). "Lipoprotein glycation and its metabolic consequences". Diabetes. 41 Suppl 2: 67–73. PMID 1526339.
- ↑ Liang K, Vaziri ND (1997). "Gene expression of LDL receptor, HMG-CoA reductase, and cholesterol-7 alpha-hydroxylase in chronic renal failure". Nephrol Dial Transplant. 12 (7): 1381–6. PMID 9249773.
- ↑ Kronenberg F, Lingenhel A, Neyer U, Lhotta K, König P, Auinger M; et al. (2003). "Prevalence of dyslipidemic risk factors in hemodialysis and CAPD patients". Kidney Int Suppl (84): S113–6. PMID 12694323.
- ↑ Wheeler DC (1996). "Abnormalities of lipoprotein metabolism in CAPD patients". Kidney Int Suppl. 56: S41–6. PMID 8914053.
- ↑ Day CP, James OF (1998). "Steatohepatitis: a tale of two "hits"?". Gastroenterology. 114 (4): 842–5. PMID 9547102.
- ↑ Fon Tacer K, Rozman D (2011). "Nonalcoholic Fatty liver disease: focus on lipoprotein and lipid deregulation". J Lipids. 2011: 783976. doi:10.1155/2011/783976. PMC 3136146. PMID 21773052.
- ↑ Longo M, Crosignani A, Podda M (2001). "Hyperlipidemia in Chronic Cholestatic Liver Disease". Curr Treat Options Gastroenterol. 4 (2): 111–114. PMID 11469968.
- ↑ Duntas LH (2002). "Thyroid disease and lipids". Thyroid. 12 (4): 287–93. doi:10.1089/10507250252949405. PMID 12034052.
- ↑ Kizawa T, Nakamura Y, Takahashi S, Sakurai S, Yamauchi K, Inoue H (2009). "Pathogenic role of angiotensin II and oxidised LDL in obstructive sleep apnoea". Eur Respir J. 34 (6): 1390–8. doi:10.1183/09031936.00009709. PMID 19574336.
- ↑ Wali SO, Bahammam AS, Massaeli H, Pierce GN, Iliskovic N, Singal PK; et al. (1998). "Susceptibility of LDL to oxidative stress in obstructive sleep apnea". Sleep. 21 (3): 290–6. PMID 9595608.
- ↑ 31.0 31.1 31.2 31.3 31.4 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001). "Executive Summary of The 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)". JAMA. 285 (19): 2486–97. PMID 11368702.
- ↑ Grundy SM, Cleeman JI, Merz CN, Brewer HB, Clark LT, Hunninghake DB; et al. (2004). "Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines". Circulation. 110 (2): 227–39. doi:10.1161/01.CIR.0000133317.49796.0E. PMID 15249516.