Lipids (fats) are transported in the plasma as water-soluble lipoprotein particles. Each particle includes one or a set of highly conserved apolipoproteins that provide structural integrity for the complex, allow for its assembly and secretion, and provide a mechanism for receptor binding. The lipoprotein particles moving cholesterol through the plasma carry hydrophobic cholesterol esters and triglycerides in a central core, enveloped with an external layer of hydrophilic phospholipids and free cholesterol.
Lipoprotein particles are classified according to their size and density, with
- Chylomicron remnants
- Very low density lipoproteins (VLDL), being relative large and light
- Low density lipoproteins (LDL), particles which are smaller and heavier than VLDL. LDL particles are the main carrier of cholesterol to peripheral tissues where they are internalized through the LDL-receptor.
- High density lipoproteins (HDL), particles which are smaller and heavier than LDL. HDL particles removes fat molecules and cholesterol from cells and transports them back to the liver for excretion or re-utilization.
Apolipoproteins and lipoprotein particles
- Apo A is the major protein component of HDL particles in plasma and enables efflux of cholesterol by accepting cholesterol from cells of the tissues
- Apo B-100 is the primary apolipoprotein of chylomicrons, VLDL, intermediate-density lipoprotein particles and LDL-particles, and as much is responsible for transport of fat molecules to all peripheral cells
- Triglycerides play an important role as transporters of dietary fat and energy sources
- Lp (a) is an LDL-like lipoprotein particle consisting of one apo A molecule covalently bound to apo B-100.
The lipoprotein transport system serves the following functions:
- Transport of dietary fats from the intestine to the liver
- The secondary transport of processed cholesterol particles to peripheral tissues for membrane synthesis and steroid hormone synthesis
- The processing of free fatty acids which serve as a source of fuel.
Dyslipidemia, a genetic or multifactorial disorder of lipoprotein metabolism, is defined by elevations in levels of total cholesterol, low density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides, or some combinations thereof, as well as lower levels of HDL cholesterol (HDL-C) .
According to the National Cholesterol Education Program (NCEP) of the U.S. none of the following markers is appropriate for routine screening: Lp(a), lipoprotein remnants, small LDL particles, HDL subspecies, apolipoprotein B, and apolipoprotein A-I.
- Children, adolescents or young adults with a family history of dyslipidemia or premature atherosclerosis
- Lipid profiling in patients > 21 years of age at increased cardiovascular risk
- Lipid profiling in order to asses total cardiovascular risk in men > 40 and women > 50 years of age with one of the following conditions: type 2 diabetes, established cardiovascular disease (CVD), hypertension, smoking, BMI ≥ 30 kg/m2 or waist circumference > 94 cm for men, > 80 cm for women, family history of premature CVD, chronic inflammatory disease, chronic kidney disease, family history of familial hypercholesterolemia .
Serum, heparinized plasma, EDTA plasma: 1 mL
Fasting sampling may be considered:
- When non-fasting triglycerides are > 440 mg/dL (5.0 mmol/l)
- In patients with non-fasting concentrations of non-HDL-C ≥ 220 mg/dL (5.7 mmol/l) or triglycerides ≥ 500 mg/dL (5.7 mmol/l) that a fasting sample was needed to inquire into an underlying genetic disorder .
In situations for which fasting is preferred or may be required patients should fast for at least 8 h prior to blood collection.
Blood is collected from outpatients after 10–15 min. of rest in a seated position, since lipid levels are 12% higher in an upright position and 6% higher in a seated position than in a recumbent position. Approximately 2 min. of stasis causes an increase in lipid levels by up to 10%. Lipid levels are 5% lower in plasma than in serum .
Acute inflammation changes the lipid pattern, however, in acute myocardial infarction, cholesterol and LDL-C can still be evaluated within the first 8 h from the onset of infarction before the acute phase, during which LDL-C levels decline by up to 30%. If no previous results are known and LDL-C was not measured in blood collected within the first 8 h, a valid evaluation of lipid metabolism will not be possible until 8–12 weeks after the myocardial infarction.
Dyslipidemia is a genetic or multifactorial disorder of lipid metabolism. Elevations in levels of total cholesterol, LDL-C, and non-HDL-C are associated with the risk of atherosclerotic cardiovascular disease (ASCVD) in adults, as are lower levels of HDL-C and, to a lesser extent, elevated triglyceride levels .
Large-scale intervention studies document that 80–90% of patients with clinically significant ASCVD have at least one of the following four classic risk factors:
- Total cholesterol above 240 mg/dL (6.22 mmol/L)
- Systolic blood pressure above 140 mmHg (hypertension)
- Diabetes mellitus
The goals of the American College of Cardiology (ACC), the American Heart Association (AHA) Guidelines, and the European Society of Cardiology (ESC) the European Atherosclerosis Society (EAS) Guidelines are to prevent ASCVD and to improve the management of people who have these diseases /, /. Contributions arising from genetic and biochemical studies and observational epidemiological and ecological studies showed associated higher LDL-C levels with greater ASCVD risk. Besides life stile modification (i.e., adhering to a heart-healthy diet, regular exercise habits, avoidance of tobacco products, and maintenance of a healthy weight) statin therapy is an important tool to lower morbidity and total mortality when used as primary and secondary prevention.
1. Identification of patients with existing ASCVD.
2. Diagnosis of asymptomatic individuals with an increased risk for ASCVD. This includes:
- Individuals with multiple risk factors. These are individuals who have a ≥ 5% risk of mortality from ASCVD within the next 10 years or a > 20% risk of suffering a fatal or non-fatal myocardial infarction
- Patients with diabetes type 2 and type 1 with micro albuminuria
- Patients with a significantly elevated risk factor, in particular if it leads to end-organ damage.
3. Screening of near relatives of individuals with premature atherosclerosis for cardiovascular risk factors.’
4. Intensive statin therapy in certain groups of people.
The main genetic (primary) dyslipidemias that lead to ASCVD include:
- Familial hypercholesterolemia which occurs in up to 1 of 100 individuals in North America and Europe and includes highly elevated LDL-C levels, e.g., ≥ 190 mg/dL (4.92 mmol/l). Heterozygous familial hypercholesterolemia occurs in approximately 1 of every 200 to 500 individuals.
- PCSK9 dyslipidemia. PCSK9 is a critical regulator of cholesterol metabolism through its interaction with the hepatic LDL receptor. PCSK9 prevents recycling of the LDL receptor to the cell surface, thereby attenuating LDL-C clearance. Higher circulating PCSK9 levels predict lower catabolism of apolipoprotein B, the main constituent of LDL.
The multifactorial dyslipidemia is the main secondary dyslipidemia that leads to athrosclerotic cardio vascular disease (ASCVD). Multifactorial dyslipidemia is defined by levels of LDL-C ≥ 130 mg/dL (3.37 mmo/l), triglycerides ≥ 200 mg/dL (2.26 mmol/l) or both that are not attributable to familial hypercholesterolemia.
The risk for ASCVD is influenced by other factors not included among major, independent risk factors (cigarette smoking, hypertension, low HDL-C, family history of premature ASCVD). Diabetes is regarded as a ASCVD. Diabetes mellitus, metabolic syndrome and ASCVD are closely linked to dyslipidemia. Obesity is associated with slight elevations in LDL-C but more strongly related to elevated triglycerides and lower HDL-C.
- There is a linear relationship between the glucose concentration, in particular the 2-h value in the oral glucose tolerance test, and the risk of ASCVD. This also applies to HbA1c. The risk exists even with levels in the upper reference interval.
- The relative risk of ASCVD is approximately 1.5 times higher with impaired glucose tolerance, 2 to 4 times higher with diabetes, and can be even higher in women.
- The risk is related to diabetes and additional risk factors.
- Ideally, the development of diabetes should be prevented.
- Good metabolic control prevents microvascular complications.
- Goals for lipids are total cholesterol below 175 mg/dL (4.5 mmol/L), preferably below 150 mg/dL (4.0 mmol/L), and LDL-C below 70 mg/dL (1.8 mmol/L).
- Age above 45 years for men and above 55 years for women or premature menopause, are risk factors.
- Smoking is a risk factor.
- Hypertension above 140/90 mm Hg or antihypertensive treatment are risk factors.
- A positive family history of ASCVD is a risk factor.
- Total cholesterol and LDL-C are etiologically associated with ASCVD. The association is strong, independent, progressive and is the primary focus of treatment.
- Reduction of total cholesterol and LDL-C reduces the incidence of ASCVD and stroke. Recommendations for treatment targets are shown in
- In routine diagnosis, most dyslipidemias need not be differentiated, since there is only a limited number of therapeutic options. Therefore, in routine diagnostics only total cholesterol, triglycerides, LDL-C, and HDL-C need to be analyzed .
- Patients with any form of clinical ASCVD (including acute coronary syndrome, history of myocardial infarction, stable or unstable angina, coronary or other arterial vascularization, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin). High-intensity statin therapy.
- Patients over 21 years of age at increased cardiovascular risk without heart failure (NYHA class II, III, or IV) or end-stage renal disease and LDL-C ≥ 190 mg/dL (4.92 mmol/l). High-intensity statin therapy.
- Patients 40 to 75 years of age who have diabetes and LDL-C of 70 to 189 mg/dL (1.81 to 4.89 mmol/l). Calculate 10-year risk of ASCVD. If risk < 7.5% moderate-intensity statin therapy, if risk ≥ 7.5%, high intensity statin therapy.
- Patients 40 to 75 years of age who have no diabetes and LDL-C of 70 to 189 mg/dL (1.81 to 4.89 mmol/l). Calculate 10-year risk of ASCVD. If risk ≥ 7.5% moderate to high-intensity statin therapy.
The first three groups are considered high risk, and treatment should focus on high-intensity statin therapy. The last group does not automatically receive statin therapy, but is engaged in a risk discussion with their physician.
The 10-year risk of ASCVD is calculated with the use of the risk calculators available at or available at ). LDL particles are the main carrier of cholesterol to peripheral tissues where they are internalized through the LDL receptor, a crucial mediator of plasma LDL concentration. Genetic defects that result in loss of function within the LDL receptor are a major determinant of inherited dyslipidemis and ASCVD .
Following their separation by ultracentrifugation, the lipoproteins are differentiated into the following classes in order of increasing density: chylomicrons < very low density lipoproteins (VLDL) < low density lipoproteins (LDL) < high density lipoproteins (HDL). The following differentiation is made based on the velocity of electrophoretic migration toward the anode in an alkaline buffer medium: alpha fraction (contains HDL) > pre-β fraction (contains VLDL) > β-fraction (contains LDL) and > chylomicrons (remain at origin).
Fredrickson classified hyperlipoproteinemias into 6 phenotypes which do not represent a defined disease description . Each phenotype can have primary or secondary causes, and a single genetic defect can cause one or several phenotypes. Similarly, a single phenotype can be caused by different genetic defects. Therefore, the Fredrickson classification has been replaced by a differentiation between hypercholesterolemia, hypertriglyceridemia, and combined hyperlipoproteinemia, which is sufficient for therapeutic decision-making ().
There are few clinical symptoms. The following are indicative:
- Xanthelasma in younger patients
- Xanthomas (planar, tendinous, tuberous, eruptive, palmar)
- Arcus lipoides, lipemia retinalis
- Abdominal troubles (pancreatitis with hyperchylomicronemia)
- Joint inflammation due to precipitation of cholesterol crystals in the synovial fluid.
2. 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 2001; 285: 2486–97.
3. The task force for the management of dyslipidemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). ESC/EAS Guidelines for the management of dyslipidaemias. European Heart J 2011; 32: 1769–1818.
4. Nordestgaard BG, Langstedt A, Mora S, Kolovou G, Baum H, Bruckert E, et al. Fasting is not routinely required for determination of a lipid profile: Clinical and laboratory implications including flagging at desirable concentration cutpoints. A joint consensus statement from the European Atherosclerosis Society and European federation of clinical chemistry and laboratory medicine. Clin Chem 2016; 62: 930–46.
5. Stone NJ, Robinson JG, Lichtenstein AH, Bairy Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. Am J Coll Cardiol 2014; 63. 2889–934.
11. Talmud PJ, Shah S, Whittall R, Futema M, Howard P, Cooper JA , et al. Use of low density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic hypercholesterolemia. Lancet 2014´3; 381 (9874): 1293–1301.
14. deGoma EM, Ahmad ZS, O’Brien EC, Kindt I, Shrader P, Newman CB, et al. Treatment gaps in adults with heterozygous familial hypercholesterolemia in the United States data from the CASCADE-FH registry. Circ Cardiovasc Genet 2016; 9: 240–9.
15. Langsted A, Kamstrup PR, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. High lipoprotein (a) as a possible cause of clinical familial hypercholesterolemia: a prospective cohort study. Lancet Diabetes Endocrinol 2016; 4: 577–87.
17. Hegele RA, Ban MR, Hsueh N, Kennedy BA, Cao H, Zou GY, et al. A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia. Hum Mol Genet 2009, 18. 189–94.
22. Ingelsson E, Schaefer EJ, Contois JH; McNamara JR, Sullivan L, Keyes MJ, et al. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA 2007; 298: 776–85.
30. Wallace RB, Hoover J, Barrett-Connor E, Rifkind B, Hunninghake DB, Machenthun A, Heiss G. Altered plasma lipid and lipoprotein levels associated with oral contraceptive and estrogen use. Lancet 1979; ii: 111–5.
Due to its low water solubility, the movement of cholesterol through plasma is mediated by lipoprotein particles that carry hydrophobic cholesterol esters and triglycerides in a central core enveloped within an external layer of hydrophobic phospholipids and free cholesterol. Each lipid particle contains one or a set of apolipoproteins that provide structural integrity for the particle and a mechanism for receptor binding. The transport of cholesterol through plasma is mediated by apo B containing low-density lipoprotein particles (LDL) and apo A-containing high-density lipoprotein particles (HDL). Cholesterol is a moderate component of very-low-density lipoproteins (VLDL) and a minor component of chylomicrons .
Cholesterol is synthesized in almost all tissues in the body and is an essential component of cell membranes and a precursor for the synthesis of steroid hormones and bile acids. The sterol ring of cholesterol cannot be metabolized. Therefore, peripherally synthesized or intestinally reabsorbed cholesterol is transported to the liver and excreted directly or together with bile after being converted to bile acids.
LDL cholesterol (LDL-C)
Approximately two thirds of the cholesterol circulating in plasma is contained in LDL particles. Etiologically LDL-C is an important component in the initiation and progression of pathological changes in the vessel wall which lead to the formation of atherosclerotic plaques.
The atherogenic potential of LDL has been demonstrated in numerous epidemiological and clinical studies. Most studies show that, apart from age, LDL-C has the strongest association with the morbidity and mortality of atherosclerotic cardiovascular disease (ASCVD).
HDL cholesterol (HDL-C)
Approximately 25% of the cholesterol in serum is transported in HDL particles. HDL are responsible for the reverse transport of cholesterol i.e., the return of excess cholesterol from the macrophages back to the liver, from where it is excreted into the intestine via the biliary tract. In contrast to LDL, HDL is inversely associated with the occurrence of ASCVD. Low levels are associated with an increased risk of ASCVD.
In screening programs for athersclerotic cardio vasculardisease (ASCVD) risk the measurement of LDL-C and HDL-C is indicated instead of total cholesterol:
- In healthy adults (males < 40 years, females > 50 years) without clinical or medical history related risk factors for ASCVD
- In all patients with ASCVD risk factors e.g., diabetes prediabetes, metabolic syndrome, suspected stroke
- In children with a family history of dyslipidemia or ASCVD
- For monitoring lipid-lowering therapy.
Reference method: the primary reference method of the National Institute of Standards and Technology (NIST) in the USA is isotope dilution mass spectrometry (IDMS). The secondary reference method for cholesterol of the Centers for Disease Control (CDC) is a modification of the Abell-Kendall extraction method. The latter shows a positive bias of 1.6% compared to IDMS .
Principle: cholesterol is determined enzymatically by use of cholesterol esterase and cholesterol oxidase, with spectrophotometric quantization of either Δ4-cholestenone or H2O2 formed in the reaction sequence. Measurement via H2O2, preferably the peroxidase catalyzed formation of a purple quinone imine dye from phenol and 4-amino antipyrine has been adopted (Trinder reaction) .
Reference method: the Working Group of the National Cholesterol Education Program (NCEP) in the USA recommends using the CDC-HDL reference method. This is a multi-step assay involving ultracentrifugation during which VLDL and chylomicrons are separated. The HDL are selectively removed from the sediment fraction (D ≥ 1.006 kg/L) by precipitating the non-HDL-lipoproteins [IDL, LDL, Lp(a)] with magnesium heparinate. HDL-C is measured in the clear supernatant using the Abell-Kendall method .
Principle: the HDL-C assays use detergents, surfactants, or antibodies to modify the surface of chylomicrons, VLDL and LDL. The modified lipoproteins have reduced activity toward cholesterol oxidase and cholesterol esterase. HDL thus becomes a primary substrate for these enzymes, and its cholesterol content can be measured directly. If polyethylene glycol (PEG) and dextran sulfate are present in the reaction mixture, the enzymes cholesterol oxidase and cholesterol esterase are modified by PEG to exhibit selective activities toward the different lipoprotein fractions, with their reactivity in the fractions increasing in the following order: LDL < VLDL and chylomicrons < HDL. HDL-C is oxidized to Δ4 cholestenone and H2O2 by cholesterol oxidase.
Reference method: the CDC reference method for HDL-C is also used for LDL-C. After HDL-C has been extracted from the sediment fraction, cholesterol is measured in the remaining β-fraction (sediment fraction cholesterol minus HDL-C = LDL-C) .
Routine method: Homogeneous (direct) method
Principle: the LDL-C assays use detergents, surfactants, or antibodies to modify the surface of chylomicrons, VLDL and LDL. The modified lipoproteins have reduced activity toward cholesterol oxidase and cholesterol esterase. LDL thus becomes the primary substrate for these enzymes and its cholesterol content can be measured directly /, /. If a detergent is involved in the enzymatic measurement of cholesterol, its reactivities in the lipoprotein fractions increase in the following order: HDL< chylomicrons < VLDL < LDL. In the presence of Mg++, the enzymatic reaction of the cholesterol measurement (cholesterol esterase and cholesterol oxidase) is significantly reduced in the VLDL and chylomicrons. The combination of a sugar compound with detergent increases the selectivity of cholesterol oxidase for LDL-C.
- LDL-C (mg/dL) = cholesterol (mg/dL) – [HDL-C (mg/dL) + triglycerides (mg/dL)/5]
- LDL-C (mmol/L) = cholesterol (mmol/L) – [HDL-C (mmol/L) + triglycerides (mmol/L)/2.22]
Besides the direct determination of LDL-C, the Friedewald equation is commonly used to determine LDL-C. It has the following limitations:
- If triglycerides exceed 400 mg/dL (4.6 mmol/L) or the patient is not in a fasting state at the time of blood collection, chylomicrons, chylomicron remnants, or VLDL remnants will be present. As a result, the triglyceride/cholesterol ratio in the VLDL will be higher than 5 : 1, leading to overestimation of VLDL cholesterol and underestimation of LDL-C.
- A small number of patients have type III hyperlipidemia (remnant hyperlipidemia, dysbetalipidemia) in which cholesterol-rich VLDL are present. In these circumstances, VLDL cholesterol is underestimated, and consequently LDL-C is overestimated.
Compared with β-quantification, the new equation is more accurate than other LDL-C equations (slope, 0.964; RMSE = 15.2 mg/dL; R2 = 0.9648; vs Friedewald equation: slope, 1.056; RMSE = 32 mg/dL; R2 = 0.8808; vs Martin equation: slope, 0.945; RMSE = 25.7 mg/dL; R2 = 0.9022), particularly for patients with hypertriglyceridemia (MAD = 24.9 mg/dL; vs Friedewald equation: MAD = 56.4 mg/dL; vs Martin equation: MAD = 44.8 mg/dL). The new equation calculates the LDL-C level in patients with TG levels up to 800 mg/dL as accurately as the Friedewald equation does for TG levels less than 400 mg/dL and was associated with 35% fewer misclassifications when patients with hypertriglyceridemia (TG levels, 400-800 mg/dL) were categorized into different LDL-C treatment groups.
Non-HDL cholesterol (non-HDL-C)
Non-HDL-C (mg/dL) = cholesterol (mg/dL) – HDL-C (mg/dL)
Ratio = LDL-C (mg/dL)/HDL-C (mg/dL)
Serum, heparinized plasma, EDTA plasma: 1 mL
The Adult Treatment Panel III of the Expert Panel of the National Cholesterol Education Program (NCEP) in the USA and the European Guidelines on Cardiovascular Disease Prevention in Clinical Practice have defined a group of risk factors associated with atherosclerotic cardiovascular disease (ASCVD). They include elevated LDL-C, cigarette smoking, hypertension, decreased HDL-C, family history of early ASCVD, and age.
The total cholesterol concentration is a basic parameter which indicates whether further lipid metabolism assays need to be performed. Cholesterol levels ≥ 200 mg/dL (5.18 mmol/L) are associated with an increased risk of ASCVD. The risk increases with increasing cholesterol levels and in the presence of additional risk factors such as overweight, hypertension, smoking, insulin resistance, and diabetes mellitus. Hypercholesterolemia has a high prevalence in the population which increases with age. The majority of individuals with hypercholesterolemia are asymptomatic, but have additional risk factors of ASCVD. In screening programs, the total cholesterol level is recommended to be used to estimate total ASCVD risk by means of a score system. An individual with a 10-year ASCVD risk of 2% can have a cholesterol of 390 mg/dL (8.0 mmol/L) while another individual with a 10-year risk of 21% can have a cholesterol of only 193 mg/dL (5.0 mmol/L) .
The total cholesterol may be misleading, especially in women who often have high HDL-C concentrations and in patients with diabetes and metabolic syndrome who often have a low HDL-C level. For adequate risk analysis, at least HDL-C and LDL-C should be analyzed .
There is general consensus that ASCVD rarely occurs with cholesterol concentrations below 160 mg/dL (4.1 mmol/L), and that the risk of CVD increases moderately with concentrations equal to or above 190 mg/dL(4.9 mmol/L) and significantly with levels equal to or above 250 mg/dL (6.5 mmol/L) . For treatment and progress monitoring, it is important to know that the mean intraindividual coefficient of variation for cholesterol is 8% .
LDL-C has become a key criterion for the assessment of atherosclerotic cardiovascular disease (ASCVD) worlwide and for the management of such risk. As a consquence guidelines for ASCVD prevention focus on LDL-C targets as a function of the level of global risk in secondary prevention.
LDL particles are the main carrier of cholesterol to peripheral tissues where they are internalized through the LDL receptor, a crucial mediator of plasma LDL concentration. Genetic defects that result in loss of function within the LDL receptor are a major determinant of familiar hypercholesterolemia and risk of ASCVD .
The increase in LDL particles plays a central role in atherogenesis. The initial process is the subendothelial incorporation of apo B-containing particles within the intima of the vessels. In cases with elevated concentration of LDL particles in blood, an increasing number of LDL particles are incorporated within the intima where they bind to proteoglycan. Following oxidation and other modifications, the LDL particles are taken up by macrophages, causing these to transform into foam cells and start the atherosclerotic process. The higher a person’s LDL particle count, the higher their risk of ASCVD. The LDL-C concentration is a surrogate marker for LDL particle number.
For clinicians epidemiological evidence shows that elevated concentrations of LDL-C are associated with an increased risk of myocardial infarction and vascular death.
LDL-C cutoff values for adults
LDL-C cutoff values for children
- Borderline high 110–129 mg/dL (2.85–3.34 mmol/L)
- High ≥ 130 mg/dL (3.37 mmol/L).
LDL-C treatment guidelines for the use of statin therapy
The European Atherosclerosis Society Consensus Panel recommends LDL-C < 100 mg/dL (2.5 mmol/l) or < 70 mg/dl (1.8 mmol/l) in adults with ASCVD. For children < 135 mg/dL (3.5 mmol/l) . An LDL concentration of < 100 mg/dL (2.5 mmol/l) as the goal of therapy in secondary prevention is recommended in the Third Report of the National Cholesterol Education Program. The American College of Cardiology/American Heart Association Guidelines for the use of statin therapy in patients with increased ASCVD are shown in .
The Third Report of the National Cholesterol Education Program recommends that non-HDL-C (cholesterol minus HDL-C) be measured if triglyceride levels are above 400 mg/dl (10.3 mmol/L), because in this case HDL-C cannot be determined correctly using the Friedewald equation . Non-HDL-C comprises all apoprotein B-containing lipoproteins. According to the Lipoprotein Management in Patients with Cardiometabolic Risk consensus statement from the American Diabetes Association and the American College of Cardiology, non-HDL-C should be part of every lipid assay panel . Data from prospective studies show that non-HDL-C is better suited for primary prevention of atherosclerotic cardio vascular disease (ASCVD) than LDL-C . The National Cholesterol Education Program has defined the cutoff for non-HDL-C as 150 mg/dL (3.9 mmol/L). It has thereby, at its own discretion, set the target for non-HDL-C 30 mg/dL (0.8 mmol/L) higher than that for LDL-C under the argument that VLDL cholesterol is 30 mg/dL at the upper-threshold triglyceride level of 150 mg/dL (1.71 mmol/L).
HDL facilitates reverse cholesterol transport. In this process, free cholesterol from macrophages is transferred to HDL and transported to the liver where it is excreted into stool together with bile. HDL cholesterol (HDL-C) uptake into the liver is mediated either by the scavenger receptor or by the cholesterol ester transfer protein(CETP) mediated transfer of the cholesterol esters to apo B containing lipoproteins which are absorbed by the liver . In plasma there are multiple sub fractions of HDL that are differentiated by HDL size, density, and charge. The main sub fractions are HDL-3 and HDL-2. The main apolipoproteins in terms of quantity are apo A-I and Apo A-II.
Epidemiological studies have found an inverse relationship between the concentration of HDL-C and the risk of ASCVD . In the Framingham Heart Study, each 10 mg/dL (0.26 mmol/L) increase in HDL-C was associated with a 19% decrease in ASCVD mortality risk in men and a 28% decrease in women . The prevalence of low HDL-C concentrations, defined by the National Cholesterol Education Program guidelines as ≤ 40 mg/dL (1.04 mmol/L) in men and ≤ 50 mg/dL (1.30 mmol/L) in women, was found to be as high as 66% in high-risk patients with ASCVD, irrespective of their absolute levels below the cutoff values . The magnitude of HDL-C elevation above the threshold values is not an indicator of a higher protective effect with regard to CVD risk.
There are some congenital diseases in which HDL-C concentrations are reduced without there being an increased risk for ASCVD. These include lecithin-cholesterol acyl transferase deficiency, apo A-I Milano mutation, and Tangier disease (mutation of the ATP-binding cassette transporter A1).
Patients with ASCVD have smaller and denser HDL particles, while large particles are thought to be inversely associated with the risk of ASCVD. HDL particles can be differentiated into three size classes by nuclear magnetic resonance (NMR) spectroscopy. However, a study showed that individuals with very large HDL particles are at increased risk of ASCVD.
Although epidemiological studies indicated that higher HDL-C serum concentrations are associated with a reduced risk for cardiovascular events, a recent study documented that genetic mechanisms raising HDL-C plasma concentrations are not associated with a lower risk of ASCVD . The results of a study provide new evidence that the remodeling of the HDL proteome in patients with coronary heart disease has important functional implications with respect to the effects of HDL on endothelial cell survival.
Method of determination
Most LDL-C direct assays met the National Cholesterol Education Program total error goals for non diseased individuals. All assays failed to meet these goals for diseased individuals, however, because of lack of specificity towards abnormal lipoproteins .
- HDL-C can be performed on samples with triglyceride levels up to 1.200 mg/dL (13.6 mmol/l)
- Different specificity for LDL-C (recovery 87–105%)
- Levels are reported to be 6 mg/dL (0.15 mmol/L) lower than those calculated with the Friedewald equation
- VLDL cholesterol is partly included in the measurement
- 31–64% of IDL cholesterol is measured
- Lp (a) is included in the measurement at different degrees.
Limitations of the Friedewald equation are listed under . The equation proposed by Sampson et al for calculation of LDL-C has two major strengths: first it alows accurate determination of LDL-C over the range of triglyceride concentrations up to almost 800 mg/dL (9.1 mmol/L) and second, it provides relable estimation of LDL-C at concentrations well below 50 mg/dL (0.57 mmol/L)
Most HDL-C direct assays met the National Cholesterol Education Program total error goals for non diseased individuals. All assays failed to meet these goals for diseased individuals, however, because of lack of specificity towards abnormal lipoproteins .
The direct measurement of HDL-C has the following advantages and disadvantages:
- Elevated levels of immunoglobulins and monoclonal gammopathies (in particular IgM) , can lead to artificially increased HDL-C results
- Levels are reported to be 6 mg/dL (0.15 mmol/L) lower than those calculated with the Friedewald equation.
Plasma and serum can be stored for up to 4 days at 4 °C.
7. Sampson M, Ling C, Sun Q, Harb R, Ashmaig M, Warnik R, et al. A new equation for calculation of low-density lipoprotein cholesterol in patients with normolipidemia and/or hypertriglyceridemia. JAMA Cardiol 2020; 5. 540-8.
8. 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 2001; 285: 2486–97.
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24. Miller WG, Myers GL, Sakurabayashi I, Bachmann LM, Caudill SP, Dziekonski A, et al. Seven direct methods for measuring HDL and LDL cholesterol compared with ultracentrifugation reference measurement procedures. Clin Chem 2010; 56: 977–86.
Triglycerides, also called triacylglycerol or neutral lipids, are esters derived from glycerol and three mono carboxylic acids (esters of fatty acids). They have a mean molecular weight of 875 D. The lipids occurring in nature consist of triglycerides and small amounts of mono- and diacylglycerides.
In human adipose tissue, fatty acid esters mainly consist of even-numbered, unbranched mono carboxylic acids with 18 or 16 carbon atoms with or without double bonds, in particular oleic acid and palmitic acid. The triglycerides are poorly soluble in water and are transported in plasma bound to apolipoproteins. Triglycerides are mostly carried in chylomicrons, very low density lipoproteins (VLDL), and chylomicron and VLDL remnants.
Triglycerides and postprandial state
One of the main sources of the triglycerides circulating in postprandial plasma is dietary fat. The triglycerides are hydrolyzed into free fatty acids and glycerol, absorbed by the microvilli in the small intestine and repackaged into chylomicron particles via which they pass into the venous blood through the thoracic duct, bypassing the liver. From the bloodstream, the triglycerides are then deposited in adipose or muscle tissue where endothelial lipoprotein lipase removes the triglyceride component. The residual particles i.e., the chylomicron and VLDL remnants, which are rich in cholesterol esters, are released into the circulation and taken up by the liver.
Triglycerides and fasting state
In the fasting state, triglycerides and cholesterol are supplied to the tissues via the endogenous pathway. The liver forms VLDL particles and releases them into the circulation where the triglyceride component is removed by lipoprotein lipase. The VLDL remnants are either directly absorbed by the liver or converted to intermediate-density lipoproteins (IDL) and then taken up by the liver.
During lipoprotein electrophoresis, VLDL migrate in the pre-β-fraction (pre-β-lipoproteins) and chylomicrons remain at the application point.
Diagnosis of primary and secondary dyslipidemias
- Primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD)
- Risk marker of the metabolic syndrome
- Calculation of LDL-C using the Friedewald formula
- Monitoring of lipid-lowering dietary and drug therapy.
Serum, plasma: 1 mL
There has been the assumption that triglycerides should be measured in the fasting state because the levels of fasting triglycerides are lower and possibly less variable from measurement to measurement compared with triglycerides measured in the non fasting. However, recent large prospective studies reported that non-fasting triglycerides predict cardiovascular disease risk more strongly than the fasting triglycerides state .
- Triglycerides (fasting) ≤ 150 mg/dL (1.71 mmol/L)*
- Triglycerides (non-fasting) ≤ 175 mg/dL (1.98 mmol/L)
* This is the recommended upper threshold value.
Conversion triglycerides: mg/dL × 0.01129 = mmol/l
High triglycerides may promote atherosclerosis via the accumulation of triglyceride-rich remnant particles within the endothelium. Although smaller triglyceride-rich particles can cross the subintimal space and be found in atherosclerotic plaques, most plaque lipid is cholesterol ester not triglycerides.
It is often difficult to differentiate between primary and secondary hypertriglyceridemias. Secondary hypertriglyceridemias occur with many types of organ damage (e.g., hepatopathy, nephropathy, hypothyroidism, pancreatitis). Primary hypertriglyceridemias are less common than the secondary type .
Hypertriglyceridemia is due to an overproduction of chylomicrons and/or VLDL particles. Most cases result from increased concentrations of VLDL due to increased, often endogenous, synthesis. Elevated triglycerides are associated with a reduced concentration of HDL particles and smaller LDL and HDL particles.
High triglyceride concentrations are often associated with low HDL-C and high levels of dense LDL particles.
Triglyceride-rich lipoproteins are increasingly considered as a direct driver of atherosclerosis in diabetic patients.The atherogenic dyslipidemia is often comorbid with hyperglycemia and low HDL-C in patients with diabetes type 2, namely associated with obesity, insulin resistance, hyperinsulinism, and the metabolic syndrome .
Normal: ≤ 150 mg/dL (1.7 mmol/l)
- Borderline: 151–193 mg/dL (1.7–2.2 mmol/L).
- High: 194–480 mg/dL (2.3–5.5 mmol/L).
- Very high: 481–960 mg/dL (5.6–11.0 mmol/L).
- Severe: Above 960 mg/dL (11.0 mmol/L).
Following food intake, triglyceride level increases rapidly in the postprandial phase, peaks at 4 h and subsequently returns to baseline level within 8 h after food intake in women and within 9 h in men. From this point on, a metabolic state exists in which the triglycerides are only present in the form of VLDL particles and not as chylomicrons .
Severe hypertriglyceridemias occur predominantly with genetic dyslipidemias. In these cases, chylomicronemia (Fredrickson type I and V) is present and there is an increased risk of acute pancreatitis. Refer to .
Hypertriglyceridemia (type IV) is a disease of adulthood. type IV is often associated with the metabolic syndrome, diabetes mellitus and obesity. Triglyceride levels are generally 200–500 mg/dL (2.3–5.7 mmol/L).
The risk of acute pancreatitis in individuals with hypertriglyceridemia
- Is not confirmed by levels < 1,000 mg/dL (11.4 mmol/l)
- Is approximately 5% by levels > 1,000 mg/dL (11.4 mmol/l)
- Is 10–20% by concentrations > 2,000 mg/dL (23 mmol/l)
Levels of triglycerides > 500 mg/dL (5.7 mmol/l) are found at 5% of the population and concentrations > 1,000 mg/dL (11.4 mmol/l) at approximately 0.05% of the population.
- Abdominal obesity
- Triglycerides ≥ 150 mg/dL (1.71 mmol/L)
- HDL-C below 40 mg/dL (1.0 mmol/L) in men and below 50 mg/dL (1.3 mmol/L) in women
- Hypertension ≥ 130/85 or antihypertensive therapy.
- Fasting glucose ≥ 100 mg/dL (5.6 mmol/L).
High triglycerides may promote atherosclerosis via the accumulation of triglyceride-rich remnant particles within the vascular endothelium . An increase in the plasma concentration of triglycerides is an established risk factor for cardiovascular disease . This applies in particular if postprandial triglyceride levels are used as a criterion. The effect of triglycerides is independent of the concentration of LDL and HDL particles . Patients with high triglyceride levels > 2.212 mg/dL (25 mmol/L) and those with familial chylomicronemia syndrome rarely develop atherosclerosis, probably because their lipoprotein particles are too large to accumulate into the vascular intima.
In contrast, patients with moderate hypertriglyceridemia i.e., metabolic syndrome, familial hypertriglyceridemia and familial combined hypertriglyceridemia, and patients with elevated chylomicron remnants and VLDL remnants develop atherosclerosis more frequently, because they have smaller lipoprotein particles that are able to pass into the vascular intima .
Because these conditions are present in the post- prandial state, it is important that triglycerides are measured within about 4 h of food intake.
shows the hazard ratios of the Copenhagen Risk Study for cardiac ischemia, cardiac infarction and death as a function of postprandial hypertriglyceridemia. In Women’s Health study the postprandial triglyceride levels were divided into tertiles ≤ 104 mg/dL (1.19 mmol/L), 105–170 mg/dL (1.20–1.71 mmol/L) and ≥ 171 mg/dL (1.95 mmol/L). Compared to the first tertile, the hazard ratios for cardiovascular events were 1.44 (0.90–2.29) in the second tertile and 1.98 (1.21–3.25) in the third tertile.
Blood should be sampled in the fasting state. For cardiovascular risk assessment, blood withdrawal is best carried after 4 h of food intake.
The intraindividual variation for triglycerides is 19.7%.
Fresh serum is required.
Method of determination
In serum, free glycerol is present in a concentration of approximately 10 mg/dL (1.1 mmol/L). Free glycerol must be subtracted from total glycerol to obtain the component from the triglycerides. In healthy individuals, this correction may be within the limits of tolerable error. Patients with diabetes and hepatopathies can have hyperglycerolemia where falsely very high values of triglycerides are obtained. Therefore a blank measurement should be carried out without hydrolysis.
Free glycerol produced by spontaneous hydrolysis (e.g., when the sample is stored at room temperature for extended periods of time) should not be subtracted from the triglyceride value, since it comes from the triglycerides.
Elevated alkaline phosphatase levels in the patient sample can lead to falsely increased triglycerides. Therefore, special attention must be paid to pediatric samples.
Bilirubin and ascorbic acid interfere chemically and spectrophotometrically with assays using colorimetric indicator reactions, leading to a decrease in the triglyceride concentration.
Concentration remains unchanged if the sample is stored at 4 °C for 4 days.
2. 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 2001; 285: 2486–97.
3. White KD, Moorthy MV, Akinkuolie AO, Demler O, Ridker PM, Cook NR, Mora S. Identifying an optimal cutpoint for the diagnosis of hypertriglyceridemia in the nonfasting state. Clin Chem 2015; 61: 1156–63.
5. Hermans MP, Valensi P. Elevated triglycerides and low high-density lipoprotein cholesterol level as marker of very high risk in type 2 diabetes. Curr Opin Endocrinol Diabetes Obes 2018; Apr; 25 (2): 118–29.
7. Sundvall J, Laatikainen T, Hakala S, Leiviskä J, Alfthan G. Systematic error of serum triglyceride measurements during three decades and the effect of fasting on serum triglycerides in population studies. Clin Chim Acta 2008; 397: 55–9.
12. Tamir I, Heiss G, Glueck CJ, Christensen B, Kwiterovich P, Rifkind B. Lipid and lipoprotein distributions in white children ages 6–19 years: the Lipid Research Clinics Program Prevalence study. J Chron Dis 1981; 34: 27–39.
The electrophoretic separation of lipoproteins is based on the classification of hyperlipoproteinemias according to Fredrickson.
Differential diagnosis of dyslipoproteinemia, in particular type III hyperlipoproteinemia.
Principle: the lipoproteins are separated on agarose gel by migration toward the anode at alkaline pH . The lipoprotein fractions are then precipitated by poly anions in the gel and densitometrically quantified. The lipoproteins of the α-fraction correspond with HDL, those of the pre-β-fraction with VLDL and those of the β-fraction with LDL. Chylomicrons in serum remain at the application point of the serum.
Serum: 1 mL
Fresh serum is required. Heparin alters the mobility of the lipoproteins.
Lp(a) comprises an LDL particle covalently linked by disulfide bridges to the highly glycosylated apolipoprotein (a) called apo(a), which is under tight genetic regulation. Lp(a) has pro inflammatory, pro oxidative and atherothrombogenic properties. The plasma concentration of Lp(a) is determined by the rate of hepatic secretion of apo(a) that in turn is inversely related to the size of apo(a) and hence the copy number of genetic variants that encode the number of K-IV type 2 repeats of the apo(a) protein . This copy number variation in the of K-IV type 2 protein domain, encoding apo(a) isoforms of varying size, results in a varying number of up to about 40 copies of identical K-IV type 2 repeats. The plasma concentration of Lp(a) is determined by the rate of hepatic secretion of apo(a) and inversely related to the copy number of genetic variants that encode the number of K-IV type 2 repeats of the apo(a) protein .
Lp(a) is involved in various processes related to atherosclerosis and vascular disease, with an overall pro atherogenic effect that is similar to LDL-C, as well as having a prothrombotic effect. Studies demonstrate strong support for Lp(a) as a causal risk factor for atheroscleroticc cardiovascular disease (ASCVD). For ASCVD prevention it is important to determine whether it is high Lp(a) levels or the number of K-IV type 2 repeats that account for the increased risk of ASCVD associated with increased Lp(a) levels /, /.
- Premature ASCVD or stroke (without evidence of risk factors)
- Individuals of an intermediate risk group (according to Framingham, Procam, the ESC Heart score, Australian and New Zealand risk score). Patients should be re-stratified into a higher risk category if Lp(a) is elevated over 500 mg/L.
- Recurrent or rapidly progressive vascular disease (presence of various recognized risk factors)
- Familial genetic dyslipidemia or low HDL-C (grossly elevated LDL-C; presence of β-VLDL; reduced levels of HDL-C)
- Genetic defects of hemostasis, homocysteine metabolism, as well as diabetes or autoimmune diseases (defects in blood clotting or platelet aggregation, elevated levels of homocysteine; insulin resistance; phospholipid antibodies)
- Elevated ASCVD risk (10-year risk of fatal ASCVD ≥ 3% according to the EAS guidelines or ≥ 10% 10-year risk of fatal or non-fatal ASCVD according to EAS or US guidelines).
Lp(a) quantitative: immunoassay (ELISA, electroimmunoassay, immunonephelometric and immunoturbidimetric assays.
Serum: 1 mL
The European atherosclerosis Society (EAS )established the 80th percentile Lp(a) mass concentration as a target level for both primary and secondary prevention corresponding to below 500 mg/l . The National Lipid Association of the US recommends a treatment goal of Lp(a) mass > 500 mg/l . The ACC/AHA guidelines recommend no treatment goals .
An essential aspect of the Lp(a) molecule is the tail of the apo(a) moiety containing kringle proteins IV and V. Kringle IV consists of 10 subtypes or segments (numbered 1–10), of which subtype 2 has an individually variable number of copies (3–40). Levels of Lp(a) mass may vary up to a 1,000-fold between individuals . The length of kringle IV type 2 repeats is genetically determined and not influenced by life stile.
Prospective epidemiological studies have reported that increased serum levels of Lp(a) and fewer K-IV repeats are associated with increased risk of atherosclerotic cardio vascular disease (ASCVD) /, , /.
In Caucasians, the threshold for increased risk of ASCVD is reported to be as low as ≥ 75 nmol/L (approximately 200 mg/L). The thresholds used for Blacks are higher and those for Asians are lower than the thresholds for Caucasians. An even higher risk is reported when elevated Lp(a) levels are accompanied by additional risk factors such as elevated LDL-C, decreased HDL-C, and hyperfibrinogenemia .
A great number of reports were published examining the role of Lp(a) as a risk factor for atherosclerosis. A comprehensive meta-analysis of prospective studies found incidence rates of ASCVD in the top and bottom tertiles of baseline Lp(a) of 4,4 and 5,6 per 1,000 years. The authors concluded that a continuous independent and modest association of the Lp(a) concentration with the risk of ASCVD and stroke exists .
Initiation of statin therapy reduces LDL-cholesterol without a significant change in Lp(a). Associations of baseline and on-statin treatment Lp(a) with cardiovascular risk are approximately linear, with increased risk at LP(a) values of 500 mg/L. A study has shown the following results: initiation of statin therapy reduced LDL cholesterol by 39%, and the hazard ratios of cardiovascular events adjusted for age and sex were 1.04 for 150 to < 300 mg/L,1.11 for 300 to < 500 mg/L, and 1.31 for 500 mg/L or higher. A possible interpretation of the study indicated that in statin treated patients Lp(a) has an independent approximately linear relation with cardiovascular disease risk.
Lp(a) variants play an important role in the development of ASCVD. For example, the chromosomal regions 6q26–27 and 1p13 are strongly associated with the risk of ASCVD. The LPA locus of 6q26–27, which encodes Lp(a), shows the strongest association. Variants rs10455872 and rs3798220 of the LPA locus have an odds ratio for ASCVD of 1.70 (1.49–1.95) and 1.92 (1.48–2.49). Both variants are strongly associated with elevated Lp(a) levels, small Lp(a) particle size and a reduced number of LPA copies (these determine the number of type 2 kringle IV repeats) .
Particular attention should be paid to patients with renal disease and hemodialysis patients. They have a 2 to 3-fold increase in Lp(a). The most important next step is to treat traditional modifiable risk factors such as LDL-C, hypertension, smoking, diabetes, and obesity. Niacin and LDL apheresis can be used to lower Lp(a) in selected patients .
Comparison of LP(a)
In a study , Lp(a) serum concentrations using six different assays, providing Lp(a) in mg/dl or in nmol/L were measured. All assays relied of five-point calibations using calibrators provided by the manufacturers. While the imprecision of all assays was in an acceptable range, the actually obtained concentration due to calibration differed most likely due to biases. The assays applied produced remarkably different values obtained for the PRM-1 reference standard, which has assigned concentrations of 43.3 mg/dL or 96.6 nmol/L, respectively.
Based on the above reference method, a secondary reference material, SRM 2B, was developed. This material is the first WHO/IFCC reference reagent for Lp(a) for the calibration of immunoassays and allows the calibration on a molar basis. SRM 2B consists of Lp(a) isoforms of the three main apo A polymorphisms (containing 16, 17 and 18 KIV kringles, respectively) and three less common polymorphisms (containing 14, 20 and 34 KIV kringles, respectively) .
It is recommended that Lp(a) no longer be expressed as mass in mg/L but as concentration in nmol/L (1 mg/L corresponds to about 3.17 nmol/L) . The reason for this is the size heterogeneity of apo(a) and the resulting multitude of isoforms of Lp(a). Most Lp(a) immunoassay manufacturers use an antibody that detects the kringle IV type 2 epitope. As a result, the Lp(a) isotypes of individuals are detected differently which can lead to reduced or increased levels of Lp(a). The broad heterogeneity of Lp(a) results from the genetic coding of kringles IV and V. Apo(a), synthesized in different individuals, can have between 1 to 10 kringle IV repeats, and consequently the Lp(a) particle can vary in size. Therefore it is important to employ assays that are independent of the apo(a) polymorphism and use standards that are calibrated on a molar basis .
Lp(a) consists of an LDL-like core lipoprotein and glycoprotein apo(a) covalently linked by a disulfide bridge . The lipid core of Lp(a) is similar in structure and composition to LDL. The composition of Lp(a) is as follows: 30% protein, 35.5% cholesterol esters, 8.5% free cholesterol, 19.5% phospholipids, 2% triglycerides.
Apo(a), a highly polymorphic glycoprotein component of Lp(a), consists of repetitive protein segments, so called kringles that are highly homologous to kringle IV of plasminogen. One kringle contains 110 amino acids forming a secondary structure. In humans more than 40 genetically determined isoforms of apo(a) exist, giving rise to substantial size heterogeneity. There is an inverse correlation between the molecular weight of a given Lp(a) molecule and the number of type IV kringles. Individuals with a high apo(a) molecular weight have a low plasma concentration of Lp(a) while those with a low apo(a) molecular weight have a high plasma concentration of Lp(a). Apo(a) is produced almost exclusively in the liver and follows classical steps of glycoprotein biosynthesis .
Blood levels of Lp(a) are highly heritable and are chiefly determined by copy number variation at the LPA locus at chromosome 6.
Lipid oxidation is the hallmark of for atherosclerotic diseases. Lp(a) promotes the development of atherosclerosis because significant amounts of oxidized phospholipids that exert pro-inflammatory actions are bound to Lp(a). In the vessel wall Lp(a), via its apo(a) component, binds to glycoproteins such as laminin, induces the activation of inflammatory cells and smooth muscle cells and causes increased synthesis of alkaline phosphatase, which catalyzes a calcification process. The accumulation of Lp(a) in the vessel wall generally leads to increased proliferation and migration of inflammatory cells and smooth muscle cells and promotes the development of atherosclerotic plaques /, /. In addition, Lp(a) is an LDL-like particle that is capable of transporting significant amounts of cholesterol. As a rule of thumb, the amount of cholesterol Lp(a) transports corresponds to a third of its, measured as protein concentration (mg/L); at a concentration of 300 mg/L, Lp(a) contributes 100 mg/L of LDL cholesterol. From a pharmacological standpoint it is important to know that this amount cannot be corrected by statin therapy. Very high concentrations of Lp(a) can therefore be the reason for statin resistance.
Competing with plasminogen, Lp(a) can inhibit the binding of plasminogen to fibrinogen and fibrin as well as the activation of plasminogen to plasmin by the tissue plasminogen activator. This may be the reason why elevated Lp(a) is associated with an increased risk for venous thrombosis and stroke, at least in children and adolescents.
The Lp(a) level is a causal risk factor for ASCVD. It is important whether it is high Lp(a) levels or the number of kringle IV (K-IV) repeats [apo(a) isoform size] that account for the increased risk of ASCVD associated with increased Lp(a) levels. The results of a study suggest that absolute levels of Lp(a), rather than apo(a) isoform size, are the main determinant of ASCVD risk.
2. Hopewell JC, Seedorf U, Farrall M, Parish S, Kyriakou T, Goel A, et al. Impact of lipoprotein (a) levels and apolipoprotein (a) isoform size on risk of coronary heart disease. J Intern Med 2014; 276: 260–8.
3. Quin SY, Liu J , Jiang HX, Hu BL, Zhou Y, Olkkonen VM. Association between baseline lipoprotein (a) levels and restenosis after coronary stenting: meta-analysis of 9 cohort studies. Atherosclerosis 2013; 227: 360–6.
7 Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts GT, et al. European Athersclerosis Socienty consensus P. Lipoprotein (a) as a cardiovascular risk factor: current status. Eur Heart J 2010; 31: 2844–53.
8. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, et al. National lipid association recommendations for patient-centered management of dyslipidemia: part 1: executive summary. J Clin Lipidol 2014, 8: 473–88.
9. The task force for the management of dyslipidemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). ESC/EAS Guidelines for the management of dyslipidaemias. European Heart J 2011; 32: 1769–1818.
11. Tregout DA, König Ir, Erdmann J, et al. Genome-wide haplotype association study identifies the SLC22A3-L-PAL2-LPA gene cluster as a risk locus for coronary artery disease. Nat Genet 2009; 41: 283–5.
12. Stefanutti C, Julius U, Watts GF, Harada-Shiba M, Schettler VJ, Soran H, et al. Toward an international consensus- Integrating lipoprotein apheresis and new lipid-lowering drugs. J Clin Lipidol 2017; 11: 858–71.
14. Emerging Risk factors Collaboration. Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, et al. Lipoprotein (a) concentration and the risk of coronary heart disease, stroke and nonvascular mortality. JAMA 2009; 302: 412–23.
16. Marcovina SM, Albers JJ, Gabel B, Koschinsky ML, Gaur VP. Effect of the number of apolipoprotein (a) Kringle 4 domains on immunochemical measurements of lipoprotein (a). Clin Chem 1995; 41: 246–55.
17. Simo JM, Camps J, Vilella E, Gomez F, Paul A, Joven J. Instability of lipoprotein (a) in plasma stored at –70 °C: Effects of concentration, apolipoprotein (a) genotype, and donor cardiovascular disease. Clin Chem 2001; 47: 1673–8.
19. Marcovina SM, Koschinsky ML, Albers JJ, Skarlatos S. Report of the National Heart, Lung, and Blood Institute Workshop on Lipoprotein (a) and Cardiovascular Disease: recent advances and future directions. Clin Chem 2003; 49: 1785–96.
20. 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) final report. Circulation 2002; 106: 3143–421.
21. Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ, Fayad ZA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2010; 122e: e584–e636.
23. Willeit P, Ridker PM, Nestel PJ, Simes J, Tonkin AM, Pedersen TR, et al. Baseline and on-statin treatment lipoprotein (a) levels for prediction of cardiovascular events: individual patient data meta-analysis of statin outcome trials. Lancet 2018; 13; 392 (10155): 1311–20.
24. Scharnagl H, Stojakovic T, Dieplinger B, Dieplinger H, Erhart G, Kostner G, et al. Comparison of lipoprotein (a) serum concentrations measured by six commercially available immunoassays. Atherosclerosis 2019; 289: 206–13.
The movement of lipids through plasma is mediated by lipoprotein particles. Each particle typically contains a set of apolipoproteins that provide structural integrity for the complex. Apolipoproteins are synthesized in the liver and besides albumin and immunoglobulins, apolipoproteins are the third largest protein fraction in plasma.
Functions of the apolipoproteins include:
- Ligand for the interaction of lipoprotein particles with receptors of the cell membrane
- Activation or inhibition of enzymes of lipid metabolism.
Since apolipoproteins have an important function in lipid metabolism, their measurement should be important markers in risk prediction of atherosclerotic cardiovascular disease (ASCVD). However apolipoprotein determination provides no benefit beyond traditional lipid markers e.g., LDL-C and Lp(a), in prevention of ASCVD .
There are two isoforms of apo B in plasma: apo B-100 and apo B-48. The first isoform is synthesized in the liver and is the structural protein of VLDL and LDL. The latter is produced in the mucosa of the small intestine and is the structural protein of the chylomicrons. The plasma concentration of apo B-48 barely exceeds 5% of total apo B.
In fasting plasma, 90–95% of apo B is present in LDL and 5–10% in VLDL. Consequently, the apo B concentration is a good indicator of the LDL concentration. Since each LDL particle contains only one apo B molecule, the apo B concentration is also an indicator of the number of LDL particles.
Serum: 1 mL
Data expressed in g/L; interval values are 5th and 95th percentiles.
* Related to the IFCC reference preparation SP3-07 (WHO International Reference Reagent) for apolipoprotein B.
Apo B is the major apolipoprotein of the atherogenic lipoprotein families LDL, IDL, and VLDL. The level of apo B is a good representative of the number of circulating LDL particles, since apo B accounts for 95% of the total protein content of LDL and each LDL particle contains only one apo B molecule . Prospective studies have shown that the number of LDL particles is an important factor in atherogenesis and the concentration of apo B is a more representative biomarker of the particle number than the concentration of LDL-C. Apo B has been shown in several prospective studies to be equal to LDL-C in risk prediction of ASCVD.
The major disadvantages of apo B are:
- that it is not include in algorithms for calculation of global risk of ASCVD
- it has not been a pre-defined treatment target in controlled trials
- it has not been evaluated as a primary target in statin trials.
Routine assays measure either total apo B (apo B-100 plus Apo B-48) or apo B-100 alone.
Serum can be stored for at least 3 days at 4 °C. In the presence of antibiotics and antioxidants, apo B will remain stable for at least 6 months at –20 °C. Frozen storage at –80 °C is preferable.
Apo A-1 is the main structural protein of HDL. It is synthesized in the intestinal mucosa and in the liver and induces the efflux of cholesterol from cells. Apo A-1 activates the enzyme lecithin-cholesterol acyl transferase.
- Detection of atherosclerosis risk, in particular as part of the apoB/apoA-I ratio.
- Characterization of rare HDL deficiency syndromes.
Serum: 1 mL
Data expressed in g/l; interval values are 5th and 95th percentiles.
* Related to the IFCC First International Reference Material for apo A-I.
The concentration of apo A-I correlates well with the level of HDL particles and the HDL-C concentration . If HDL-C cannot be measured in serum that is turbid due to hypertriglyceridemia, apo A-I can be determined as an alternative.
If HDL cholesterol is very low or not detectable, the concentration of apo A-I can provide etiological clues, although without allowing a diagnosis. With apo A-I deficiency, apo A-I is not detectable. In patients with Tangier disease apo A-I is often below 10 mg/L, and with LCAT deficiency it is generally in the range of 40–50 mg/L.
Serum can be stored for at least 3 days at 4 °C. In the presence of antibiotics and antioxidants, apo B will remain stable for at least 6 months at –20 °C. Frozen storage at –80 °C is preferable.
Apo E mediates the uptake of chylomicron remnants and VLDL remnants in the liver and is involved in the transformation into LDL particles. Apo E is a ligand for the LDL receptor. Apo E shows a genetic polymorphism and occurs in three alleles (epsilon 2, epsilon 3, and epsilon 4) which encode six phenotypes: Apo E2/2, E2/3, E2/4, E3/3, E3/4, E4/4.
The binding of apo E to the LDL receptor is an important mechanism for clearing remnants from the circulation.
Diagnosis of hyperlipoproteinemia type III, in particular apo E2 homozygosity.
Quantification of apo E
Phenotyping of apo E
Immunoblotting following isoelectric focusing.
Genotyping of apo E
DNA hybridization of allele-specific PCR.
Serum: 1 mL
Percentiles 2.5 and 97.5
Data expressed in mg/L
The determination of apo E and the apo E/apo B ratio are criteria for the diagnosis of hyperlipoproteinemia type III. This type of hyperlipoproteinemia is suspected if cholesterol and triglyceride levels are between 250 mg/dl and 800 mg/dL and lipoprotein electrophoresis detects a broad β-band. The band is sensitive, but not very specific. Clinically, 50% of cases present with cutaneous xanthomas.
Hyperlipoproteinemia type III is caused by a dysfunctional isoform of apo E, a glycoprotein with a molecular weight of 34 kDa. Over 90% of type III patients are homozygous for the E2 isoform. Lipoprotein particles with this isoform do not bind to the apolipoprotein B, E receptors, resulting in delayed clearance of chylomicron and VLDL remnants from the plasma. A study showed an apo E/apo B ratio of 0.056 ± 0.037 in controls and of 0.197 ± 0.073 in type III patients.
However, the apo E2/2 phenotype is far more common than hyperlipoproteinemia type III. Therefore, other genetic, metabolic or environmental factors (e.g., diabetes mellitus, hypothyroidism or LDL receptor mutation) play a significant role in the severity of hyperlipoproteinemia type III.
1. The task force for the management of dyslipidemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). ESC/EAS Guidelines for the management of dyslipidaemias. European Heart J 2011; 32: 1769–1818.
2. Contois JH, McNamara JR, Lammi-Keefe CJ, Wilson PWF, Massov T, Schaefer EJ. Reference intervals for plasma apolipoprotein B determined with a standard commercial immunoturbidimetric assay: results from the Framingham Offspring study. Clin Chem 1996; 42: 515–23.
3. Contois JH, McConnell JP, Sethi AA, Csako G, Devaraj S, Hoefner DM, Warnick GR. Apolipoprotein B and cardiovascular disease risk: position statement from the AACC Lipoproteins and Vascular Disease Division Working Group on Best Practices. Clin Chem 2009; 55: 407–19.
4. Contois JH, McNamara JR, Lammi-Keefe CJ, Wilson PWF, Massov T, Schaefer EJ. Reference intervals for plasma apolipoprotein A-I determined with a standard commercial immunoturbidimetric assay: results from the Framingham Offspring Study. Clin Chem 1996; 42: 507–14.
Intravenous administration of heparin causes the endothelium to release the triglyceride lipases lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL). Both enzymes act as clearing factors and ensure that the tissues are supplied with free fatty acids via the hydrolysis of triglyceride-rich lipoprotein particles and HDL.
LPL (EC 220.127.116.11), an enzyme with glycerol ester hydrolase activity, is located on the endothelium surfaces of extrahepatic capillaries, in particular in adipose tissue and skeletal and heart muscles. The enzyme catalyzes the hydrolysis of lipoprotein associated triglycerides, yielding free fatty acids (FFS) for supply of the tissues.
LPL is not actually produced by the endothelia, but by adipocytes and muscle cells, and is transported to the endothelia of the vessels via transcytosis on the luminal side. LPL is activated by apolipoprotein C-II and regulated mainly by insulin. In the postprandial phase the LPL activity of adipose tissue is high in order to store the FFS produced after food ingestion in the tissues. In the post absorptive phase it is high in muscle in order to provide sufficient FFS to supply the myocytes with energy under load .
Clinical symptoms such as recurrent upper abdominal pain (pancreatitis), eruptive xanthomas, hepatosplenomegaly, lipemia retinalis, in particular in children.
The lipolytic activity of LPL is triggered by injection of 60–100 U of heparin/kg of body weight. Blood is collected 10 min (15 min) after injection. LPL activity is measured in the amount of radio labeled fatty acids released from glycerol-tri-[1-14C] oleate substrate per time unit following inhibition of HTGL with sodium dodecyl sulfate (SDS) .
EDTA plasma, cool and centrifuge, deep-freeze and transport to laboratory: 2 mL
LPL activities of less than 25% of normal values indicate LPL deficiency which, however, needs to be confirmed by molecular genetic analysis. In heterozygous mutation carriers, LPL activity is reduced to half of normal values and triglycerides are only slightly to moderately elevated.
At least 3 months at –70 °C.
HTGL (EC 18.104.22.168) is located on the capillary endothelia of liver cells and, like LPL, is released by heparin. Its function is the hydrolysis of triglyceride-rich lipoproteins and the degradation of HDL particles, in particular HDL2. It is measured analogously to LPL, but LPL is inactivated by NaCl 1.0 mol/L. Genetic HTGL deficiency is very rare.
Two thirds of cholesterol in plasma is esterified with free fatty acids. This is mediated by LCAT (EC 22.214.171.124), which is synthesized in the liver. The cofactor is apo A-I. LCAT plays a key role in the metabolism of lipoproteins, in particular HDL.
Suspected LCAT deficiency or fish-eye disease, if the following symptoms are present: low HDL, cloudy cornea, renal dysfunction, hemolytic anemia, xanthomas.
The transfer of fatty acids (e.g., oleic acids) to radioactive cholesterol from phosphatidylcholine is measured. This was either equilibrated with endogenous lipoproteins (cholesterol esterification rate) or obtained in the form of apo A-I, phosphatidylcholine and cholesterol-containing artificial HDL, to which exogenous plasma was added (LCAT activity in a narrower sense).
Plasma, cool and centrifuge, deep-freeze and transport to laboratory: 2 mL
In classic LCAT deficiency, LCAT can neither esterify cholesterol equilibrated with endogenous lipoproteins nor unesterified radioactive cholesterol added in the form of exogenous HDL.
In fish-eye disease (partial LCAT deficiency), this endogenous cholesterol esterification rate is normal, but the LCAT activity proper measured with exogenous proteoliposomes is reduced.
1 week at 4 °C, long-term storage requires a temperature of –20 °C.
The low-density lipoprotein receptor (LDL receptor) is a glycoprotein of the cell membrane consisting of 839 amino acids. The receptor binds apo B-100 and Apo E. The receptor is synthesized as a precursor protein in the endoplasmic reticulum and transported to the cell membrane within 45 min. After the binding of LDL, an endocytotic vesicle is formed within 3 to 5 min. which transports LDL to the inside of the cell where it is then released.
The synthesis of the LDL receptor is encoded by the LDLR gene located on chromosome 19. More than 1,000 mutations of the LDLR gene have been identified in patients with familial hypercholesterolemia. The resulting functional defects of the receptor are differentiated into 5 classes :
- Defect in the expression of protein synthesis
- Impaired transport of the receptor from the endoplasmic reticulum to the cell membrane
- Defective receptor binding of apo B and apo E
- Defective internalization of the receptor
- Defective recycling of the receptor.
Type II hyperlipoproteinemia with tendon xanthomas and suspected familial hypercholesterolemia.
Determination of the binding of radio labeled LDL particles to cultured fibroblasts in the patient.
An alternative method is the flow cytometric measurement of LDL receptors on the surface of monocytes as well as sequencing of the LDL receptor gene.
Skin biopsy sample from which fibroblasts are derived.
EDTA blood: 5 mL
Homozygous patients with familial hypercholesterolemia exhibit only little binding activity compared to normal controls. Heterozygous mutation carriers, in contrast, exhibit 50–60% binding activity.
Lipids include free fatty acids, neutral glycerides, free cholesterol, cholesterol esters, glycerophospholipids, sphingolipids, and glycolipids. None of these lipids have significant aqueous solubility and so their carriage from blood into and through tissues acquires an association with proteins. A lipoprotein transport system and lipid transfer system are differentiated .
Proteins with which the lipids associate are plasma lipoproteins, such as chylomicrons, chylomicron remnants, VLDL, and LDL. Although these lipoproteins are remodeled in the plasma by transfer proteins, their uptake into cells and tissues is mediated by specific receptors e.g., LDL receptor. The receptors primarily recognize protein of the lipoprotein particle as ligand . Refer also to .
- Proteins that mediate the assembly and metabolisms of lipoproteins
- Proteins which are engaged in the distribution of lipids within the cell and that may modify the lipid composition of individual cellular membranes
Lipids from diet, mostly triglycerides and cholesterol esters in the intestinal lumen are hydrolyzed yielding free fatty acids and free cholesterol. These products enter the enterocyte and are re-sythesized into triglycerides and cholesterol esters. The triglycerides are either packaged into lipoprotein particles containing the apolipoprotein Apo B48, or are stored as droplets that may later be mobilized for the assembly of chylomicrons . The coupling of triglycerides with apo B48 is mediated by the microsomal triglyceride transfer protein (MTTP). The surface of the chylomicron is coated by a monolayer of phospholipid that is mediated by the phospholipid transfer protein (PLTP) :
Free cholesterol in the intestinal lumen is released by the hydrolysis of dietary cholesterol ester and taken up into the enterocyte mediated by the Niemann-Pick C1 Like-1 (NPC1L1) transfer protein. The enterocyte is also a source of HDL particles. About 30% of the HDL particles in plasma are generated via the action of the ABCA1 transporter providing glycerphospholipid and cholesterol to the nascent HDL particle .
Circulating lipoprotein particles are complexes including a hydrophobic core of triglyceride and/or cholesterol ester. The surface contains amphipathic phospholipids, free cholesterol, apo B or a set of exchangeable apoproteins. Lipoproteins transport dietary fats from the intestine to the liver and the processed particles to the peripheral tissues. Before entering the cells plasma lipoprotein particles are remodeled by the exchange of their surface components. The core components are remodeled mediated by the cholesterol ester transfer protein (CETP). The CETP mediates the exchange of cholesterol ester for triglycerides between HDL and VLDL and LDL. Individuals lacking CETP have elevated levels of HDL-C and low levels of LDL-C .
The metabolism of lipoprotein particles in blood is divided into an exogenous and endogenous pathway and reverse lipid transport.
This transport takes place in the postprandial phase, starting in the small intestine (). After dietary lipids, mainly triglycerides, have been hydrolyzed, they are absorbed by the mucosa of the small intestine and resynthesized by mucosa cells and packaged into chylomicrons together with a set of apolipoproteins (A-I, A-IV, B, C, E).
Bypassing the liver, the chylomicrons pass into blood via the thoracic duct. In blood they are present only during the post- prandial phase i.e., for up to 4 h following food ingestion. The presence of apo C-III in the chylomicrons prevents premature interaction of these triglyceride-rich particles with the liver.
The triglycerides of the chylomicrons are consecutively hydrolyzed to chylomicron remnants in the tissues, in particular adipose tissue and muscle, by lipoprotein lipase (LPL) at the surface of the capillary endothelium. The activation of LPL is mediated by apo C-II of the chylomicrons. The hydrolyzed fatty acids are available as energy sources for muscle and adipose tissue ().
The resulting chylomicron remnants are cleared by the liver through LDL receptor mediated endocytosis. The binding to the receptor is mediated by apo E.
In the fasting state (at least 8–9 h after food ingestion), the endogenous pathway supplies the tissues with triglycerides and cholesterol (). The liver releases triglyceride-rich VLDL particles containing apo B-100 and apo E into the blood. Like the chylomicrons, the triglycerides of VLDL are also hydrolyzed by the enzyme LPL, leaving VLDL remnants (intermediate-density lipoproteins, IDL). Due to the apolipoprotein E, one part of the IDL bind to the LDL receptor, mainly of the liver, and enter the hepatocytes. The other part is remodeled into LDL-particles and taken up by the liver via the LDL receptor. The ligand for the LDL receptor is apo B-100. About two thirds of the cholesterol in the blood is transported by LDL particles, and three quarters are converted to bile acids following absorption by the liver via the LDL receptor, or directly excreted into the gall bladder. The remainder of dietary cholesterol or synthesized daily serves for steroid hormone production and membrane synthesis.
The reverse transport of excess cholesterol from the peripheral tissues, in particular macrophages, to the liver starts with the synthesis of pre-β HDL particles, in particular in the liver and the enterocytes of the small intestine. The pre-β HDL particles consist of apolipoprotein A-I and phospholipids. They are loaded with phosphatidylcholine and free cholesterol from cell membranes by the ATP-binding cassette transporter A1 (ABCA1) (). Cholesterol is then esterified in the resulting discoidal HDL, catalyzed by lecithin-cholesterol acyltransferase (LCAT). This results in small dense particles (HDL3) which grow in size as they are loaded with lipids from cells and lipoproteins (HDL2). Part of the HDL are taken up by the liver via the scavenger receptor BI, while another part is transferred to triglyceride-rich lipoprotein particles mediated by cholesterol ester transfer protein (CETP), and the remnants or LDL are absorbed by the liver.
5. Contois JH, McConnell JP, Sethi AA, Csako G, Devaraj S, Hoefner DM, Warnick GR. Apolipoprotein B and cardiovascular disease risk: position statement from the AACC Lipoproteins and Vascular Disease Division Working Group on Best Practices. Clin Chem 2009; 55: 407–19.
6. Charlton-Menys, Betteridge DJ, Colhoun H, Fuller J, France M, Hitman GA, et al. Targets of statin therapy. LDL cholesterol, non-HDL-cholesterol, and apolipoprotein B in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS). Clin Chem 2009; 55: 473–80.
The upper reference values for children are according to the National Cholesterol Education Program 1992: LDL-C < 130 mg/dL (3.36 mmol/L), triglycerides < 200 mg/dL (2.26 mmol/L).
LDL-C mg/dL (mmol/L) at which to initiate TLC
LDL-C mg/dL (mmol/L) at which to consider therapy
NCEP, National Cholesterol Education Program of the USA; risk assessment in% according to Framingham or PROCAM score
Clinical and laboratory significance
95th Percentile. Data expressed in mg/dl (mmol/l)
Explanation of symbols: LP, lipoprotein; HLP, hyperlipoproteinemia, N, normal; 1+ slightly elevated; 2+ moderately elevated; 3+ markedly elevated; 4+, severely elevated
Following lipid measurement, keep serum refrigerated overnight. Serum is clear if only LDL are elevated (type IIa), and homogenously turbid if VLDL or remnants (IDL) are elevated (types IIb, III or IV). If chylomicrons are present, the serum has a milky white, creamy top layer (type I). Differentiation of type III requires lipoprotein electrophoresis.
Hazard ratio (women)
Hazard ratio (men)
LCAT, lecithin-cholesterol acyltransferase; *serum concentration expressed in mg/dL;
MW, molecular weight
Figure 4.2-2 American College of Cadiology/American Heart Association guidelines for the use of statin therapy in patients with increased atheroscleotic vascular risk (ASCVD). Modification according to Ref.
Figure 4.9-1 Exogenous and endogenous pathway of lipoprotein metabolism. Dietary lipids absorbed in the intestine are packaged into chylomicrons in the mucosa of the small intestine. In the blood, lipoprotein lipase (LPL) cleaves off free fatty acids (FFS), which are metabolized by the peripheral tissues. The remaining chylomicron remnants are taken up by the liver. In the endogenous pathway, VLDL are released by the liver, and free fatty acids are cleaved from them by lipoprotein lipase (LPL), resulting in VLDL remnants (intermediate density lipoproteins, IDL), which are either taken up by the liver via the remnant receptor or are converted to low density lipoproteins (LDL) by hepatic lipoprotein lipase (HL).
Figure 4.9-2 Metabolism of triglyceride-rich chylomicrons and VLDL by heparin-sensitive (endothelial) lipoprotein lipase (LPL) in blood . FFS, free fatty acids; 2-MG, 2-monoacylglycerol, HDL, high density lipoprotein, VLDL, very low density lipoprotein.
Figure 4.9-3 Reverse transport of cholesterol by HDL particles. Lipid-poor apo A-I takes up free (non-esterified) cholesterol (FC), (e.g., from macrophages) via the ABCA1 transporter, forming a discoidal particle. This particle takes up further FC from the peripheral tissues, which is converted to cholesteryl ester (CE) by lecithin-cholesteryl acyltransferase (LCAT). The discoidal HDL particle becomes spherical. The HDL particle is either taken up by the hepatic SR-BI receptor, or the cholesteryl ester transfer protein (CETP) transfers CE from HDL to LDL and VLDL particles in exchange for triglycerides (TG), resulting in the HDL particles becoming small and dense. The apo B containing particles are taken up by the LDL receptor (LDL-R) of the liver which then eliminates the cholesterol.