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Biochemistry, Intermediate Density Lipoprotein
Introduction
Lipids are transported between cells through 5 types of lipoproteins, listed in order of increasing density: chylomicrons, very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). IDL particles are VLDL remnants formed after the partial removal of triglycerides in muscle and adipose tissue. These biomolecules represent an intermediate stage between LDL and VLDL in the catabolic cascade.
Recent studies suggest that IDL particles contribute to the progression of atherosclerotic plaques and an increased risk of adverse cardiovascular and cerebrovascular events.[1][2] IDL cholesterol may also be associated with a higher risk of other age-related diseases.[3] A deeper understanding of the biochemistry and clinical significance of IDL particles is essential for clinicians treating patients with age-related lipid metabolism disorders, including cardiovascular and cerebrovascular diseases.
Fundamentals
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Fundamentals
IDL particles are 25 to 35 nm in size and have a relative density of 1.006 to 1.019, which falls between the densities of VLDL and LDL particles.[4] The shape of these particles resembles that of VLDL, exhibiting polyhedral symmetry. Cholesteryl ester is the predominant lipid, comprising 60% of the core components, while triglycerides occupy the remaining low-density core. The hydrophilic membrane consists of a phospholipid bilayer, apolipoproteins, and unesterified cholesterol, forming the high-density shell.[5]
The apolipoproteins associated with IDL particles include the following:
- A single ApoB100: Facilitates hepatic secretion of VLDL and acts as a ligand for the LDL receptor (LDLR)
- Multiple ApoE units: Mediate hepatic clearance via LDLR and LDLR-related protein (LRP)
- ApoCI: Facilitates lecithin-cholesterol acyltransferase (LCAT) activation
- ApoCII: Mediates lipoprotein lipase (LPL) activation
- ApoCIII: Promotes LPL inhibition
The ApoE isoform ApoE2 is clinically significant due to its reduced affinity for LRP and LDLR. Poor binding of this isoform decreases hepatic clearance of IDL particles and elevates serum triglyceride levels.[6] ApoCIII is considered pathogenic, as it promotes atherosclerosis by delaying the clearance of ApoB-containing lipoproteins and prolonging their presence in plasma.[7]
Mechanism
IDL particles are formed through the LPL-mediated removal of triglycerides from VLDL. Hepatic lipase subsequently converts these particles to LDL. Thus, IDL represents an essential transition state and determines the cholesterol levels of circulating LDL particles.[8]
VLDL synthesis occurs in 2 steps. First, the scaffold protein ApoB100 undergoes partial lipidation by microsomal triglyceride transfer protein (MTP) during translation and transport to the rough endoplasmic reticulum, forming pre-VLDL particles. Lipidation is completed when pre-VLDL binds to triglyceride-rich particles from the smooth endoplasmic reticulum. These sequential steps are thought to be regulated by chaperone proteins, including protein disulfide isomerase and glucose-regulated protein 78.[9]
Incomplete lipidation results in ubiquitinylation and degradation of precursor particles, as seen in abetalipoproteinemia, a condition characterized by the loss of functional MTP, reducing the assembly of VLDL and chylomicrons.[10] In contrast, increased production and stability of these precursor particles occur in insulin resistance, which is associated with diabetes. Consequently, large VLDL particles are released, contributing to hypertriglyceridemia in patients with diabetes.[11]
Upon liberation in plasma, VLDL is degraded to IDL through the hydrolytic action of LPL on the capillary endothelium. LPL acts on VLDL triglycerides via its N-terminal domain, releasing free fatty acids, which are subsequently taken up by adipocytes or myocytes.[12]
ApoCII is essential to LPL activation. During the lipolytic process, ApoCII is transferred to HDL particles, leading to self-arrest of LPL activity. Approximately half of the newly formed IDL particles are taken up by hepatocytes through LDLR-ApoE-mediated endocytosis. Hepatic lipase, localized on the sinusoidal surface, functions independently of ApoCII and continues hydrolyzing triglycerides and phospholipids in the remaining IDL particles, ultimately leading to LDL formation. The fate of LDL particles largely depends on the number of LDLRs on the hepatocyte surface, as a reduced number of LDLRs is associated with decreased clearance and elevated LDL levels.[13]
Cholesteryl ester transfer protein (CETP), a plasma glycoprotein synthesized in the liver, facilitates the transfer of cholesteryl esters from HDL and LDL particles to VLDL particles in exchange for triglycerides. These VLDL particles are subsequently internalized by hepatocytes, providing an alternative pathway for cholesterol delivery to the liver. CETP levels are elevated in patients with metabolic syndrome.[14] The interaction between HDL, CETP, and LDL particles is believed to generate small, dense LDL particles, which contribute to atherosclerosis in patients with metabolic syndrome.[15]
Lipoprotein metabolism exhibits heterogeneity within each lipoprotein fraction, with multiple parallel biochemical pathways contributing to the formation of distinct lipoprotein subfractions, each with unique metabolic properties. For instance, VLDL consists of 2 subfractions, VLDL1 and VLDL2, that may be separated by ultracentrifugation. VLDL1, or large VLDL particles, primarily transport triglycerides and are implicated in insulin resistance and metabolic syndrome.[16] In contrast, VLDL2, or small VLDL particles, are cholesterol-rich and contribute to variations in LDL cholesterol levels. Elevated VLDL2 levels are observed in familial hypercholesterolemia.[17]
Ultracentrifugation can also separate IDL particles into 2 subfractions, IDL1 and IDL2. Alternatively, IDL particles may yield 3 midbands, midbands A (MIDA), B (MIDB), and C (MIDC), on electrophoresis. Larger IDL1 (or MIDB/C) particles are triglyceride-rich, whereas smaller IDL2 (or MIDA) particles are cholesterol-rich. Large IDL particles are associated with VLDL and may contribute to an increased risk of atherosclerotic cardiovascular disease (ASCVD). The functional heterogeneity within lipoprotein fractions likely explains the imperfect correlation between LDL cholesterol levels and the risk of macrovascular diseases.[18]
Testing
A routine lipid panel includes total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels. All parameters are measured directly except LDL cholesterol, which is calculated using the Friedewald equation. Fasting serum is preferred for accurate lipid profile assessment, as triglyceride levels increase after meals. Researchers hypothesize that LDL particles transfer cholesterol to triglyceride-rich lipoproteins in exchange for triglycerides via CETP following a meal. Consequently, a nonfasting state may underestimate LDL cholesterol levels, a key target for lipid-lowering therapy.[19][20]
However, total and HDL cholesterol levels do not vary significantly after eating and may still provide useful information without fasting. Measuring nonfasting triglyceride levels, also known as the oral lipid tolerance test (OLTT), may be beneficial for patients with hypertriglyceridemia, especially individuals at risk of pancreatitis. However, the clinical application of OLTT is limited due to the absence of standardized methods and reference ranges.[21]
In a routine lipid profile, IDL cholesterol is included in the calculation of LDL cholesterol using the Friedewald equation.[22][23] While most research has focused on the benefits of targeting LDL cholesterol, IDL cholesterol remains understudied, has limited clinical significance, and is rarely reported separately.
Analytical techniques such as ultracentrifugation and high-performance liquid chromatography (HPLC) have been used in studies to measure IDL cholesterol levels. Ultracentrifugation, considered the gold standard for lipoprotein separation, isolates particles based on density, sequentially separating VLDL, IDL, LDL, and HDL as density increases. HPLC differentiates particles by lipoprotein size, though overlap between fractions can occur. For example, IDL and LDL particles may not be completely separated due to size similarity. In such cases, anion-exchange HPLC may be used to improve fraction separation.[24] Other methods, including lipoprotein electrophoresis and overnight refrigeration tests, are rarely utilized except in cases of primary hyperlipoproteinemia.
In lipoprotein electrophoresis, neutral staining is performed after electrophoresis on a fasting serum sample, producing bands at the origin, pre-β, slow pre-β, β, and α regions. These bands correspond to the lipoprotein fractions of chylomicrons, VLDL, IDL, LDL, and HDL, respectively. Due to its longer turnaround time, lipoprotein electrophoresis remains underutilized in clinical practice. Nevertheless, this technique is critical in diagnosing primary hyperlipoproteinemia, where a routine lipid profile may provide ambiguous results.
The overnight refrigeration or standing plasma method involves visually assessing a sample stored upright at 4 °C for 12 to 24 hours. Chylomicrons, being the least dense lipoproteins, form a creamy supernatant, whereas VLDL particles create a cloudy infranatant. This method is a cost-effective screening tool for inherited hypertriglyceridemia.[25]
Pathophysiology
In vitro studies have demonstrated the presence of IDL particles in atherosclerotic plaques and their pathogenic role in atherosclerosis.[26] IDL particles possess the highest reactivity to arterial wall proteoglycans belonging to the ApoB lipoprotein fraction. The interaction between lipoprotein particles and arterial proteoglycans mediates the uptake of lipids in the macrophages, leading to the transformation of macrophages into foam cells within the intimal layer and promoting atherosclerotic plaque formation.[27]
IDL levels fluctuate due to various extrinsic and intrinsic factors. An increase may result from either accelerated production or impaired clearance of metabolites. Influx is influenced by the production and fractional catabolic rate (FCR) of VLDL particles, while efflux depends on hepatic lipase activity and hepatic clearance mediated by ApoE.
Both genetic and extrinsic factors influence IDL cholesterol levels. Genetic disorders, such as type III hyperlipoproteinemia and hepatic lipase deficiency, are linked to reduced IDL catabolism. Various comorbidities, including metabolic syndrome and diabetes, and medications like protease inhibitors can increase VLDL particle influx, elevating IDL levels.
Renal insufficiency also affects IDL cholesterol levels by altering hepatic activity.[28][29][30] A diet rich in saturated fatty acids and a sedentary lifestyle also impact IDL cholesterol levels, especially in individuals with an abnormal lipid profile.[31] A recent study associated red meat consumption with increased IDL particle concentration.[32] Environmental factors, such as air pollution, may further promote atherogenesis by enhancing the uptake of IDL cholesterol by macrophages.[33][34]
Triglyceride-rich lipoproteins, including IDL particles, contribute to the pathogenesis of metabolic syndrome. The combination of hypertension, diabetes, and atherogenic dyslipidemia in metabolic syndrome increases the risk of ASCVD. Triglycerides play a central role in this process, as hypertriglyceridemia develops in response to insulin resistance, leading to increased lipolysis in adipocytes and the release of nonesterified fatty acids (NEFAs) into the bloodstream.[35] Hypertension aggravates this rise in circulating NEFAs, which are key contributors to fasting triglyceride levels.[36][37] These fatty acids promote hepatic VLDL production and stability, with triglycerides undergoing further oxidation as VLDL is converted to IDL.[38]
IDL particles exhibit a reduced FCR and prolonged plasma residence in patients with metabolic syndrome.[39] Such tendencies may explain the association between IDL cholesterol levels and the progression of metabolic syndrome.[40] Lipid-lowering drugs, such as fibrates and statins, can enhance the FCR of IDL particles, lowering both IDL and LDL cholesterol levels. Therefore, these agents may be used to manage dyslipidemia in metabolic syndrome.[41][42]
Clinical Significance
As discussed, IDL particles are implicated in various inherited and acquired lipid metabolism disorders. These conditions are associated with an increased risk of ASCVD.
Dysbetalipoproteinemia
Dysbetalipoproteinemia, or type III hyperlipoproteinemia by Fredrickson, Levy, and Lees' classification, is a rare condition with a prevalence of 1 in 1,000 to 1 in 5,000. This disorder is associated with the production of the ApoE2 (Arg158Cys) isoform, which has a reduced affinity for LDL receptors and LDL receptor-related proteins, impairing hepatic clearance of IDL particles and chylomicron remnants. This impairment results in the accumulation of β-VLDL and IDL1.[43] LDL cholesterol levels may be low due to reduced conversion of IDL to LDL.
An autosomal recessive inheritance pattern is observed in up to 90% of cases. However, only 4% of individuals with the ApoE E2/E2 genotype develop the disorder, indicating low penetrance. Additional environmental and genetic factors are believed to contribute to the manifestation of dysbetalipoproteinemia.[44]
The condition is more common in men. Cutaneous features of dysbetalipoproteinemia include palmar and tuberoeruptive xanthomas, which may be seen in up to 50% of affected individuals. Palmar xanthomas are considered pathognomonic for type III hyperlipoproteinemia.[45] These lesions appear as yellow to orange macules along the palmar creases. Tuberoeruptive xanthomas present as inflammatory red papules or nodules on the elbows, knees, or buttocks, often coalescing into larger plaques. Similar lesions may also occur in individuals with type II hyperlipoproteinemia.[46]
Due to the proatherogenic nature of IDL particles, type III hyperlipoproteinemia is associated with a significantly increased risk of macrovascular disease. The risk of coronary artery disease in affected individuals is estimated to be approximately 10 times higher than in healthy controls.[47] Type III hyperlipoproteinemia is also associated with a high prevalence of peripheral artery disease.[48]
The initial approach to treating type III hyperlipoproteinemia involves dietary and lifestyle modifications. Recommendations include reducing carbohydrate and fat intake, with an emphasis on replacing saturated fats with unsaturated fats. Obesity, diabetes mellitus, and metabolic syndrome can influence the clinical course, necessitating evaluation and management of these conditions. Combination therapy involving statins and fibrates is the treatment of choice if the lipid levels remain elevated despite lifestyle modification.[49] Indicators of therapeutic response include a reduction in non-HDL cholesterol levels and the resolution of palmar xanthomas.
Hepatic Lipase Deficiency
Hepatic lipase deficiency is a rare dyslipidemic disorder associated with mutations in the hepatic lipase gene, including S267F and T383M. Although familial hepatic lipase deficiency is uncommon, heterozygous individuals carrying these mutations may exhibit clinical manifestations. Hepatic lipase facilitates the conversion of IDL to LDL and promotes the hepatic uptake of HDL. Deficiency of this enzyme results in elevated IDL cholesterol, VLDL cholesterol, and triglyceride content in LDL and HDL particles. Serum HDL cholesterol levels are also increased and inversely correlate with hepatic lipase enzymatic activity.[50]
The clinical presentation of hepatic lipase deficiency resembles that of type III hyperlipoproteinemia, but patients with hepatic lipase deficiency have normal ApoE lipoprotein levels. The absence of postheparin hepatic lipase activity distinguishes hepatic lipase deficiency from type III hyperlipoproteinemia.[51]
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