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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.

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]

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]