Lipids and lipoproteins in cardiovascular diseases: a classification
Authors: Shruti Bhargava, Sofia de la Puente-Secades, Leon Schurgers, Joachim Jankowski
Journal: Trends in Endocrinology and Metabolism (2022)

A new classification of lipids and lipoproteins based on their mechanistic impact on cardiovascular disease (CVD) and not only on their intrinsic function is urgently needed to discover new therapeutic opportunities, focusing on lipid classes impacting CVDs and not individual lipid subclasses.Lipids and lipoproteins classified under 'lipids and lipoproteins enhancing CVDs' lead to similar outcomes of CVD, and their synergistic effect should be targeted for CVD treatment.Lipids and lipoproteins are emerging as targeted drug delivery systems for drugs such as urokinase and tanshinone II.Lipids and lipoproteins are ideal imaging probes for atherosclerotic plaques and as in vivo trackers for diagnosis of CVDs. Lipids and lipoproteins, their metabolism, and their transport are essential contributing factors of cardiovascular disease (CVD) as they regulate plasma cholesterol concentration, enhancing cholesterol uptake by macrophages, leading to foam cell formation and ultimately resulting in plaque formation and inflammation. However, lipids and lipoproteins have cardioprotective functions as well, such as preventing oxidation of proatherogenic molecules and downregulating inflammatory proteins. Lipids and lipoproteins, their metabolism, and their transport are essential contributing factors of cardiovascular disease (CVD) as they regulate plasma cholesterol concentration, enhancing cholesterol uptake by macrophages, leading to foam cell formation and ultimately resulting in plaque formation and inflammation. However, lipids and lipoproteins have cardioprotective functions as well, such as preventing oxidation of proatherogenic molecules and downregulating inflammatory proteins. This review gives an update about our current knowledge of the mechanisms of lipid and lipoprotein subclasses impacting CVD and 'classifies' them on this basis as 'lipids and lipoproteins enhancing CVDs' or 'lipids and lipoproteins with a conditional impact on CVDs' or 'lipids and lipoproteins with no known effect on CVDs'. Low and dysfunctional high-density lipoprotein cholesterol (HDL-C), high low-density lipoprotein cholesterol (LDL-C), and elevated triglycerides (TGs) are the most common targets for reducing CVD risk, and therefore, the mechanisms by which they impact cardiovascular health are emphasised. Lipids have recently emerged as targeted delivery agents for therapeutic drugs and as imaging probes because they are localised within plaques, facilitating the targeted application of the drugs and probes. Recent studies show that liposomes and HDL-mimicking nanoparticles (HDL-NPs) have promising results in animal models and are now being extended to human trials. This review summarises our knowledge about the impact of lipids and lipoproteins on CVD genesis, progression, diagnosis, and treatment. CVDs are the leading causes of mortality worldwide [1.World Health Organisation Cardiovascular diseases (CVDs) fact sheet.2017Google Scholar]. Lipids and lipoproteins have a major impact on the genesis and progression of CVD by means of their cellular synthesis, transportation, assembly, degradation, oxidation, and plasma concentrations [2.Upadhyay R.K. Emerging risk biomarkers in cardiovascular diseases and disorders.J. Lipids. 2015; 2015971453Crossref PubMed Google Scholar,3.Yu X.H. et al.Cholesterol transport system: an integrated cholesterol transport model involved in atherosclerosis.Prog. Lipid Res. 2019; 73: 65-91Crossref PubMed Scopus (103) Google Scholar]. Traditionally, lipids are classified based on their function as 'storage lipids' [e.g., fatty acids (FAs), TGs, and sterols] or 'structural lipids' [e.g., phospholipids (PLs), glycolipids, and ceramides] (Figure 1A ) because lipids are essential for various physiological processes supporting biological life. A third group comprises the lipoproteins, subclassified into five types based on their density and size: chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), LDL, and HDL [4.Nelson D.L. et al.Lehninger Principles of Biochemistry. 4th edn. W.H. Freeman, 2005Google Scholar] (Table 1).Table 1Types of lipoproteins and their propertiesSizeDensity (g/cm3)ApolipoproteinsSurface composition (protein/phospholipids/free cholesterol in %)Core composition (triacylglycerols/cholesteryl esters in %)FunctionChylomicrons75–100<0.95A-I, A-II, A-IV, B-48, C-I, C-II, C-III, E2/7/385/3Transport of dietary exogenous core substances from the intestine to the tissuesVery low-density lipoprotein30–70<1.006B-100, C-I, C-II, C-III, E8/17/855/12Transport of endogenous core substances from the liver to the tissuesIntermediate-density lipoprotein25–401.006–1.019B-100, C-I, C-II, C-III, E17/22/922/30Transport of endogenous core substances from the liver to the tissuesLow-density lipoprotein17–251.019–1.063B-10022/17/89/44Transport of endogenous core substances from the liver to the tissuesHigh-density lipoprotein2–101.063–1.210A-I, A-II, C-I, C-II, C-III, D, E50/28/46/12Transport of endogenous cholesterol from the tissues to the liver Open table in a new tab Blood cholesterol level was identified as the first direct link between circulating lipids and CVD by the Framingham Heart Study (FHS) [5.Kannel W.B. et al.Factors of risk in the development of coronary heart disease – six year follow-up experience. 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The correlation of the TG/HDL ratio and cardiovascular risk compared with serum HDL levels is more accurate than individual values because it correlates with the negative impact of TGs and the positive impact of HDL on CVD. To assess CVD risk, specific lipids and lipoprotein concentrations in plasma are measured. Usually, LDL-C, non-HDL-C, and apolipoprotein B (ApoB) concentrations are correlated; hence, only LDL-C is the commonly quantified parameter, but it might underestimate the concentrations of the other lipids and lipoproteins, and therefore, a total lipid analysis accurately assessing CVD risk is highly recommended [16.Mach F. et al.2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.Eur. Heart J. 2020; 41: 111-188Crossref PubMed Scopus (2549) Google Scholar]. Because imbalances of lipids and lipoproteins play a major role in CVD genesis and progression, there is an increasingly evident need to classify them based on their mechanistic impact on CVD in order to find novel CVD prediction and treatment options. Therefore, there is an urgent demand for a new classification of lipids based on their impact on CVD. The synergistic effect of lipids with similar mechanistic outcomes is of high relevance for identifying potential therapeutic biomolecules for CVD prevention and treatment. Classification of lipids is necessary based on the mechanistic impact of lipids and lipoproteins on CVD, instead of the traditional classification of lipids that is based on their essential biological functions. Therefore, we suggest classifying lipids and lipoproteins into three novel categories: lipids and lipoproteins (i) enhancing CVDs, (ii) with a conditional impact on CVDs, and (iii) with no known effect on CVDs due to a lack of evidence (Figure 1B). This classification, which is in line with the current CVD treatment guidelines [16.Mach F. et al.2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.Eur. Heart J. 2020; 41: 111-188Crossref PubMed Scopus (2549) Google Scholar], reflects the current mechanistic knowledge of lipids affecting CVD discussing the major lipid classes that are vital for survival but are pathological only under altered concentrations (Figure 1A). In addition, HDL increase [17.Parolini C. et al.HDL therapy for the treatment of cardiovascular diseases.Curr. Vasc. Pharmacol. 2009; 7: 550-556Crossref PubMed Scopus (16) Google Scholar], LDL decrease [18.Stein E.A. Raal F.J. Lipid-lowering drug therapy for CVD prevention: looking into the future.Curr. Cardiol. 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LPA suppresses autophagy, leading to cardiac dysfunction and hypertrophy by activating the LPA receptor-3 and the protein kinase B/mammalian target of rapamycin signalling pathway [46.Yang J. et al.Lysophosphatidic acid is associated with cardiac dysfunction and hypertrophy by suppressing autophagy via the LPA3/AKT/mTOR pathway.Front. Physiol. 2018; 9: 1315Crossref PubMed Scopus (18) Google Scholar]. The lipids of this subclass have a profound effect on CVDs; however, the positive impact of this lipid subclass is conditional based on factors such as oxidation, presence of cofactors, and plasma concentration of other lipids. This section characterises these lipids, their impact on CVD, and the conditions that negate their cardioprotective effects. Remodelling of nascent HDL particles to mature HDL through the esterification of cholesterol by the enzyme lecithin-cholesterol acyltransferase, as well as by the transfer of additional cellular cholesterol to HDL by the cell surface transporter ATP-binding cassette subfamily G member 1, and the action of SR-B1, is essential for the prevention of atherosclerosis [47.Rader D.J. Hovingh G.K. HDL and cardiovascular disease.Lancet. 2014; 384: 618-625Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar,48.Zannis V.I. et al.Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL.J. Mol. Med. (Berl.). 2006; 84: 276-294Crossref PubMed Scopus (301) Google Scholar] (Figure 2C). Lipid-poor pre-β-HDL particles remove abundant cholesterol and oxLDL from macrophages via reverse cholesterol transport, which otherwise transforms them into foam cells having a proatherosclerotic effect [49.Rosenson R.S. et al.Dysfunctional HDL and atherosclerotic cardiovascular disease.Nat. Rev. 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High-density lipoprotein (HDL) dysfunction and the future of HDL.Curr. Vasc. Pharmacol. 2018; 16: 490-498Crossref Scopus (19) Google Scholar]. Oxidised cargo molecules, glycated ApoA-I, and high glucose reduce the anti-inflammatory activity of HDL particles and promote HDL dysfunction [54.Hedrick C.C. et al.Glycation impairs high-density lipoprotein function.Diabetologia. 2000; 43: 312-320Crossref PubMed Scopus (252) Google Scholar]. A comparison between the cardiovascular risk-predicting potential of HDL-related analytes such as ApoA-I, HDL subfractions HDL2 and HDL3, and the HDL particle number (HDL-P) results in HDL-P emerging as a better predictor of incident events [55.Mackey R.H. et al.High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (Multi-Ethnic Study of Atherosclerosis).J. Am. Coll. 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