Egg yolk, source of bad cholesterol and good lipids?

The association between dietary cholesterol and atherosclerotic cardiovascular disease (ASCVD) has been controversial. Since the Framingham Heart Study found in the mid-20th century that elevated serum cholesterol concentrations were strongly linked with the risk of cardiovascular disease, there have been continued efforts to explore the effects of dietary cholesterol intake on serum cholesterol concentrations and cardiovascular disease. A large meta-analysis of prospective cohort studies found that dietary cholesterol increased both serum total cholesterol and LDL cholesterol, but no statistically significant association was found with coronary artery disease (1).

Egg consumption is one of the main sources of dietary cholesterol; a large egg contains ∼186 mg of cholesterol (2). Eggs also contain important nutrients (e.g., high-quality protein, saturated and unsaturated fat, vitamins, minerals, and phospholipids). Dietary phospholipids have emerged as a potential source of bioactive lipids that may have widespread effects on pathways related to inflammation, cholesterol metabolism, and HDL function (3).

Nonetheless, excessive egg consumption is generally discouraged due to the high cholesterol content in egg yolk. A meta-analysis found that the addition of 100 mg dietary cholesterol from eggs minimally increased total cholesterol and HDL cholesterol (4). However, some randomized controlled trials reported that egg consumption did not significantly alter plasma total cholesterol, LDL cholesterol, or HDL cholesterol (5–7). More recently, an analysis of 29,615 adults from 6 prospective US cohorts examined the association of self-reported baseline macronutrient intake with incident cardiovascular disease and mortality over a median period of 17.5 y (8). The consumption of dietary cholesterol from eggs was associated with a dose-dependent higher association with incident ASCVD and mortality. These associations were stronger in women than men. Among the limitations of this analysis was the absence of data to support the associations between egg consumption and LDL cholesterol (9).

Interestingly, during menopause HDL cholesterol may be positively correlated with ASCVD (10), but it is unknown whether higher HDL cholesterol is correlated with reduced HDL function in this population. HDL particles are acceptors of cholesterol from lipid-laden macrophages (11). The first step in macrophage cholesterol efflux involves interaction between the cellular acceptor ATP-binding cassette transporter A1 (ABCA1) and cholesterol-deficient and phospholipid-depleted apoA-I complexes (12, 13). Phospholipid composition influences the cholesterol efflux capacity of HDL (14). The interaction of apoA-I with ABCA1 results in a conformational change in apoA-I that limits further binding via the ABCA1 pathway. The free cholesterol in very small (or pre-β) HDL particles is esterified via lecithin:cholesteryl acyl transferase particles. Cholesterol loading of very small HDL particles results in the formation of spherical particles (small HDL) that become increasingly larger in size as more cholesterol accumulates. These more cholesterol-enriched particles are termed medium HDL, large HDL, and very large HDL particles. Spherical HDL particles interact with ATP-binding cassette G1 (ABCG1). Other steps in the reverse cholesterol transport include hepatic removal of cholesterol in spherical HDL via the scavenger receptor class B type I receptor and elimination of fecal sterols and bile acids.

HDL-mediated cholesterol efflux capacity is an established HDL functional measure associated with lower risk of incident cardiovascular events in several large population studies (15–17). Using this approach to measure HDL function, Sawrey-Kubicek et al. (18) in this issue of the Journal conducted a randomized, single-blind crossover trial in 20 overweight postmenopausal women to examine the effects of consuming whole eggs compared with yolk-free eggs on measures of HDL function. Study participants were randomly assigned to consume frozen breakfast meals containing 100 g of liquid whole eggs or 100 g of yolk-free eggs per day separated by a 4-wk washout. The main finding of this study was an increase in cholesterol efflux capacity with whole eggs compared with yolk-free treatment. HDL compositional changes associated with egg consumption compared with yolk-free eggs included higher HDL phosphatidylcholine (HDL-POPC) and HDL phosphatidylethanolamine (HDL-PE). Cholesterol efflux was associated with HDL-POPC, HDL-PE content, and odd-chain fatty acids in sphingomyelin (SM). No treatment differences were detected in apoA-I concentrations, nor in LDL or HDL concentrations, although of course the power to detect these differences was very limited. Of note, the yolk-free egg breakfast was higher in carbohydrate content compared with the whole egg meals, although no macronutrient differences were seen across all dietary intakes during the study period.

In an earlier study of participants with metabolic syndrome, whole egg consumption compared with yolk-free egg substitute was shown to increase HDL-PE (19). PE enhances binding of amphipathic helices of apoA-I, thereby increasing cholesterol efflux. Changes in HDL-PE were positively associated with increases in HDL cholesterol in the study by Andersen et al. (19); however, in this current study of Sawrey-Kubicek et al. (18), there was no association between HDL-PE content and cholesterol efflux capacity. Schwendman et al. (14) prepared HDL-like 5A-POPC and 5A-SM complexes from reconstituted HDL and egg SM and POPC to investigate cellular cholesterol efflux. Both lipid formulations exhibited similar ABCA1-mediated efflux, but 5A-SM exhibited more ABCG1- and SRB1-mediated efflux than 5A-POPC did. In an experimental atherosclerosis model, only 5A-SM induced a reduction in total plaque area in ApoE^−/– mice when compared with placebo control and baseline. From this study, the type of phospholipid influences both HDL cholesterol efflux and HDL-mediated antiatherosclerotic properties.

Further research is needed to ascertain the importance of the findings in this study. Currently, there is inconsistency in the associations between various phospholipids and cholesterol efflux–mediated and cellular acceptors. Studies that investigate cholesterol efflux in humans should be accompanied by coronary or carotid atherosclerosis imaging studies. Following this proof-of-concept experiment, further support for this hypothesis could be obtained by review of dietary records for egg consumption in completed prospective population studies of cholesterol efflux capacity. Similarly, HDL-mediated cholesterol efflux capacity could be measured in specimens from studies reporting detailed dietary compositional analysis. On the other hand, a surrogate endpoint may not always translate into clinical outcome. HDL function is multifaceted and improvement in a single function may not necessarily reduce cardiovascular disease. Recently, egg POPC was shown to be a substrate for the generation of trimethylamine N-oxide, a gut microbe–dependent metabolite associated with increased cardiovascular disease risk (20). Finally, egg consumption may also change the atherogenicity of the triglyceride-rich lipoproteins such as LDL by changing the phospholipid composition of these lipoprotein particles. Until these knowledge gaps have been investigated, cautious guidance on the use of eggs in dietary guidelines and recommendations should continue.

Notes

Abbreviations used: ASCVD, atherosclerotic cardiovascular disease; ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; PE, phosphatidylethanolamine; POPC, phosphatidylcholine; SM, sphingomyelin.

RSR and W-LS: wrote this editorial; and both authors: read and approved the final version. RSR reports no relevant conflicts of interest. He receives research grants to his institution from Akcea, Amgen, Medicines Company, Regeneron; consulting fees from C5 and CVS Caremark; honoraria from Akcea, Amgen, Kowa and Pfizer, royalties from UpToDate, Inc.; and stock holdings in MediMergent, LLC. W-LS reports no conflicts of interest.