When Dietary Cholesterol is Most Hazardous to Cardiovascular Health

Ever since Anitschkow’s (also referred to as Anichkov) astute observation more than a century ago that cholesterol feeding caused atherosclerosis in rabbits¹, the role of dietary cholesterol in promoting cardiovascular disease (CVD) has been continually debated, though less well established in otherwise healthy normocholesterolemic humans. While unequivocal evidence exists for the advancement of CVD when animal derived sources of saturated fat are substituted for either mono and/or polyunsaturated fat², it has been considerably more challenging to tease out the singular contribution of dietary cholesterol in this process. In part, this reflects differences in the metabolic regulation between cholesterol and dietary fat; only the former is represented by an inherent negative feedback loop that regulates the uptake of cholesterol via high affinity LDL receptors, referred to by Nobel Laureates, Brown and Goldstein as the LDL receptor dependent pathway3. Under normal physiologic conditions, when dietary cholesterol intake increases, intracellular cholesterol synthesis is suppressed. If this regulatory mechanism was not operative, LDL receptors would easily saturate with cholesterol, due to unimpeded overloading from both dietary and intracellular sources. Because dietary cholesterol intake only accounts for a small percentage (~25%) of the total cholesterol processed daily (the vast majority originating from biliary sources), it would be exceedingly uncommon for a moderate intake (~300-500 mg) under normal physiologic conditions to singularly raise LDL cholesterol levels appreciably. Moreover, in the absence of allelic defects in cholesterol or triglyceride regulating genes, healthy individuals consuming a low saturated (to unsaturated) fat, low-cholesterol diet (e.g., Mediterranean, Dietary Approaches to Stop Hypertension (DASH), or primarily plant based) are also more likely to exhibit physiologic LDL cholesterol levels (~50-80 mg/dL) than consumers of a diet enriched in animal-based products (as described below)^3-5.

Conversely, deregulation of cholesterol homeostasis activates LDL receptor independent pathways including unregulated uptake of LDL particles by macrophages that over time, contributes to foam cell deposition, atherosclerotic plaques and eventual CVD. This process occurs in genetically predisposed individuals with defective or deficient LDL receptors (e.g., familial hypercholesterolemia). Analogous to genetically imposed high LDL, are patients with high triglyceride levels owing to defects in genes regulating the clearance of remnant lipoproteins. As a consequence of defective/deficient remnant receptors, circulating cholesterol-enriched remnant particles are also avidly incorporated by macrophages thereby facilitating plaque formation/promotion and the devastating sequalae (e.g., myocardial infarction, stroke) that accompanies CVD⁶.

Excessive daily intake of saturated and/or trans fats in otherwise normocholesterolemic men and women can also result in LDL cholesterol elevation owing to direct suppression and/or inhibition of LDL receptor activity^7,8. Finally, excessive absorption of dietary cholesterol (e.g., cholesterol "hyperabsorbers") may also contribute to high levels of LDL cholesterol⁹ and raise risk of CVD. In all of the aforementioned cases, even moderate intake of cholesterol daily may be hazardous to cardiovascular health and should be restricted.

As noted above and elaborated upon by Carson and colleagues in the new AHA scientific advisory¹⁰, a diet high in cholesterol is often replete with animal-based saturated (and trans) fats, making it inordinately challenging to parse out the singular contribution of dietary cholesterol in CVD risk assessment. Among studies examining egg supplementation, the results have generally been mixed with limited data supporting egg restriction in otherwise healthy individuals. In fact, the new advisory supports up to 1-2 eggs daily in young and older patients respectively, who have normal cholesterol levels. Because exogenous cholesterol is solely obtained from animal sources, recommending a diet enriched in plant rather than animal-based nutrients that coincides with a favorable saturated-unsaturated fat ratio as endorsed in the current AHA advisory statement and by the American College of Cardiology¹¹ represents the most sensible long-term approach for optimizing CVD health.