How Important Is Dietary Cholesterol?

There has been considerable controversy
There has been considerable controversy

Dietary cholesterol has classically been considered a significant contributor to elevated serum cholesterol levels and atherosclerotic cardiovascular disease (ASCVD)—a viewpoint that originated in animal studies.1 There has been considerable controversy, however, whether serum cholesterol levels in human beings are actually responsive to high intakes of cholesterol. Paradoxically, while some studies show that human beings do not develop hypercholesterolemia from high cholesterol diets, other studies show that high intakes of cholesterol can indeed raise serum cholesterol levels.1 A recent article by Scott Grundy, MD, reviews the controversy.

Studies of Dietary Cholesterol and Serum Cholesterol

According to the author, two types of studies have been conducted to investigate the influence of dietary cholesterol on serum cholesterol levels. Metabolic studies,2-5 which have been done in “relatively small numbers of subjects,” have shown a positive relationship between cholesterol intake and serum cholesterol, with an average rise in serum total cholesterol of 10mg/dL for every 100mg increase in dietary cholesterol/1000 calories.1 On the other hand, studies with a larger number of subjects, but less carefully controlled conditions, have yielded ambiguous results, perhaps because of confounding factors.1

Dietary Cholesterol and Other Cholesterol-Raising Nutrients

Several nutrients other than cholesterol influence serum cholesterol levels. These include saturated fatty acids, trans fatty acids, dietary soluble fiber, and overnutrition (ie, obesity).1 The relative contribution of each of these elements can be found in Table 1. While each factor contributes only modestly to elevating serum cholesterol, the aggregate of these factors raises serum cholesterol levels about 25%.6

Cholesterol Absorption

It is estimated that approximately 50% of dietary cholesterol is absorbed; however, absorption may range between 40% to 60%.1 This variability may partially contribute to the extent to which dietary cholesterol affects serum cholesterol levels. The key mediator of absorption is a protein called Neiman-Pick C1-like protein-1 (NPC1L1), which binds cholesterol at the surface of the enterocyte.7 The resulting complex is internalized into lysosomes. Polymorphisms in NPC1L1 have been demonstrated to modify the quantity of cholesterol being absorbed.8

A larger quantity of cholesterol enters the intestine through the bile. The author terms dietary cholesterol “exogenous” and cholesterol derived from bile “endogenous,” stating that about 50% of endogenous cholesterol is absorbed and eventually is taken up by the liver.1 A more detailed sequence is outlined in Table 2.

The Role of the Liver in Protection Against Dietary Cholesterol-Induced Hypercholesterolemia

Although dietary cholesterol does raise serum cholesterol levels, there are nevertheless mechanisms in place that protect against extreme hypercholesterolemia.1

Cholesterol synthesis: The steps through which cholesterol synthesis takes place in the liver are complex and involve several enzymes. (Table 3) In animal studies, diets high in cholesterol actually suppress cholesterol synthesis, thereby protecting against hypercholesterolemia.1 This suppression is caused by several factors, including coordinate changes in mRNA levels that encode multiple enzymes in the cholesterol biosynthetic pathway.1 While it is not possible to measure cholesterol synthesis in the human liver, it has been shown through cholesterol balance measurements that high intakes of cholesterol decrease whole body synthesis—a process that likely occurs in the liver, apparently through the suppression of endogenous cholesterol synthesis.

Bile acid synthesis: Enhanced conversion of cholesterol into bile acids may also protect against diet-induced hypercholesterolemia.1

Biliary cholesterol output: During high-cholesterol ingestion, excess hepatic cholesterol may be re-secreted into the bile; and, in fact, high cholesterol intake appears to enhance biliary cholesterol output and play an important role in avoiding hypercholesterolemia in high-cholesterol diets.9

Storage of cholesterol esters in the liver:  Consumption of cholesterol has been shown to expand the pool of cholesterol ester in animal models.10 Some increase in LDL cholesterol resulting from high cholesterol diets could be “secondary to enrichment of LDL particles with liver-derived cholesterol esters.”1

Suppression of hepatic LDL receptor expression: In diet-responsive species, excess dietary cholesterol appears to suppress hepatic LDL receptor expression, thereby raising serum LDL cholesterol levels.1

Atherogenicity of Dietary Cholesterol

LDL cholesterol (LDL-C): Increased LDL-C is implicated in most of the effect of dietary cholesterol on serum total cholesterol levels.1 Since a high-cholesterol diet raises LDL-C levels, on average, by about 5%, the risk for ASCVD is likely raised by at least a similar percentage. Genetic studies suggest that over a lifetime, a 1% higher LDL-C will raise long-term risk by approximately 3%, suggesting that a lifetime of high cholesterol intake could raise ASCVD risk to 15%.1 Lowering dietary cholesterol is not sufficient to significantly lower LDL-C levels. It is also necessary to reduce cholesterol-raising fatty acids, reduce weight, and add soluble fiber to the diet.1

Chylomicron remnants may be atherogenic and will be higher in cholesterol-rich diets. If these remnants accumulate in the arterial wall, they might promote atherogenesis.1