Endogenous Cholesterol Excretion Is Negatively Associated With Carotid Intima-Media Thickness in Humans

Abstract

Objective: Epidemiological studies strongly suggest that lipid factors independent of low-density lipoprotein cholesterol contribute significantly to cardiovascular disease risk. Because circulating lipoproteins comprise only a small fraction of total body cholesterol, the mobilization and excretion of cholesterol from plasma and tissue pools may be an important determinant of cardiovascular disease risk. Our hypothesis is that fecal excretion of endogenous cholesterol is protective against atherosclerosis.

Approach and results: Cholesterol metabolism and carotid intima-media thickness were quantitated in 86 nondiabetic adults. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d7 solubilized in a lipid emulsion and dietary cholesterol by cholesterol-d5 and the nonabsorbable stool marker sitostanol-d4. Plasma and stool samples were collected while subjects consumed a cholesterol- and phytosterol-controlled metabolic kitchen diet and were analyzed by mass spectrometry. Carotid intima-media thickness was negatively correlated with fecal excretion of endogenous cholesterol (r=-0.426; P<0.0001), total cholesterol (r=-0.472; P≤0.0001), and daily percent excretion of cholesterol from the rapidly mixing cholesterol pool (r=-0.343; P=0.0012) and was positively correlated with percent cholesterol absorption (r=+0.279; P=0.0092). In a linear regression model controlling for age, sex, systolic blood pressure, hemoglobin A1c, low-density lipoprotein, high-density lipoprotein cholesterol, and statin drug use, fecal excretion of endogenous cholesterol remained significant (P=0.0008).

Conclusions: Excretion of endogenous cholesterol is strongly, independently, and negatively associated with carotid intima-media thickness. The reverse cholesterol transport pathway comprising the intestine and the rapidly mixing plasma, and tissue cholesterol pool could be an unrecognized determinant of cardiovascular disease risk not reflected in circulating lipoproteins. Further work is needed to relate measures of reverse cholesterol transport to atherosclerotic disease.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603758.

Keywords: atherosclerosis; carotid intima-media thickness; cholesterol; clinical trial; mass spectrometry.

© 2017 American Heart Association, Inc.

Figures

Figure 1. Relation between CIMT and FEEC

Simple regression of carotid intima-media thickness (CIMT) (mm) with fecal excretion of endogenous cholesterol (FEEC) (g/day) is presented for 86 subjects.

Figure 2. Partial model of body and intestinal endogenous cholesterol metabolism

Solid arrows depict cholesterol pathways with statistically significant negative correlations to carotid intima-media thickness (CIMT) while dotted lines show pathways with significant positive correlations to CIMT. Dietary cholesterol was controlled at a low level during measurements and is not included in the model. Cholesterol pathways that tend to reduce the rapidly-mixing body cholesterol pool are associated with reduced CIMT. Primary data are found in Table 3. Endogenous cholesterol input into the rapidly-mixing pool is estimated as the percent fall in plasma enrichment between days 2 and 15.