Measurement of Reverse Cholesterol Transport Pathways in Humans: In Vivo Rates of Free Cholesterol Efflux, Esterification, and Excretion

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Abstract
Background: Reverse cholesterol transport from peripheral tissues is considered the principal atheroprotective mechanism of high‐density lipoprotein, but quantifying reverse cholesterol transport in humans in vivo remains a challenge. We describe here a method for measuring flux of cholesterol though 3 primary components of the reverse cholesterol transport pathway in vivo in humans: tissue free cholesterol ( FC ) efflux, esterification of FC in plasma, and fecal sterol excretion of plasma‐derived FC . Methods and Results: A constant infusion of [2,3‐ 13 C 2 ]‐cholesterol was administered to healthy volunteers. Three‐compartment SAAM II (Simulation, Analysis, and Modeling software; SAAM Institute, University of Washington, WA) fits were applied to plasma FC , red blood cell FC , and plasma cholesterol ester 13 C–enrichment profiles. Fecal sterol excretion of plasma‐derived FC was quantified from fractional recovery of intravenous [2,3‐ 13 C 2 ]‐cholesterol in feces over 7 days. We examined the key assumptions of the method and evaluated the optimal clinical protocol and approach to data analysis and modeling. A total of 17 subjects from 2 study sites (n=12 from first site, age 21 to 75 years, 2 women; n=5 from second site, age 18 to 70 years, 2 women) were studied. Tissue FC efflux was 3.79±0.88 mg/kg per hour (mean ± standard deviation), or ≈8 g/d. Red blood cell–derived flux into plasma FC was 3.38±1.10 mg/kg per hour. Esterification of plasma FC was ≈28% of tissue FC efflux (1.10±0.38 mg/kg per hour). Recoveries were 7% and 12% of administered [2,3‐ 13 C 2 ]‐cholesterol in fecal bile acids and neutral sterols, respectively. Conclusions: Three components of systemic reverse cholesterol transport can be quantified, allowing dissection of this important function of high‐density lipoprotein in vivo. Effects of lipoproteins, genetic mutations, lifestyle changes, and drugs on these components can be assessed in humans.

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