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  • Title: Inhibition of intestinal cholesterol absorption with ezetimibe increases components of reverse cholesterol transport in humans.
    Author: Davidson MH, Voogt J, Luchoomun J, Decaris J, Killion S, Boban D, Glass A, Mohammad H, Lu Y, Villegas D, Neese R, Hellerstein M, Neff D, Musliner T, Tomassini JE, Turner S.
    Journal: Atherosclerosis; 2013 Oct; 230(2):322-9. PubMed ID: 24075764.
    Abstract:
    OBJECTIVE: Reverse cholesterol transport (RCT) can be defined as a pathway of flux of cholesterol from peripheral tissues to the liver for potential excretion into feces. This prospective, placebo-controlled, double-blind crossover study assessed the effect of ezetimibe on several RCT parameters in hyperlipidemic patients. METHODS: Following 7 weeks of treatment (ezetimibe 10 mg/day or placebo), 26 patients received 24-h continuous IV infusions of [3,4-(13)C2]-cholesterol, then took heavy water ((2)H2O) by mouth. Cholesterol excretion was measured by quantification of neutral/acid sterols in stool and blood samples during 7 days post-infusion with continued treatment. Plasma de novo cholesterol synthesis was assessed by (2)H-labeling from (2)H2O. RESULTS: Ezetimibe significantly reduced levels of low-density lipoprotein cholesterol (22%, P < 0.001) without significant changes in triglycerides and high-density lipoprotein cholesterol and significantly increased the flux of plasma-derived cholesterol into fecal neutral sterols by 52% (P = 0.04) without change in flux into fecal bile acids. Total fecal neutral sterol output increased by 23% (P = 0.02). Plasma de novo cholesterol synthesis increased by 57% (P < 0.001). The fractional clearance rate (FCR) of plasma cholesteryl-ester trended higher (7%; P = 0.055) with a reduction in absolute cholesteryl-ester production rate (9%, P < 0.01). Whole-body free cholesterol efflux rate from extra-hepatic tissues into plasma was not measurably changed by ezetimibe. CONCLUSION: Ezetimibe treatment approximately doubled the flux of plasma-derived cholesterol into fecal neutral sterols, in association with increases in total fecal neutral sterol excretion, FCR of plasma cholesterol ester, and plasma de novo cholesterol synthesis. These effects are consistent with increased cholesterol transport through the plasma compartment and excretion from the body, in response to ezetimibe treatment in hyperlipidemic humans. Clintrials.gov: NCT00701727.
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