Transintestinal Cholesterol Transport Is Active in Mice and Humans and Controls Ezetimibe-Induced Fecal Neutral Sterol Excretion

Jakulj, Lily; Dijk, Theo H. van; Boer, Jan Freark de; Kootte, Ruud S.; Schonewille, Marleen; Paalvast, Yared; Boer, Th. J. de; Bloks, Vincent W.; Boverhof, Renze; Nieuwdorp, Max; Beuers, Ulrich; Stroes, Erik S.G.; Groen, Albert K.

doi:10.1016/j.cmet.2016.10.001

Cited by 124 publications

(119 citation statements)

References 51 publications

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“…29 Taken together, it is possible that ezetimibe increased cholesterol efflux from extra-hepatic tissues into the plasma. Ezetimibe did not affect plasma HDL cholesterol levels, as reported previously, 14, 16 which suggests that ezetimibe may increase endogenous cholesterol excretion independently of HDL.…”

Section: Discussionsupporting

confidence: 83%

“…25 In contrast, ezetimibe enhanced endogenous cholesterol excretion in humans predominantly by increasing TICE, mediated by intestinal ABCG5/ABCG8. 26 …”

Section: Discussionmentioning

confidence: 99%

“…1416 However, this conclusion is tempered by limitations present in one or both of those trials, including lack of a control group, lack of concurrent ezetimibe treatment during metabolic measurements, collection of stool samples without control of either dietary cholesterol or phytosterol intake, lack of measurement of intestinal cholesterol absorption efficiency or total endogenous cholesterol excretion, and a focus on analyses performed during rapid changes in cholesterol enrichment, where repeatability of calculated parameters is limited. In the present work, we tried to optimize the experimental conditions while emphasizing the critical roles of the rapidly-mixing endogenous cholesterol pool and the intestine in the action of ezetimibe.…”

Section: Introductionmentioning

confidence: 99%

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Ezetimibe Increases Endogenous Cholesterol Excretion in Humans

Lin

Racette

et al. 2017

ATVB

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Objective Ezetimibe improves cardiovascular outcomes when added to optimum statin treatment. It lowers LDL cholesterol and percent intestinal cholesterol absorption, but the exact cardioprotective mechanism is unknown. We tested the hypothesis that the dominant effect of ezetimibe is to increase the reverse transport of cholesterol from rapidly-mixing endogenous cholesterol pool into the stool. Approach and Results In a randomized, placebo-controlled, double-blind parallel trial in 24 healthy subjects with LDL cholesterol 100–200 mg/dL, we measured cholesterol metabolism before and after a 6-week treatment period with ezetimibe 10 mg/day or placebo. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d7 in a lipid emulsion and dietary cholesterol with cholesterol-d5 and sitostanol-d4 solubilized in oil. Plasma and stool samples collected during a cholesterol- and phytosterol-controlled metabolic kitchen diet were analyzed by mass spectrometry. Ezetimibe reduced intestinal cholesterol absorption efficiency 30 ± 4.3% (SE, P < 0.0001) and LDL cholesterol 19.8 ± 1.9% (P = 0.0001). Body cholesterol pool size was unchanged, but fecal endogenous cholesterol excretion increased 66.6 ± 12.2% (P < 0.0001) and percent cholesterol excretion from body pools into the stool increased 74.7 ± 14.3% (P < 0.0001) while plasma cholesterol turnover rose 26.2 ± 3.6% (P = 0.0096). Fecal bile acids were unchanged. Conclusions Ezetimibe increased the efficiency of reverse cholesterol transport from rapidly-mixing plasma and tissue pools into the stool. Further work is needed to examine the potential relation of reverse cholesterol transport and whole body cholesterol metabolism to coronary events and the treatment of atherosclerosis.

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Section: Discussionsupporting

confidence: 83%

“…25 In contrast, ezetimibe enhanced endogenous cholesterol excretion in humans predominantly by increasing TICE, mediated by intestinal ABCG5/ABCG8. 26 …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ezetimibe Increases Endogenous Cholesterol Excretion in Humans

Lin

Racette

et al. 2017

ATVB

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“…Finally, sterol removal and excretion are parts of the entire balance. It is now clear that LDLRs mediate an important component of sterol removal due to catabolism and excretion after uptake (Favari et al 2015, Jakulj et al 2016). Furthermore, the reactions that break down sterols to foster their exit from the gut as bile acids compose another regulated component of sterol flux through mammals.…”

Section: Introductionmentioning

confidence: 99%

Proteostatic Tactics in the Strategy of Sterol Regulation

Wangeline

Vashistha

Hampton

2017

Annu. Rev. Cell Dev. Biol.

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In eukaryotes, the synthesis and uptake of sterols undergo stringent multivalent regulation. Both individual enzymes and transcriptional networks are controlled to meet changing needs of the many sterol pathway products. Regulation is tailored by evolution to match regulatory constraints, which can be very different in distinct species. Nevertheless, a broadly conserved feature of many aspects of sterol regulation is employment of proteostasis mechanisms to bring about control of individual proteins. Proteostasis is the set of processes that maintain homeostasis of a dynamic proteome. Proteostasis includes protein quality control pathways for the detection, and then the correction or destruction, of the many misfolded proteins that arise as an unavoidable feature of protein-based life. Protein quality control displays not only the remarkable breadth needed to manage the wide variety of client molecules, but also extreme specificity toward the misfolded variants of a given protein. These features are amenable to evolutionary usurpation as a means to regulate proteins, and this approach has been used in sterol regulation. We describe both well-trod and less familiar versions of the interface between proteostasis and sterol regulation and suggest some underlying ideas with broad biological and clinical applicability.

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“…Similarly, recent studies indicate that TICE is active in humans and is stimulated by ezetimibe treatment. 6 Thus, the rodent models not only recapitulate features of TICE in humans, but also suggest that TICE is a druggable pathway. Further investigation into the key mediators of TICE and their regulation in the intestine are critical to unlock the therapeutic potential of this anti-atherosclerotic pathway.…”

mentioning

confidence: 89%