Project details

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A novel pathway for the disposal of cholesterol from the body: intestinal cholesterol excretion as a preventive and therapeutic target.

Keywords:
cholesterol fluxes Treatment intestine

Researchers:
dr. J.W. Jonker
prof. dr. H.J. Verkade
J.F. de Boer

Nature of the research:
fundamental, experimental animal

Fields of study:
pediatrics gastroenterology medical physiology

Background / introduction
Cholesterol is a very interesting molecule in human physiology. On the one hand, it is an indispensable structural component of membranes and a precursor of steroid hormones, vitamin D and bile acids (bile acids are critical for efficient fat absorption and lipid metabolism). On the other hand, however, accumulation of cholesterol in blood or blood vessels is an important risk factor for cardiovascular disease. The two features of benign and toxic effects of cholesterol underline the importance of a proper balance of cholesterol in the body. The balance is determined by (new) cholesterol entering the body (absorption of dietary cholesterol and de novo synthesis of cholesterol) and by its disposal. The main route of cholesterol disposal from the body occurs via fecal excretion, either in the form of bile acids or neutral sterols (cholesterol and its microbial metabolites).

Recently, intriguing new insight into the cholesterol balance has been obtained. For long it has been assumed that the major route by which cholesterol entered the intestinal lumen was via its secretion by the liver into the bile. In the last decade, however, another pathway has been discovered and characterized, the transintestinal cholesterol excretion (TICE). TICE is currently recognized as a major cholesterol excretion pathway in both mice and humans.(1, 2) The exact mechanism by which the intestine secretes cholesterol, however, has only partly become understood. It is also still unclear how and to what extent the TICE pathway could be a target for prevention or treatment of cholesterol accumulation in the body, and thus for cardiovascular disease.

(see Figure)

Recently we demonstrated in a mouse model that cholesterol that is excreted into the intestine via the TICE pathway can partly be reabsorbed (3) This observation indicates that the body can regulate the cholesterol balance via TICE at different levels namely 1. at the level of excretion into the intestinal lumen and 2. at the level of re-absorption of TICE-cholesterol. These observations offer the possibility that each of these levels separately or both levels combined could be targets of prevention and treatment of hypercholesterolemia. By using pharmacological and genetic approaches, we aim to further characterize the TICE pathway and to address to what extent novel preventive or therapeutic interventions can be developed for hypercholesterolemia.(4)
Research question / problem definition
we hypothesize that induction of the transintestinal cholesterol excretion and inhibition of its reabsorption can be a means to augment cholesterol disposal from the body and prevent of diminish cholesterol accumulation.
Workplan
In mice with a genetically induced hypercholesterolemia and in control mice, the preventive and therapeutic effects of dual TICE treatments will be evaluated, consisting of induction of TICE cholesterol excretion into the intestine (by so-called FXR and LXR agonists) and inhibition of cholesterol reabsorption (by ezetimibe, an inhibitor if the cholesterol uptake transport protein Npc1l1). We will determine the effects on cholesterol accumulation (blood, blood vessels, liver), on biomarkers of atherosclerosis, on biliary cholesterol and bile acid secretion, and on de novo cholesterol synthesis.
References
1. Jakulj L, van Dijk TH, de Boer JF, Kootte RS, Schonewille M, Paalvast Y, et al. Transintestinal Cholesterol Transport Is Active in Mice and Humans and Controls Ezetimibe-Induced Fecal Neutral Sterol Excretion. Cell Metab. 2016;24:783-94.
2. de Boer JF, Schonewille M, Boesjes M, Wolters H, Bloks VW, Bos T, et al. Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice. Gastroenterology. 2017; 152:1126,1138.e6.
3. van de Peppel IP, Bertolini A, van Dijk TH, Groen AK, Jonker JW, Verkade HJ. Efficient reabsorption of transintestinally excreted cholesterol is a strong determinant for cholesterol disposal in mice. J Lipid Res. 2019;60:1562-72.
4. de Boer JF, Kuipers F, Groen AK. Cholesterol Transport Revisited: A New Turbo Mechanism to Drive Cholesterol Excretion. Trends Endocrinol Metab. 2018;29:123-33.
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