Peroxisome proliferator-activated receptor delta activation leads to increased transintestinal cholesterol efflux

Carlos L. J. Vrins¹^,2^,*^,, Astrid E. van der Velde¹^,, Karin van den Oever, Johannes H. M. Levels, Stephane Huet^**, Ronald P. J. Oude Elferink, Folkert Kuipers and Albert K. Groen^*

^* Department of Medical Biochemistry, AMC Liver Center, Amsterdam, The Netherlands
Department of Experimental Vascular Medicine, AMC Liver Center, Amsterdam, The Netherlands
Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
^** Biology Department, GlaxoSmithKline, Les Ulis, France
Biology Department, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands

² To whom correspondence should be addressed. e-mail: vrins{at}amc.uva.nl

Peroxisome proliferator-activated receptor delta (PPAR ${delta}$ ) is involvedin regulation of energy homeostasis. Activation of PPAR ${delta}$ markedlyincreases fecal neutral sterol secretion, the last step in reversecholesterol transport. This phenomenon can neither be explainedby increased hepatobiliary cholesterol secretion, nor by reducedcholesterol absorption. To test the hypothesis that PPAR ${delta}$ activationleads to stimulation of transintestinal cholesterol efflux (TICE),we quantified it by intestine perfusions in FVB mice treatedwith PPAR ${delta}$ agonist GW610742. To exclude the effects on cholesterolabsorption, mice were also treated with cholesterol absorptioninhibitor ezetimibe or ezetimibe/GW610742. GW601742 treatmenthad little effect on plasma lipid levels but stimulated bothfecal neutral sterol excretion ( $~$ 200%) and TICE ( $~$ 100%). GW610742decreased intestinal Npc1l1 expression but had no effect onAbcg5/Abcg8. Interestingly, expression of Rab9 and LIMPII, encodingproteins involved in intracellular cholesterol trafficking,was increased upon PPAR ${delta}$ activation. Although treatment withezetimibe alone had no effect on TICE, it reduced the effectof GW610742 on TICE. These data show that activation of PPAR ${delta}$ stimulates fecal cholesterol excretion in mice, primarily bythe two-fold increase in TICE, indicating that this pathwayprovides an interesting target for the development of drugsaiming at the prevention of atherosclerosis.

Supplementary key words intestine • transintestinal cholesterol efflux • reverse cholesterol transport

Abbreviations: Apo, apolipoprotein; HPGC, high performance gel-filtration chromatography; HPRT, hypoxanthine-guanine phosphoribosyl transferase; Ldlr^–/–, Ldl receptor knockout; NPC1L1, Niemann-Pick C1-like 1; PC, phosphatidylcholine; PPAR, peroxisome proliferator-activated receptor; RCT, reverse cholesterol transport; TC, taurocholate; TICE, transintestinal cholesterol transport

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