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

Carlos L.J Vrins,Astrid E Van Der Velde,Karin Van Den Oever,Johannes H.M Levels,Stephane Huet,Ronald P.J Oude Elferink,Folkert Kuipers,Albert K Groen

doi:10.1194/jlr.m800579-jlr200

Carlos L.J Vrins, Astrid E Van Der Velde + Show 6 more

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https://doi.org/10.1194/jlr.m800579-jlr200

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Abstract

Peroxisome proliferator-activated receptor delta (PPARdelta) is involved in regulation of energy homeostasis. Activation of PPARdelta markedly increases fecal neutral sterol secretion, the last step in reverse cholesterol transport. This phenomenon can neither be explained by increased hepatobiliary cholesterol secretion, nor by reduced cholesterol absorption. To test the hypothesis that PPARdelta activation leads to stimulation of transintestinal cholesterol efflux (TICE), we quantified it by intestine perfusions in FVB mice treated with PPARdelta agonist GW610742. To exclude the effects on cholesterol absorption, mice were also treated with cholesterol absorption inhibitor ezetimibe or ezetimibe/GW610742. GW601742 treatment had little effect on plasma lipid levels but stimulated both fecal neutral sterol excretion ( approximately 200%) and TICE ( approximately 100%). GW610742 decreased intestinal Npc1l1 expression but had no effect on Abcg5/Abcg8. Interestingly, expression of Rab9 and LIMPII, encoding proteins involved in intracellular cholesterol trafficking, was increased upon PPARdelta activation. Although treatment with ezetimibe alone had no effect on TICE, it reduced the effect of GW610742 on TICE. These data show that activation of PPARdelta stimulates fecal cholesterol excretion in mice, primarily by the two-fold increase in TICE, indicating that this pathway provides an interesting target for the development of drugs aiming at the prevention of atherosclerosis.

Highlights

Peroxisome proliferator-activated receptor delta (PPAR␦) is involved in regulation of energy homeostasis
These data show that activation of peroxisome proliferator-activated receptor (PPAR)␦ stimulates fecal cholesterol excretion in mice, primarily by the two-fold increase in transintestinal cholesterol efflux (TICE), indicating that this pathway provides an interesting target for the development of drugs aiming at the prevention of atherosclerosis.—Vrins, C
Mice ( n = 7 for each group) received a reference diet (20% casein, ref no 4068.02, Arie Blok BV, The Netherlands), a diet containing PPAR␦ agonist [reference diet supplemented with 0.017% (w/w) GW610742, resulting in an approximate intake of 20 mg/kg/day based on an average food intake of 3 g], a diet containing ezetimibe, or a reference diet supplemented with ezetimibe (10 mg/kg/day) and the PPAR␦ agonist GW610742 [0.017% (w/w)] for 2 weeks

Summary

Introduction

Peroxisome proliferator-activated receptor delta (PPAR␦) is involved in regulation of energy homeostasis. Activation of PPAR␦ markedly increases fecal neutral sterol secretion, the last step in reverse cholesterol transport. GW601742 treatment had little effect on plasma lipid levels but stimulated both fecal neutral sterol excretion (‫ف‬200%) and TICE (‫ف‬100%). Treatment with ezetimibe alone had no effect on TICE, it reduced the effect of GW610742 on TICE These data show that activation of PPAR␦ stimulates fecal cholesterol excretion in mice, primarily by the two-fold increase in TICE, indicating that this pathway provides an interesting target for the development of drugs aiming at the prevention of atherosclerosis.—Vrins, C. PPAR␣ modulates various aspects of lipid metabolism [2,3,4,5] and is highly expressed in heart, liver, kidney, intestine, brown fat, i.e., organs that display high rates of fatty acid ␤-oxidation [6].

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