Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestinal expression of NPC1L1.
Peroxisome proliferator-activated receptors (PPARs) control the transcription of genes involved in lipid metabolism. Activation of PPARdelta may have antiatherogenic effects through the increase of plasma HDL, theoretically promoting reverse cholesterol transport from peripheral tissues toward the liver for removal via bile and feces. Effects of PPARdelta activation by GW610742 were evaluated in wild-type and Abca1-deficient (Abca1(-/-)) mice that lack HDL. Treatment with GW610742 resulted in an approximately 50% increase of plasma HDL-cholesterol in wild-type mice, whereas plasma cholesterol levels remained extremely low in Abca1(-/-) mice. Yet, biliary cholesterol secretion rates were similar in untreated wild-type and Abca1(-/-) mice and unaltered upon treatment. Unexpectedly, PPARdelta activation led to enhanced fecal neutral sterol loss in both groups without any changes in intestinal Abca1, Abcg5, Abcg8, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase expression. Moreover, GW610742 treatment resulted in a 43% reduction of fractional cholesterol absorption in wild-type mice, coinciding with a significantly reduced expression of the cholesterol absorption protein Niemann-Pick C1-like 1 (Npc1l1) in the intestine. PPARdelta activation is associated with increased plasma HDL and reduced intestinal cholesterol absorption efficiency that may be related to decreased intestinal Npc1l1 expression. Thus, PPARdelta is a promising target for drugs aimed to treat or prevent atherosclerosis.
van der Veen
Jelske N
JN
Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Hospital Groningen, Groningen, The Netherlands. j.n.van.der.veen@med.rug.nl
Kruit
Janine K
JK
Havinga
Rick
R
Baller
Julius F W
JF
Chimini
Giovanna
G
Lestavel
Sophie
S
Staels
Bart
B
Groot
Pieter H E
PH
Groen
Albert K
AK
Kuipers
Folkert
F
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018938:Caco-2 Cells / Q000187:drug effects; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism*; D011506:Proteins / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D013261:Sterols / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; C425931:GW 501516; C503394:GW 610742; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human; C482445:Npc1l1 protein, mouse; D047494:PPAR delta; D011506:Proteins; D012333:RNA, Messenger; D013261:Sterols; D013844:Thiazoles; D002784:Cholesterol