December 17, 2004Journal of Lipid Research184 citationsOpen Access

Reduced cholesterol absorption upon PPARδ activation coincides with decreased intestinal expression of NPC1L1

JVJelske N. van der VeenUniversity of Alberta JKJanine K. KruitUniversity Medical Center Groningen RHRick HavingaUniversity Medical Center Groningen

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Abstract

Peroxisome proliferator-activated receptors (PPARs) control the transcription of genes involved in lipid metabolism. Activation of PPARδ 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 PPARδ activation by GW610742 were evaluated in wild-type and Abca1-deficient (Abca1−/−) mice that lack HDL. Treatment with GW610742 resulted in an ∼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, PPARδ 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. PPARδ activation is associated with increased plasma HDL and reduced intestinal cholesterol absorption efficiency that may be related to decreased intestinal Npc1l1 expression.Thus, PPARδ is a promising target for drugs aimed to treat or prevent atherosclerosis. Peroxisome proliferator-activated receptors (PPARs) control the transcription of genes involved in lipid metabolism. Activation of PPARδ 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 PPARδ activation by GW610742 were evaluated in wild-type and Abca1-deficient (Abca1−/−) mice that lack HDL. Treatment with GW610742 resulted in an ∼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, PPARδ 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. PPARδ activation is associated with increased plasma HDL and reduced intestinal cholesterol absorption efficiency that may be related to decreased intestinal Npc1l1 expression. Thus, PPARδ is a promising target for drugs aimed to treat or prevent atherosclerosis. Plasma levels of HDL-cholesterol are inversely related to the development of atherosclerosis (1Castelli W.P. Garrison R.J. Wilson P.W. Abbott R.D. Kalousdian S. Kannel W.B. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study.J. Am. Med. Assoc. 1986; 256: 2835-2838Crossref PubMed Scopus (2060) Google Scholar). This protective effect has been attributed to a role of HDL in reverse cholesterol transport (RCT), defined as the flux of excess cholesterol from peripheral cells to nascent HDL particles followed by transport to the liver. The liver is able to secrete cholesterol into bile, either as free cholesterol or after conversion into bile salts, for removal via the feces. Stimulation of HDL-mediated cholesterol efflux is considered an attractive approach to diminish the development of atherosclerosis. ABCA1 is considered to be essential in RCT (2Brooks-Wilson A. Marcil M. Clee S.M. Zhang L.H. Roomp K. Dam M. van Yu L. Brewer C. Collins J.A. Molhuizen H.O. Loubser O. Ouelette B.F. Fichter K. Ashbourne-Excoffon K.J. Sensen C.W. Scherer S. Mott S. Denis M. Martindale D. Frohlich J. Morgan K. Koop B. Pimstone S. Kastelein J.J. Hayden M.R. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.Nat. Genet. 1999; 22: 336-345Crossref PubMed Scopus (1481) Google Scholar). ABCA1 is ubiquitously expressed and probably involved in the formation of preβ-HDL particles and the efflux of cholesterol from peripheral tissues toward HDL (3Tall A.R. Costet P. Wang N. Regulation and mechanisms of macrophage cholesterol efflux.J. Clin. Invest. 2002; 110: 899-904Crossref PubMed Scopus (185) Google Scholar). HDL is considered a major source for bile-destined cholesterol (4Schwartz C.C. Halloran L.G. Vlahcevic Z.R. Gregory D.H. Swell L. Preferential utilization of free cholesterol from high-density lipoproteins for biliary cholesterol secretion in man.Science. 1978; 200: 62-64Crossref PubMed Scopus (216) Google Scholar). However, we recently demonstrated that, despite the absence of HDL, hepatobiliary cholesterol flux and fecal sterol excretion are not affected in Abca1-deficient (Abca1−/−) mice (5Groen A.K. Bloks V.W. Bandsma R.H. Ottenhoff R. Chimini G. Kuipers F. Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL.J. Clin. Invest. 2001; 108: 843-850Crossref PubMed Scopus (142) Google Scholar, 6Plösch T. Kok T. Bloks V.W. Smit M.J. Havinga R. Chimini G. Groen A.K. Kuipers F. Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1.J. Biol. Chem. 2002; 277: 33870-33877Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). The ABCG5/ABCG8 heterodimer was recently shown to be of crucial importance for hepatobiliary cholesterol secretion and for transport of cholesterol from enterocytes back into the intestinal lumen, thereby promoting net cholesterol removal from the body (7Kosters A. Frijters R.J. Schaap F.G. Vink E. Plösch T. Ottenhoff R. Jirsa M. De Cuyper I.M. Kuipers F. Groen A.K. Relation between hepatic expression of ATP-binding cassette transporters G5 and G8 and biliary cholesterol secretion in mice.J. Hepatol. 2003; 38: 710-716Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 8Yu L. Li-Hawkins J. Hammer R.E. Berge K.E. Horton J.D. Cohen J.C. Hobbs H.H. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol.J. Clin. Invest. 2002; 110: 671-680Crossref PubMed Scopus (594) Google Scholar). Several genes involved in the control of cholesterol metabolism are transcriptionally regulated by nuclear receptors. Peroxisome proliferator-activated receptors (PPARs) constitute a subgroup of the nuclear receptor superfamily, designated PPARα (NR1C1), PPARδ/β (NR1C2), and PPARγ (NR1C3), all of which serve functions in lipid homeostasis and energy metabolism (9Duval C. Chinetti G. Trottein F. Fruchart J.C. Staels B. The role of PPARs in atherosclerosis.Trends Mol. Med. 2002; 8: 422-430Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). PPARδ is ubiquitously expressed and activated by long-chain fatty acids and prostacyclins. Recent work suggests that activation of PPARδ may induce RCT and hence have antiatherogenic effects (10Oliver Jr., W.R. Shenk J.L. Snaith M.R. Russell C.S. Plunket K.D. Bodkin N.L. Lewis M.C. Winegar D.A. Sznaidman M.L. Lambert M.H. Xu H.E. Sternbach D.D. Kliewer S.A. Hansen B.C. Willson T.M. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport.Proc. Natl. Acad. Sci. USA. 2001; 98: 5306-5311Crossref PubMed Scopus (956) Google Scholar). Whether or not PPARδ activation, like PPARα activation (11Kok T. Bloks V.W. Wolters H. Havinga R. Jansen P.L. Staels B. Kuipers F. Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice.Biochem. J. 2003; 369: 539-547Crossref PubMed Scopus (141) Google Scholar, 12Post S.M. Duez H. Gervois P.P. Staels B. Kuipers F. Princen H.M. Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase expression.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1840-1845Crossref PubMed Scopus (168) Google Scholar), is associated with altered bile formation and fecal sterol loss is not known. This study shows that PPARδ activation in mice increased plasma HDL concentrations and accelerated fecal cholesterol removal from the body without changing hepatobiliary sterol excretion. Moreover, intestinal cholesterol absorption efficiency was reduced upon PPARδ activation, which coincided with the downregulation of intestinal gene expression of the very recently identified cholesterol absorption protein Niemann-Pick C1-like 1 (NPC1L1) (13Altmann S.W. Davis Jr., H.R. Zhu L.J. Yao X. Hoos L.M. Tetzloff G. Iyer S.P. Maguire M. Golovko A. Zeng M. Wang L. Murgolo N. Graziano M.P. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1387) Google Scholar). Female Abca1−/− mice with a DBA/1 background and age-matched DBA/1 wild-type mice were purchased from IFFA Credo (Saint-Germain-sur-l'Arbesle, France). Separate groups of wild-type DBA/1 mice were obtained from Harlan (Horst, The were in with for the of GW610742 a for The of as evaluated by of for PPARδ and for PPARα and and the are and M.L. A. E. D. M.L. C. Xu H.E. Lambert M.H. Willson T.M. W.R. Sternbach D.D. selective for peroxisome proliferator-activated receptor delta and Med. Chem. 2003; PubMed Scopus Google The of has been (10Oliver Jr., W.R. Shenk J.L. Snaith M.R. Russell C.S. Plunket K.D. Bodkin N.L. Lewis M.C. Winegar D.A. Sznaidman M.L. Lambert M.H. Xu H.E. Sternbach D.D. Kliewer S.A. Hansen B.C. Willson T.M. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport.Proc. Natl. Acad. Sci. USA. 2001; 98: 5306-5311Crossref PubMed Scopus (956) Google Scholar, M.L. A. E. D. M.L. C. Xu H.E. Lambert M.H. Willson T.M. W.R. Sternbach D.D. selective for peroxisome proliferator-activated receptor delta and Med. Chem. 2003; PubMed Scopus Google Scholar). Abca1−/− and DBA/1 wild-type mice were GW610742 through a of for an of an of to an plasma of 1 mice without was from mice. were by of and was for after the and a was by and were of both liver and were in and for and for were in and or in were and hepatic and biliary were of lipid and J. Scopus Google Scholar). and plasma concentrations of and were as T. Kok T. Bloks V.W. Smit M.J. Havinga R. Chimini G. Groen A.K. Kuipers F. Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1.J. Biol. Chem. 2002; 277: 33870-33877Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). neutral and fatty acids were by in and in bile were plasma were for lipoprotein by and were as by Plösch T. Kok T. Bloks V.W. Smit M.J. Havinga R. Chimini G. Groen A.K. Kuipers F. Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1.J. Biol. Chem. 2002; 277: 33870-33877Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). and for Abca1, Abcg5, Abcg8, 3-hydroxy-3-methylglutaryl-coenzyme A reductase liver X receptor multidrug resistance 2 and receptor T. Kok T. Bloks V.W. Smit M.J. Havinga R. Chimini G. Groen A.K. Kuipers F. Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1.J. Biol. Chem. 2002; 277: 33870-33877Abstract Full Text Full Text PDF PubMed Scopus (176) Google as as for (11Kok T. Bloks V.W. Wolters H. Havinga R. Jansen P.L. Staels B. Kuipers F. Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice.Biochem. J. 2003; 369: 539-547Crossref PubMed Scopus (141) Google have been the were and and and and DBA/1 wild-type mice were with the for of and untreated DBA/1 wild-type mice were as by N. M. lipoprotein receptor of formation in Thromb. Vasc. Biol. PubMed Scopus Google Scholar). were and and were as absorption was the plasma and of the plasma for the of intestinal cholesterol absorption in the Full Text PDF PubMed Google Scholar). DBA/1 wild-type mice a with or without mice an of of in and an of of in and after were by and was mice were and bile was for and in bile, and was by obtained after were for the of cholesterol were obtained from and were obtained from France). cells were in a in essential and with and and the intestinal for the cells and were a of cells and in the was after were in with in the and in the were cells were activated with for PPARα PPARγ or PPARδ for in the were with and and was France). were reverse and reverse were by a for was in a of of the as by the and France). The were for followed by of and levels were to The activated was to the control was in of and was after were by and peroxisome was by was after a were for and untreated groups were by was considered 1 shows that body of DBA/1 wild-type and Abca1−/− mice were similar and not by treatment with of untreated wild-type and Abca1−/− mice not treatment with the PPARδ agonist resulted in increased liver in both This was probably related to peroxisome as by enhanced in liver of not Treatment with GW610742 not induce liver as by plasma and and plasma and hepatic lipid concentrations in untreated and DBA/1 wild-type and Abca1−/− of body between and untreated mice with the between and untreated mice with the between wild-type and Abca1−/− mice with the treatment. cholesterol between wild-type and Abca1−/− mice with the between and untreated mice with the between wild-type and Abca1−/− mice with the cholesterol between and untreated mice with the are expressed as in all between and untreated mice with the between wild-type and Abca1−/− mice with the treatment. in a are expressed as in all with (5Groen A.K. Bloks V.W. Bandsma R.H. Ottenhoff R. Chimini G. Kuipers F. Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL.J. Clin. Invest. 2001; 108: 843-850Crossref PubMed Scopus (142) Google Scholar, J. R.J. D. T. C. C. M.L. L.J. J. C. Chimini G. lipoprotein and in mice with of ATP-binding cassette Natl. Acad. Sci. USA. PubMed Scopus Google Scholar), plasma cholesterol levels were in Abca1−/− mice in wild-type mice Treatment with GW610742 increased plasma cholesterol by in wild-type mice, whereas cholesterol levels in Abca1−/− mice remained extremely the lack of HDL-cholesterol in Abca1−/− mice and an ∼50% increase in HDL-cholesterol levels in wild-type mice upon PPARδ levels of both and in of wild-type mice were upon PPARδ activation that GW610742 induce concentrations of and were similar in wild-type and Abca1−/− mice and were not affected by PPARδ activation in wild-type mice, whereas hepatic were increased upon treatment in Abca1−/− mice. secretion rates of bile salts, and were similar in untreated Abca1−/− mice with wild-type mice in with (5Groen A.K. Bloks V.W. Bandsma R.H. Ottenhoff R. Chimini G. Kuipers F. Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL.J. Clin. Invest. 2001; 108: 843-850Crossref PubMed Scopus (142) Google Scholar). Treatment with GW610742 not significantly biliary secretion rates in wild-type or Abca1−/− mice. This is in with the absence of any effect the hepatic expression of genes involved in cholesterol metabolism and transport hepatic (Mdr2) expression was significantly upon not biliary a expression of the PPARδ target gene S. J.A. Winegar D.A. J.C. acid homeostasis and of lipid genes in of peroxisome proliferator-activated receptor alpha mice. for regulation by Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google was expression of gene was upon PPARδ activation in both of and biliary secretion rates in untreated and DBA/1 wild-type and Abca1−/− body body body are expressed as in all in a are expressed as in all excretion of was similar in all groups However, fecal excretion of neutral of which was to increased upon PPARδ activation in wild-type and Abca1−/− mice hepatobiliary efflux of cholesterol was not upon increased sterol excretion be by intestinal shows that intestinal expression levels of Abca1, Abcg5, and were not affected upon treatment with of which is for the of cholesterol in enterocytes and crucial for cholesterol and of the in cholesterol were increased intestinal may have to the increased fecal cholesterol excretion through accelerated was intestinal not any of accelerated upon PPARδ activation not that PPARδ activation led to a 43% reduction of cholesterol absorption efficiency in DBA/1 wild-type mice, despite the expression levels of and was identified as a critical of the intestinal cholesterol absorption (13Altmann S.W. Davis Jr., H.R. Zhu L.J. Yao X. Hoos L.M. Tetzloff G. Iyer S.P. Maguire M. Golovko A. Zeng M. Wang L. Murgolo N. Graziano M.P. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1387) Google Scholar). we levels of Npc1l1 the of the of untreated and mice. of the gene was decreased by in the upon PPARδ activation and was in of A similar in intestinal Npc1l1 expression was in Abca1−/− mice upon treatment with of Niemann-Pick C1-like 1 (Npc1l1) the of the of untreated and DBA/1 wild-type mice, by are as of in are to and expression in of untreated mice was to by cholesterol absorption is from increased fecal of in mice. shows that fecal excretion of was upon treatment with which is in to of biliary However, the increase in fecal loss is the of a reduction in cholesterol absorption that cholesterol may be from plasma into the intestinal Plösch T. Havinga R. R. Groen A.K. Kuipers F. Increased fecal neutral sterol loss upon liver X receptor activation is independent of biliary sterol secretion in 2004; Full Text Full Text PDF Scopus Google Scholar). of cholesterol into bile was not affected by PPARδ activation, as shown in excretion of bile was in the mice, probably of the efficiency of cholesterol absorption in absorption was not affected by treatment with the PPARδ as by similar fecal excretion rates in both groups not the of the effects Npc1l1 we evaluated the of and PPARδ activation by in that both the PPARα agonist and the PPARγ agonist effect Npc1l1 whereas the PPARδ agonist a reduction in Npc1l1 expression. This that the reduced expression of Npc1l1 is for PPARδ This study shows that activation of PPARδ in increased plasma HDL levels in DBA/1 wild-type mice. increased HDL levels theoretically cholesterol to the liver for excretion into bile, hepatobiliary excretion of cholesterol and bile was not affected upon PPARδ activation in wild-type mice. excretion rates were similar in wild-type and Abca1−/− mice, that HDL is not an essential source of biliary cholesterol in mice (5Groen A.K. Bloks V.W. Bandsma R.H. Ottenhoff R. Chimini G. Kuipers F. Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL.J. Clin. Invest. 2001; 108: 843-850Crossref PubMed Scopus (142) Google Scholar, 6Plösch T. Kok T. Bloks V.W. Smit M.J. Havinga R. Chimini G. Groen A.K. Kuipers F. Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1.J. Biol. Chem. 2002; 277: 33870-33877Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). of the unaltered biliary excretion fecal loss of neutral was in both after treatment with which not be to either increased intestinal cholesterol synthesis or accelerated intestinal PPARδ activation reduced cholesterol absorption efficiency in wild-type mice without any in intestinal Abca1, Abcg5, or expression not of cholesterol absorption without changes in and expression has been upon treatment of mice with the cholesterol J.J. of cholesterol absorption by in the is not via changes in the expression of for or ABCG8 in the 2002; Full Text Full Text PDF PubMed Scopus Google intestinal expression of the recently target of Npc1l1 (13Altmann S.W. Davis Jr., H.R. Zhu L.J. Yao X. Hoos L.M. Tetzloff G. Iyer S.P. Maguire M. Golovko A. Zeng M. Wang L. Murgolo N. Graziano M.P. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1387) Google Scholar), to be decreased upon PPARδ to the in and (10Oliver Jr., W.R. Shenk J.L. Snaith M.R. Russell C.S. Plunket K.D. Bodkin N.L. Lewis M.C. Winegar D.A. Sznaidman M.L. Lambert M.H. Xu H.E. Sternbach D.D. Kliewer S.A. Hansen B.C. Willson T.M. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport.Proc. Natl. Acad. Sci. USA. 2001; 98: 5306-5311Crossref PubMed Scopus (956) Google Scholar), PPARδ activation altered plasma lipid in wild-type mice by HDL-cholesterol This increase in HDL-cholesterol levels was not in Abca1−/− mice, the essential role of ABCA1 in HDL The of by which PPARδ activation HDL-cholesterol concentrations to be expression of as as in from wild-type mice suggests that of efflux may However, M. R.J. expression of ABCA1 has to plasma HDL Clin. Invest. 2001; 108: PubMed Scopus Google that the of cholesterol to plasma HDL levels is in plasma HDL-cholesterol levels probably efflux in all peripheral and cholesterol efflux to be a major source of plasma HDL-cholesterol in mice F. L. A. J. T. M.J. J. N. S. Brewer of the hepatic ABCA1 in cholesterol and plasma HDL cholesterol 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). Yet, we not the of hepatic expression. The for the in effects expression between and liver to be HDL-cholesterol is considered a source of biliary cholesterol (4Schwartz C.C. Halloran L.G. Vlahcevic Z.R. Gregory D.H. Swell L. Preferential utilization of free cholesterol from high-density lipoproteins for biliary cholesterol secretion in man.Science. 1978; 200: 62-64Crossref PubMed Scopus (216) Google Scholar). However, despite the in plasma HDL-cholesterol in biliary cholesterol excretion were between untreated wild-type and Abca1−/− mice or between and untreated wild-type mice. are with work (5Groen A.K. Bloks V.W. Bandsma R.H. Ottenhoff R. Chimini G. Kuipers F. Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL.J. Clin. Invest. 2001; 108: 843-850Crossref PubMed Scopus (142) Google Scholar, 6Plösch T. Kok T. Bloks V.W. Smit M.J. Havinga R. Chimini G. Groen A.K. Kuipers F. Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1.J. Biol. Chem. 2002; 277: 33870-33877Abstract Full Text Full Text PDF PubMed Scopus (176) Google that of HDL-cholesterol to the liver is not for biliary cholesterol secretion in mice. fecal excretion of neutral was to increased upon PPARδ activation in both wild-type and Abca1−/− mice, in of the that biliary cholesterol excretion was not This theoretically be to a intestinal cholesterol This has not been intestinal expression of was not affected upon PPARδ activation, which suggests unaltered intestinal cholesterol cholesterol is in the peripheral tissues in mice of cholesterol in the Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar), and peripheral synthesis may have been enhanced upon PPARδ activation to body cholesterol is that accelerated intestinal was the of enhanced fecal sterol of intestinal between and untreated mice. absorption efficiency was reduced upon PPARδ activation in wild-type mice. the of bile and into the intestinal lumen, for cholesterol absorption M. Russell of bile acid synthesis in the cholesterol 7alpha-hydroxylase are not by either cholesterol or 2001; Full Text Full Text PDF PubMed Google Scholar, Havinga R. Wolters H. Ottenhoff R. Princen H.M. Groen A.K. Kuipers F. plasma cholesterol and increased fecal sterol loss in multidrug resistance gene 2 Full Text Full Text PDF PubMed Scopus Google Scholar), as as expression were be as the of the reduced cholesterol reduced cholesterol absorption was not associated with any in the intestinal expression of and that PPARδ may cholesterol absorption by with by a that is related to the of of the cholesterol absorption J.J. of cholesterol absorption by in the is not via changes in the expression of for or ABCG8 in the 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). (13Altmann S.W. Davis Jr., H.R. Zhu L.J. Yao X. Hoos L.M. Tetzloff G. Iyer S.P. Maguire M. Golovko A. Zeng M. Wang L. Murgolo N. Graziano M.P. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1387) Google to be critical for intestinal cholesterol absorption and to a target of that PPARδ activation reduced intestinal expression of in the of the of the cholesterol absorption in that reduced expression of Npc1l1 is for PPARδ was effect of selective PPARα and PPARγ Npc1l1 expression in was a by the PPARδ that Npc1l1 is to PPARδ are the involved in Npc1l1 transcription PPARδ intestinal Npc1l1 expression by or to be the of protein is reduced in enterocytes of mice (13Altmann S.W. Davis Jr., H.R. Zhu L.J. Yao X. Hoos L.M. Tetzloff G. Iyer S.P. Maguire M. Golovko A. Zeng M. Wang L. Murgolo N. Graziano M.P. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1387) Google Scholar), is that the reduction in Npc1l1 levels was associated with reduced of the of absorption in mice into plasma and liver to be reduced by with wild-type mice, to Jr., H.R. Zhu L.J. Hoos L.M. Tetzloff G. Maguire M. J. Yao X. Iyer S.P. M.H. Graziano M.P. S.W. Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal and cholesterol and a of cholesterol Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). A reduction in fractional cholesterol absorption in mice with wild-type was after a (13Altmann S.W. Davis Jr., H.R. Zhu L.J. Yao X. Hoos L.M. Tetzloff G. Iyer S.P. Maguire M. Golovko A. Zeng M. Wang L. Murgolo N. Graziano M.P. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1387) Google Scholar). has been that PPARδ induce antiatherogenic (10Oliver Jr., W.R. Shenk J.L. Snaith M.R. Russell C.S. Plunket K.D. Bodkin N.L. Lewis M.C. Winegar D.A. Sznaidman M.L. Lambert M.H. Xu H.E. Sternbach D.D. Kliewer S.A. Hansen B.C. Willson T.M. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport.Proc. Natl. Acad. Sci. USA. 2001; 98: 5306-5311Crossref PubMed Scopus (956) Google Scholar). PPARδ activation resulted in increased HDL-cholesterol levels. However, antiatherogenic effects not be to be by of the of fecal cholesterol loss was enhanced without of hepatobiliary cholesterol excretion. Activation of PPARδ may excretion of cholesterol via the a that has been by Plösch T. Havinga R. R. Groen A.K. Kuipers F. Increased fecal neutral sterol loss upon liver X receptor activation is independent of biliary sterol secretion in 2004; Full Text Full Text PDF Scopus Google Scholar), as by the fecal excretion of neutral in mice enhanced fecal neutral sterol loss as a of impaired intestinal cholesterol absorption upon PPARδ activation, which in effect be considered a have shown a reduction of levels in H.E. S. R.H. L.J. B. C. and of in with of 2001; Full Text PDF PubMed Scopus Google and of atherosclerosis development in mice Jr., H.R. Hoos L. Tetzloff G. a cholesterol absorption the development of atherosclerosis in Thromb. Vasc. Biol. 2001; 21: PubMed Scopus Google upon of cholesterol absorption by that reduction of cholesterol absorption upon treatment with GW610742 in by reduced intestinal expression of a target of was shown to increase plasma HDL-cholesterol in mice and by an of Thus, PPARδ is a promising target for the development of drugs aimed atherosclerosis. The and Bloks for is for and This work was by from the for

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