Reduced cholesterol absorption upon PPAR activation coincides with decreased intestinal expression of NPC 1 L 1

Peroxisome proliferator-activated receptors (PPARs) control the transcription of genes involved in lipid metabolism. Activation of PPAR 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 PPAR 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, PPAR 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 NiemannPick C1-like 1 ( Npc1l1 ) in the intestine. PPAR activation is associated with increased plasma HDL and reduced intestinal cholesterol absorption efficiency that may be related to decreased intestinal Npc1l1 expression. Thus, PPAR is a promising target for drugs aimed to treat or prevent atherosclerosis. —van der Veen, J. N., J. K. Kruit, R. Havinga, J. F. W. Baller, G. Chimini, S. Lestavel, B. Staels, P. H. E. Groot, A. K. Groen, and F. Kuipers. Reduced cholesterol absorption upon PPAR activation coincides with decreased intestinal expression of NPC1L1. J. Lipid Res. 2005. 46: 526–534. Supplementary key words Niemann-Pick C1-like 1 • peroxisome proliferator-activated receptor • nuclear receptors • high density lipoprotein-cholesterol Plasma levels of HDL-cholesterol are inversely related to the development of atherosclerosis (1). 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 (2). ABCA1 is ubiquitously expressed and probably involved in the formation of pre -HDL particles and the efflux of cholesterol from peripheral tissues toward HDL (3). HDL is considered a major source for bile-destined cholesterol (4). 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 (5, 6). 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 (7, 8). Several genes involved in the control of cholesterol meAbbreviations: Abca1 / , Abca1-deficient; FPLC, fast-protein liquid chromatography; Hmgr, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; Mdr2, multidrug resistance P-glycoprotein 2; NPC1L1, Niemann-Pick C1-like 1; Pdk4, pyruvate dehydrogenase kinase isoenzyme 4; PPAR, peroxisome proliferator-activated receptor; RCT, reverse cholesterol transport; Sr-b1, scavenger receptor B1. 1 To whom correspondence should be addressed. e-mail: j.n.van.der.veen@med.rug.nl 2 J. N. van der Veen and J. K. Kruit contributed equally to this work. Manuscript received 12 October 2004 and in revised form 23 November 2004. Published, JLR Papers in Press, December 16, 2004. DOI 10.1194/jlr.M400400-JLR200 at P E N N S T A T E U N IV E R S IT Y , on F ebuary 3, 2013 w w w .j.org D ow nladed fom