Nuclear receptors in control of cholesterol transport

Objectives-Peroxisome proliferator-activated receptors (PPARs) control transcription of genes involved in lipid metabolism. Activation of PPAR d may have anti-atherogenic effects through elevation of plasma HDL, theoretically promoting reverse cholesterol transport from peripheral tissues towards the liver for removal via bile and feces. Methods and results-Effects of PPAR d activation by GW610742 were evaluated in wild-type and Abca1-deficient ( Abca1 -/- ) mice that lack HDL. Treatment with GW610742 resulted in a ~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 d activation led to enhanced fecal neutral sterol loss in both groups without any changes in intestinal Abca1 , Abcg5 , Abcg8 and HMG-CoA 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. Conclusions-PPAR d activation is associated with elevated plasma HDL and reduced intestinal cholesterol absorption efficiency that may be related to decreased intestinal Npc1l1 expression. Thus, PPAR d is a promising target for drugs aimed to treat or prevent atherosclerosis.

[1]  Jianjun Liu,et al.  Niemann-Pick C1 Like 1 (NPC1L1) Is the Intestinal Phytosterol and Cholesterol Transporter and a Key Modulator of Whole-body Cholesterol Homeostasis* , 2004, Journal of Biological Chemistry.

[2]  F. Kuipers,et al.  Relation between hepatic expression of ATP-binding cassette transporters G5 and G8 and biliary cholesterol secretion in mice. , 2003, Journal of hepatology.

[3]  H. Brewer,et al.  Role of the hepatic ABCA1 transporter in modulating intrahepatic cholesterol and plasma HDL cholesterol concentrations Published, JLR Papers in Press, November 4, 2002. DOI 10.1194/jlr.M200414-JLR200 , 2003, Journal of Lipid Research.

[4]  B. Staels,et al.  Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice. , 2003, The Biochemical journal.

[5]  J. Repa,et al.  Inhibition of cholesterol absorption by SCH 58053 in the mouse is not mediated via changes in the expression of mRNA for ABCA1, ABCG5, or ABCG8 in the enterocyte Published, JLR Papers in Press, August 16, 2002. DOI 10.1194/jlr.M200144-JLR200 , 2002, Journal of Lipid Research.

[6]  A. Tall,et al.  Regulation and mechanisms of macrophage cholesterol efflux. , 2002, The Journal of clinical investigation.

[7]  M. Smit,et al.  Increased Hepatobiliary and Fecal Cholesterol Excretion upon Activation of the Liver X Receptor Is Independent of ABCA1* , 2002, The Journal of Biological Chemistry.

[8]  B. Staels,et al.  The role of PPARs in atherosclerosis. , 2002, Trends in molecular medicine.

[9]  Jonathan C. Cohen,et al.  Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. , 2002, The Journal of clinical investigation.

[10]  W. Kraus,et al.  Fatty Acid Homeostasis and Induction of Lipid Regulatory Genes in Skeletal Muscles of Peroxisome Proliferator-activated Receptor (PPAR) α Knock-out Mice , 2002, The Journal of Biological Chemistry.

[11]  J. Dietschy,et al.  Control of Cholesterol Turnover in the Mouse* , 2002, The Journal of Biological Chemistry.

[12]  H. Davis,et al.  Ezetimibe, a Potent Cholesterol Absorption Inhibitor, Inhibits the Development of Atherosclerosis in ApoE Knockout Mice , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[13]  O. Francone,et al.  Monocyte/macrophage expression of ABCA1 has minimal contribution to plasma HDL levels. , 2001, The Journal of clinical investigation.

[14]  B Staels,et al.  Fibrates Suppress Bile Acid Synthesis via Peroxisome Proliferator–Activated Receptor-&agr;–Mediated Downregulation of Cholesterol 7&agr;-Hydroxylase and Sterol 27-Hydroxylase Expression , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[15]  D. Russell,et al.  Alternate pathways of bile acid synthesis in the cholesterol 7alpha-hydroxylase knockout mouse are not upregulated by either cholesterol or cholestyramine feeding. , 2001, Journal of lipid research.

[16]  H. Bays,et al.  Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies. , 2001, Clinical therapeutics.

[17]  S. Kliewer,et al.  A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[18]  F. Kuipers,et al.  Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL. , 2001, The Journal of clinical investigation.

[19]  T. V. van Berkel,et al.  Low density lipoprotein receptor of macrophages facilitates atherosclerotic lesion formation in C57Bl/6 mice. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[20]  C. Gabel,et al.  High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[21]  C. Sensen,et al.  Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency , 1999, Nature Genetics.

[22]  F. Kuipers,et al.  Reduced plasma cholesterol and increased fecal sterol loss in multidrug resistance gene 2 P-glycoprotein-deficient mice. , 1998, Gastroenterology.

[23]  J. Dietschy,et al.  Reevaluation and application of the dual-isotope plasma ratio method for the measurement of intestinal cholesterol absorption in the hamster. , 1994, Journal of lipid research.

[24]  P. Wilson,et al.  Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. , 1986, JAMA.

[25]  D. H. Gregory,et al.  Preferential utilization of free cholesterol from high-density lipoproteins for biliary cholesterol secretion in man. , 1978, Science.

[26]  W. J. Dyer,et al.  A rapid method of total lipid extraction and purification. , 1959, Canadian journal of biochemistry and physiology.

[27]  F. Kuipers,et al.  Increased fecal neutral sterol loss upon liver X receptor activation is independent of biliary sterol secretion in mice. , 2005, Gastroenterology.

[28]  T. Willson,et al.  Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)--synthesis and biological activity. , 2003, Bioorganic & medicinal chemistry letters.

[29]  Luquan Wang,et al.  Materials and Methods Figs. S1 to S4 Tables S1 and S2 References Niemann-pick C1 like 1 Protein Is Critical for Intestinal Cholesterol Absorption , 2022 .