Atorvastatin increases intestinal expression of NPC1L1 in hyperlipidemic men

Inhibition of cholesterol synthesis by 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) inhibitors has been associated with an increase in intestinal cholesterol absorption. This study examined how HMG-CoAR inhibition by atorvastatin modulates expression of key genes involved in intestinal cholesterol metabolism. A crossover study was conducted in which 22 hyperlipidemic men received atorvastatin, 40 mg/day, or placebo, each for 12 weeks. Gene expression was assessed by real-time PCR using duodenal biopsy samples obtained at the end of each phase of treatment. Treatment with atorvastatin was associated with a 76% reduction in lathosterol and significant increases in sitosterol (70%). Atorvastatin significantly increased intestinal mRNA levels of HMG-CoAR (59%), LDL receptor (LDLR) (52%), PCSK9 (187%), SREBP-2 (44%), and HNF-4α (13%). Furthermore, atorvastatin significantly increased intestinal mRNA levels of NPC1L1 by 19% and decreased mRNA levels of both ABCG5 and ABCG8 by 14%. Positive correlations were observed between changes in SREBP-2 and HNF-4α expression and concurrent changes in the intestinal mRNA levels of HMG-CoAR, LDLR, and NPC1L1. These results indicate that HMG-CoAR inhibition with atorvastatin stimulates the intestinal expression of NPC1L1, LDLR, and PCSK9; increases cholesterol absorption; and reduces expression of ABCG5/8; these effects are most likely mediated by upregulation of the transcription factors SREBP-2 and HNF-4α. Inhibition of cholesterol synthesis by 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) inhibitors has been associated with an increase in intestinal cholesterol absorption. This study examined how HMG-CoAR inhibition by atorvastatin modulates expression of key genes involved in intestinal cholesterol metabolism. A crossover study was conducted in which 22 hyperlipidemic men received atorvastatin, 40 mg/day, or placebo, each for 12 weeks. Gene expression was assessed by real-time PCR using duodenal biopsy samples obtained at the end of each phase of treatment. Treatment with atorvastatin was associated with a 76% reduction in lathosterol and significant increases in sitosterol (70%). Atorvastatin significantly increased intestinal mRNA levels of HMG-CoAR (59%), LDL receptor (LDLR) (52%), PCSK9 (187%), SREBP-2 (44%), and HNF-4α (13%). Furthermore, atorvastatin significantly increased intestinal mRNA levels of NPC1L1 by 19% and decreased mRNA levels of both ABCG5 and ABCG8 by 14%. Positive correlations were observed between changes in SREBP-2 and HNF-4α expression and concurrent changes in the intestinal mRNA levels of HMG-CoAR, LDLR, and NPC1L1. These results indicate that HMG-CoAR inhibition with atorvastatin stimulates the intestinal expression of NPC1L1, LDLR, and PCSK9; increases cholesterol absorption; and reduces expression of ABCG5/8; these effects are most likely mediated by upregulation of the transcription factors SREBP-2 and HNF-4α. The relationship between elevated plasma levels of LDL-cholesterol (LDL-C) and the risk of atherosclerosis has been very well established (1Coronary heart disease in seven countries.Circulation. 1970; 41: I1-I211PubMed Google Scholar, 2Castelli W.P. Epidemiology of coronary heart disease: the Framingham study.Am. J. Med. 1984; 76: 4-12Abstract Full Text PDF PubMed Scopus (856) Google Scholar, 3Stamler J. Wentworth D. Neaton J.D. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT).JAMA. 1986; 256: 2823-2828Crossref PubMed Scopus (1772) Google Scholar). Clinical trials have shown that reduction of LDL-C constitutes a primary strategy for the prevention and regression of coronary heart disease (4Genest J. McPherson R. Frohlich J. Anderson T. Campbell N. Carpentier A. Couture P. Dufour R. Fodor G. Francis G.A. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult—2009 recommendations.Can. J. Cardiol. 2009; 25: 567-579Abstract Full Text PDF PubMed Scopus (622) Google Scholar). Plasma cholesterol levels are regulated by feedback mechanisms including exogenous cholesterol absorption through the gastrointestinal tract and endogenous cholesterol synthesis by various tissues. Several studies have shown that the amount of dietary cholesterol absorbed also influences endogenous cholesterol synthesis (5Tilvis R.S. Miettinen T.A. Serum plant sterols and their relation to cholesterol absorption.Am. J. Clin. Nutr. 1986; 43: 92-97Crossref PubMed Scopus (273) Google Scholar, 6Matthan N.R. Raeini-Sarjaz M. Lichtenstein A.H. Ausman L.M. Jones P.J. Deuterium uptake and plasma cholesterol precursor levels correspond as methods for measurement of endogenous cholesterol synthesis in hypercholesterolemic women.Lipids. 2000; 35: 1037-1044Crossref PubMed Scopus (46) Google Scholar, 7Rajaratnam R.A. Gylling H. Miettinen T.A. Independent association of serum squalene and noncholesterol sterols with coronary artery disease in postmenopausal women.J. Am. Coll. Cardiol. 2000; 35: 1185-1191Crossref PubMed Scopus (143) Google Scholar). The newly identified Niemann-Pick C1-like 1 (NPC1L1) protein expressed at the apical membrane of enterocytes has been shown to play a crucial role in the absorption of cholesterol and plant sterol (8Altmann 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. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1410) Google Scholar). Several physiological determinants and pharmacological agents modulate cholesterol homeostasis, including genetic factors, body weight, ezetimibe therapy, and 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoAR) inhibitors (statins) therapy, the rate-limiting step in the cholesterol biosynthesis pathway (9Dietschy J.M. Turley S.D. Spady D.K. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans.J. Lipid Res. 1993; 34: 1637-1659Abstract Full Text PDF PubMed Google Scholar). For instance, obese subjects show an increase in cholesterol synthesis with an associated decrease in cholesterol absorption (10Stahlberg D. Rudling M. Angelin B. Bjorkhem I. Forsell P. Nilsell K. Einarsson K. Hepatic cholesterol metabolism in human obesity.Hepatology. 1997; 25: 1447-1450Crossref PubMed Scopus (76) Google Scholar, 11Miettinen T.A. Gylling H. Cholesterol absorption efficiency and sterol metabolism in obesity.Atherosclerosis. 2000; 153: 241-248Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar). Ezetimibe therapy has been shown to reduce intestinal cholesterol absorption while reciprocally elevating synthesis (12Sudhop T. Lutjohann D. Kodal A. Igel M. Tribble D.L. Shah S. Perevozskaya I. von Bergmann K. Inhibition of intestinal cholesterol absorption by ezetimibe in humans.Circulation. 2002; 106: 1943-1948Crossref PubMed Scopus (451) Google Scholar). These findings suggest the presence of a reciprocal relationship between cholesterol absorption and synthesis, as a change in one vector results in a compensatory and opposing change in the other. Although recent data suggest that statin therapy is associated with a rise in intestinal cholesterol absorption (13Miettinen T.A. Strandberg T.E. Gylling H. Noncholesterol sterols and cholesterol lowering by long-term simvastatin treatment in coronary patients: relation to basal serum cholestanol.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1340-1346Crossref PubMed Scopus (196) Google Scholar), the impact of HMG-CoAR inhibitors on cholesterol absorption and the molecular mechanisms underlying this effect has not been fully characterized. Therefore, the primary objective of the present study was to gain further insight into this key physiological process by examining the impact of a 12-week regimen of atorvastatin therapy, 40 mg/day, on intestinal expression of the sterol transporter NPC1L1 in subjects with mixed hyperlipidemia. Furthermore, we examined the impact of atorvastatin therapy on intestinal expression of the key gene products involved in cholesterol metabolism, such as ATP-binding cassette transporter 5 (ABCG5) and ABCG8, HMG-CoAR, LDL receptor, sterol regulatory element binding transcription factor 2 (SREBP-2), hepatocyte nuclear factor 4 α (HNF-4α), proprotein convertase subtilisin kexin-9 (PCSK9), and microsomal triglyceride transfer protein (MTTP). Gene expression studies were undertaken using a human duodenal biopsy model, which we have recently developed. Twenty-three men with plasma LDL-C levels above the 50th percentile for their age were recruited from the Quebec City area to participate in the study (14Connelly P.W. MacLean D.R. Horlick L. O'Connor B. Petrasovits A. Little J.A. Plasma lipids and lipoproteins and the prevalence of risk for coronary heart disease in Canadian adults. Canadian Heart Health Surveys Research Group.CMAJ. 1992; 146: 1977-1987PubMed Google Scholar). One subject had to be withdrawn from analyses because of poor RNA quality. Subjects were excluded if they had persistent elevation of serum transaminases; monogenic hyperlipidemia such as familial hypercholesterolemia; plasma triglyceride (TG) levels >4.5 mmol/l; a recent history of alcohol or drug abuse; diabetes mellitus; or a history of cancer. Furthermore, all participants were unrelated at the first and second degree. All eligible subjects had to be withdrawn from lipid-lowering medications for at least 6 weeks before the beginning of the study. The study consisted of a 1 week screening period and a 4 week placebo run-in period, followed by two consecutive 12 week double-blind treatment periods with atorvastatin, 40 mg/day, or placebo in random order. Fasting blood samples and duodenal biopsies were performed following each phase of treatment. Participants were instructed to take one capsule at the time of their evening meal. Compliance was assessed by pill counting. Participants were asked not to change their dietary habits or use of alcohol and level of physical exercise during the study. The research protocol was approved by the Laval University Medical Center ethical review committee, and written informed consent was obtained from each subject. Twelve hour fasting venous blood samples were obtained from an antecubital vein and collected in Vacutainer tubes containing EDTA (0.1%, final concentration) at the end of each phase of treatment. Plasma was separated from blood cells by centrifugation at 3,000 rpm for 10 min at 4°C. Plasma cholesterol and TG concentrations were determined with an Analyzer RA-1000 (Technicon Instruments Corporation, Tarrytown, NY), as previously described (15Moorjani S. Dupont A. Labrie F. Lupien P.J. Brun D. Gagné C. Giguère M. Bélanger A. Increase in plasma high-density lipoprotein concentration following complete androgen blockage in men with prostatic carcinoma.Metabolism. 1987; 36: 244-250Abstract Full Text PDF PubMed Scopus (191) Google Scholar). The LDL-C level was also calculated according to the equation described by Friedewald et al. (16Friedewald W.T. Levy R.I. Fredrickson D.S. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.Clin. Chem. 1972; 18: 499-502Crossref PubMed Scopus (63) Google Scholar): [LDL-C] = [total cholesterol] − [HDL-C] − [TG]/2.2, and HDL-cholesterol was measured as previously described (17Albers J.J. Warnick G.R. Wiebe D. King P. Steiner P. Smith L. C. A. K. S. of for cholesterol in high-density Chem. PubMed Scopus Google Scholar). Plasma was assessed by M. M. T. T. of in serum by a PubMed Scopus Google Scholar). protein concentrations were measured with a as described previously M. J. G.R. B. B. and of as of the risk for heart disease associated with plasma protein levels in Med. PubMed Scopus Google Scholar). Plasma concentrations of a precursor in the biosynthesis of and of the plant sterols and as plasma of intestinal cholesterol were at Laval using a to that described previously N.R. A. Lichtenstein A.H. of on cholesterol metabolism in with low Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). of between and sterols are in plasma by their concentrations have been expressed to the concentration of cholesterol to for of lipoprotein This for cholesterol absorption has been to that of the continuous of a continuous for measurement of cholesterol absorption in Lipid Res. Full Text PDF PubMed Google Scholar), both in H. Miettinen T.A. intestinal absorption and synthesis of cholesterol to in coronary 2002; Full Text Full Text PDF PubMed Scopus Google and T.A. R.S. Serum plant sterols and cholesterol cholesterol absorption and synthesis in of a J. PubMed Scopus Google Scholar). samples were obtained from the second of the during biopsy samples were collected using biopsy and in and at before RNA biopsy samples were in using a and a The RNA from samples were using an samples were also with an to RNA was into and at RNA was assessed with a as previously described N. J. real-time for using second and PubMed Scopus Google Scholar). and were performed using the second and as described in the study by et al. J.A. A. M. M. of human and expression and of 2000; PubMed Scopus Google and using the genes 1 and The and genes have been shown to have expression levels from through in various tissues. mRNA expression levels are expressed as the of using a of the of the The was established by using of PCR products and and by the samples were and protein from each was to and by (8Altmann 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. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1410) Google with S.P. Yao X. Hoos L.M. Tetzloff G. Davis Jr., H.R. S.W. of the and sterol transporter Niemann-Pick C1 Like 1 (NPC1L1) PubMed Scopus Google Scholar). NPC1L1 was with the (8Altmann 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. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1410) Google Scholar). Plasma PCSK9 was measured by using a human PCSK9 G. M. G. H. J. S. L. J. L. A for measurement of plasma Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). analyses were to the effects of atorvastatin on the and on mRNA were determined to the of were significant at a of All analyses were performed using body and were and Subjects their the study. One subject had to be withdrawn from the analyses because of poor RNA quality. 1 the of the 22 subjects following a 12-week treatment with atorvastatin and 40 mg/day, significantly levels of plasma cholesterol LDL-C TG = and = had significant effect on plasma concentrations and The impact of atorvastatin on plasma of cholesterol absorption and and on synthesis was also with placebo, atorvastatin significantly increased plasma and sitosterol and was associated with a significant reduction in plasma lathosterol The and of cholesterol homeostasis, were significantly following therapy with Atorvastatin significantly increased plasma levels of PCSK9 a binding protein the of the LDL receptor in PCSK9 as a of 2009; PubMed Scopus Google Scholar). in of plasma plasma and sitosterol is in of 22 participants changes in and sitosterol levels in the while changes in plasma TG and were in and for study expression level treatment of protein and of cholesterol synthesis and absorption from 22 subjects following 12-week treatment with atorvastatin, 40 are the between and treatment proprotein convertase subtilisin in a and of cholesterol synthesis and absorption from 22 subjects following 12-week treatment with atorvastatin, 40 are the between and treatment proprotein convertase subtilisin shown in studies of gene expression that atorvastatin significantly increased intestinal mRNA levels of HMG-CoAR LDL receptor = SREBP-2 and HNF-4α = mRNA expression levels of PCSK9 and NPC1L1 were also significantly increased by the atorvastatin decreased mRNA expression levels of ABCG5 and ABCG8 by = and = treatment with atorvastatin had significant impact on mRNA levels of binding transporter and shown in the changes in mRNA levels of HMG-CoAR, LDL receptor, and SREBP-2 were in at least of 22 while participants changes in NPC1L1 and expression in the gene mRNA expression of of gene of not binding binding protein transporter protein HMG-CoAR, hepatocyte nuclear microsomal triglyceride transfer NPC1L1, Niemann-Pick C1-like proprotein convertase subtilisin and sterol regulatory element binding transcription factors and in a not binding binding protein transporter protein HMG-CoAR, hepatocyte nuclear microsomal triglyceride transfer NPC1L1, Niemann-Pick C1-like proprotein convertase subtilisin and sterol regulatory element binding transcription factors and shown in changes in intestinal mRNA levels of ABCG5 were significantly with changes in mRNA levels of ABCG8, while changes in HNF-4α expression were and with changes in mRNA levels of 4 correlations between changes in SREBP-2 mRNA levels and concurrent changes in mRNA levels of HMG-CoAR = = LDL receptor = = and NPC1L1 = = correlations were also observed between changes in HNF-4α mRNA levels and concurrent changes in mRNA levels of HMG-CoAR = = LDL receptor = and NPC1L1 = between changes in HMG-CoAR, LDL receptor, and intestinal NPC1L1 mRNA expression and changes in intestinal SREBP-2 and HNF-4α mRNA expression following treatment with atorvastatin, 40 mg/day, placebo are treatment with atorvastatin, of changes in NPC1L1 protein expression in intestinal biopsy samples was increased by this not to a in protein significant was observed between changes in NPC1L1 protein levels and changes in mRNA levels of NPC1L1 not the present the 12-week treatment with atorvastatin, 40 mg/day, in a significant reduction in levels of plasma cholesterol TG LDL-C and Furthermore, atorvastatin significantly decreased plasma lathosterol a of cholesterol synthesis, and significantly increased plasma and sitosterol two of cholesterol absorption. treatment with atorvastatin intestinal mRNA levels of NPC1L1 HMG-CoAR LDL receptor (52%), SREBP-2 HNF-4α and PCSK9 and expression by 14%. The homeostasis of cholesterol levels is by cholesterol absorption and synthesis J.M. of cholesterol and fasting on sterol synthesis in of the Lipid Res. Full Text PDF PubMed Google Scholar, D.K. J.M. synthesis in in of the and Lipid Res. Full Text PDF PubMed Google Scholar). Several factors have been shown to cholesterol homeostasis including genetic factors, body weight, and various agents such as and plant sterols (9Dietschy J.M. Turley S.D. Spady D.K. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans.J. Lipid Res. 1993; 34: 1637-1659Abstract Full Text PDF PubMed Google Scholar). data have that the of cholesterol synthesis by statin therapy is by a rise in intestinal cholesterol absorption T.A. Gylling H. Cholesterol absorption efficiency and sterol metabolism in obesity.Atherosclerosis. 2000; 153: 241-248Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar). study is with this Jones P.J. Frohlich J.J. of 3-hydroxy-3-methylglutaryl A reductase on sterol absorption in hypercholesterolemic Full Text PDF PubMed Scopus Google Scholar, T.A. Gylling H. and absorption of cholesterol in serum and lipoproteins during a of statin J. Clin. PubMed Scopus (119) Google Scholar), shown a reduction in plasma lathosterol levels by an increase in both and sitosterol following treatment with the present treatment with atorvastatin significantly increased intestinal mRNA levels of NPC1L1, which was by a increase in NPC1L1 protein with a study with that NPC1L1 expression was increased in both the and the liver by therapy with ezetimibe and simvastatin J.D. The molecular mechanisms underlying the reduction of LDL by ezetimibe Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). of the nuclear transcription factor SREBP-2 is to be regulated by sterols and was recently to NPC1L1 transcription F. A. S. A. of human Niemann-Pick C1-like 1 gene expression by Role of sterol regulatory element binding protein J. PubMed Scopus Google Scholar). a key of and metabolism, has also been to with SREBP-2 in the of NPC1L1 expression T. H. is a crucial of the of Res. 25: PubMed Scopus Google Scholar). results a between changes in NPC1L1 and changes in both SREBP-2 and HNF-4α mRNA a that the that these transcription factors intestinal NPC1L1 Therefore, is likely that the increase in mRNA expression of NPC1L1 cholesterol the with by sterols the NPC1L1 (8Altmann 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. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1410) Google Scholar). 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RNA levels of genes involved in of lipoproteins in 2 the role of Niemann-Pick C1-like ATP-binding and and of microsomal triglyceride transfer PubMed Scopus Google a significant increase in intestinal mRNA expression in following treatment with These with findings that intestinal mRNA expression of was decreased following atorvastatin Therefore, in different in the in to cholesterol associated with HMG-CoAR studies are to this Although was a between expression of the two the between changes in ABCG5 and ABCG8 expression observed in the present study the that these two are and that of ABCG5 and ABCG8 be regulated at the the of and of cholesterol absorption was that of NPC1L1 and that or play an role in cholesterol metabolism. these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and increases cholesterol and reduces these effects are mediated most likely by of the transcription factors SREBP-2 and HNF-4α. 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