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62: Increased degradation of cholesterol via the alternate pathway of bile acid biosynthesis in primary hypercholesterolemia
Journal of Clinical Lipidology, Vol 2, No 5S, October 2008
(PCNA) expression, and Transwell assay, respectively. Moreover, overexpression of constitutively active Notch 1 IC blocked the EtOHinduced inhibition of SMC proliferation. Ligation of the murine carotid artery induced a reproducible remodeling response, including SMC proliferation, neointimal lesion formation and an increase in medial thickness. Notch 1 and Hrt 1 and 2 mRNA expression was increased in the ligated remodeled vessel, compared to control vessels. The remodeling response was inhibited in mice that received ‘moderate’ amounts of alcohol (15 mM) by gavage daily. Moreover, Notch and Hrt expression induced following vascular injury was inhibited by alcohol feeding, as determined by immunohistochemical staining.Conclusions: EtOH inhibits Notch signaling in vascular smooth muscle cells. These novel actions of EtOH may be relevant to the cardiovascular protective effects of alcohol consumption purported by epidemiological studies. Funding: National Institutes of Health (USA) RO1 AA-12610 to E.M.R.
i.v. infusion of deuterated 27-hydroxycholesterol. Isotope enrichment and 27-OH rates were determined by GC-MS. The data were compared with those obtained in 4 normolipidemic controls. In some patients the infusions were repeated during treatment with atorvastatin or rosuvastatin. Results: 27-OH rates were higher in HCH patients (8.7±2.7 mg/h vs controls, 3.7±1.2 mg/h, mean±SD, p < 0.01). After treatment with either statin, hydroxylation rates dropped by nearly 50% along with a drastic reduction in plasma total and LDL-cholesterol. Regression analysis showed a correlation trend between plasma cholesterol and 27-OH rates. Conclusions: Primary HCH associates with increased 27-OH, which tend to normalize during hypocholesterolemic treatment. Such relationship supports the view that 27-OH may act as a compensatory mechanism in a condition of larger plasma cholesterol pool. A regulatory role for hepatic and extrahepatic nuclear receptors seems reasonable. These data encourage novel approaches for the management of HCH and the prevention of atherosclerosis. Funding: GRANT SUPPORT. Supported by COFIN-PRIN grant 2004067491
62 INCREASED DEGRADATION OF CHOLESTEROL VIA THE ALTERNATE PATHWAY OF BILE ACID BIOSYNTHESIS IN PRIMARY HYPERCHOLESTEROLEMIA M. Bertolotti1, M. Del Puppo2, C. Gabbi1, C. Anzivino1, L. Carulli1, M. Galli Kienle2, N. Carulli1. 1University of Modena and Reggio Emilia, Dept. of Medicine Endocrinology Metabolism and Geriatrics, Modena, Italy, 2University of Milano Bicocca, Dept. of Experimental Medicine, Monza, Italy Background: The first step in the alternate pathway of bile acid synthesis is represented by cholesterol 27-hydroxylation (27-OH), which takes place both in liver and in extrahepatic tissues. Such pathway is believed to play a role in peripheral degradation of cholesterol. Aim: of the present study was to investigate 27-OH rates in hypercholesterolemia (HCH), and to assess the effects induced by treatment with statins. Methods: Seven patients with primary HCH underwent determination of 27-OH rates in vivo by
63 DOES THE EFFICACY OF EZETIMIBE/SIMVASTATIN 10/40 MG DIFFER FROM DOSE-DOUBLING OF DIFFERENT POTENCY STATINS IN PATIENTS WITH A RECENT CORONARY EVENT? P. Brudi1, J.P.D Reckless2, P. Henry3, T. Pomykaj4, S.T. Lim5, R. Massaad6, K. Vandormael6, A.O. Johnson-Levonas7. 1Merck Schering-Plough, Whitehouse Station, NJ, USA, 2Royal United Hospital, Bath, United Kingdom, 3Hospital Lariboisiere, Paris, France, 4Stadtisches Klinikum Braunschweig, Braunschweig, Germany, 5National Heart Center, Singapore, 6Merck Sharp & Dohme, Brussels, Belgium, 7Merck Research Laboratories, Rahway, NJ, USA Objective: Does doubling doses of low, medium and high potency statins have different lipid efficacy than switching to ezetimibe/simvastatin (EZE/SIMVA) 10/40 mg in 424 pts on stable statin dose (>6 wks) with a recent coronary event (RCE)? Methods: Open-label study stratified by baseline-
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(PCNA) expression, and Transwell assay, respectively. Moreover, overexpression of constitutively active Notch 1 IC blocked the EtOHinduced inhibition of SMC proliferation. Ligation of the murine carotid artery induced a reproducible remodeling response, including SMC proliferation, neointimal lesion formation and an increase in medial thickness. Notch 1 and Hrt 1 and 2 mRNA expression was increased in the ligated remodeled vessel, compared to control vessels. The remodeling response was inhibited in mice that received ‘moderate’ amounts of alcohol (15 mM) by gavage daily. Moreover, Notch and Hrt expression induced following vascular injury was inhibited by alcohol feeding, as determined by immunohistochemical staining.Conclusions: EtOH inhibits Notch signaling in vascular smooth muscle cells. These novel actions of EtOH may be relevant to the cardiovascular protective effects of alcohol consumption purported by epidemiological studies. Funding: National Institutes of Health (USA) RO1 AA-12610 to E.M.R.
i.v. infusion of deuterated 27-hydroxycholesterol. Isotope enrichment and 27-OH rates were determined by GC-MS. The data were compared with those obtained in 4 normolipidemic controls. In some patients the infusions were repeated during treatment with atorvastatin or rosuvastatin. Results: 27-OH rates were higher in HCH patients (8.7±2.7 mg/h vs controls, 3.7±1.2 mg/h, mean±SD, p < 0.01). After treatment with either statin, hydroxylation rates dropped by nearly 50% along with a drastic reduction in plasma total and LDL-cholesterol. Regression analysis showed a correlation trend between plasma cholesterol and 27-OH rates. Conclusions: Primary HCH associates with increased 27-OH, which tend to normalize during hypocholesterolemic treatment. Such relationship supports the view that 27-OH may act as a compensatory mechanism in a condition of larger plasma cholesterol pool. A regulatory role for hepatic and extrahepatic nuclear receptors seems reasonable. These data encourage novel approaches for the management of HCH and the prevention of atherosclerosis. Funding: GRANT SUPPORT. Supported by COFIN-PRIN grant 2004067491
62 INCREASED DEGRADATION OF CHOLESTEROL VIA THE ALTERNATE PATHWAY OF BILE ACID BIOSYNTHESIS IN PRIMARY HYPERCHOLESTEROLEMIA M. Bertolotti1, M. Del Puppo2, C. Gabbi1, C. Anzivino1, L. Carulli1, M. Galli Kienle2, N. Carulli1. 1University of Modena and Reggio Emilia, Dept. of Medicine Endocrinology Metabolism and Geriatrics, Modena, Italy, 2University of Milano Bicocca, Dept. of Experimental Medicine, Monza, Italy Background: The first step in the alternate pathway of bile acid synthesis is represented by cholesterol 27-hydroxylation (27-OH), which takes place both in liver and in extrahepatic tissues. Such pathway is believed to play a role in peripheral degradation of cholesterol. Aim: of the present study was to investigate 27-OH rates in hypercholesterolemia (HCH), and to assess the effects induced by treatment with statins. Methods: Seven patients with primary HCH underwent determination of 27-OH rates in vivo by
63 DOES THE EFFICACY OF EZETIMIBE/SIMVASTATIN 10/40 MG DIFFER FROM DOSE-DOUBLING OF DIFFERENT POTENCY STATINS IN PATIENTS WITH A RECENT CORONARY EVENT? P. Brudi1, J.P.D Reckless2, P. Henry3, T. Pomykaj4, S.T. Lim5, R. Massaad6, K. Vandormael6, A.O. Johnson-Levonas7. 1Merck Schering-Plough, Whitehouse Station, NJ, USA, 2Royal United Hospital, Bath, United Kingdom, 3Hospital Lariboisiere, Paris, France, 4Stadtisches Klinikum Braunschweig, Braunschweig, Germany, 5National Heart Center, Singapore, 6Merck Sharp & Dohme, Brussels, Belgium, 7Merck Research Laboratories, Rahway, NJ, USA Objective: Does doubling doses of low, medium and high potency statins have different lipid efficacy than switching to ezetimibe/simvastatin (EZE/SIMVA) 10/40 mg in 424 pts on stable statin dose (>6 wks) with a recent coronary event (RCE)? Methods: Open-label study stratified by baseline-
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