Alemanno, Natalina

Bo, Simona

Cassader, Maurizio

Gambino, Roberto

Musso, G.

Pinach, Silvia

Potenza, Matteo

Saba, F.

English

Institutional Research Information System University of Turin

ABSTRACTABSTRACT57predictor of PWV in healthy subjects points to the relevance of HDL function in vascular physiology and arterial stiffness preven-tion along life.DEVELOPMENT OF NEW RAC1 INHIBITORS AS POTENTIAL PHARMACOLOGICAL AGENTS FOR THE TREATMENT OF ATHEROSCLEROSISN. Ferri1, S. Kevin Bernini1, A. Corsini1, A. Contini21Dipartimento di Scienze Farmacologiche e Biomolecolari e 2Dipartimento di Scienze Farmaceutiche, Università degli Studi di MilanoE-mail: nicola.ferri@unimi.it Experimental and clinical observations have documented the role of the small GTPase Rac1 protein and cardiovascular diseases opening to the development of new potential pharmacological in-tervention. In this study we characterized a new class of selective small molecule Rac inhibitors with the 3-aryl-1H-pyrazole-5-car-boxamide nucleus. Starting from our previous identiication of Rac inhibitors (1), through a computational approach, 57 chemical enti-ties were identiied and their Rac inhibitory eficacy evaluated by G-LISA assay. 23 compounds were found to reduce, Rac-GTP levels in cultured cells by more than 24.8%. A comparative analysis at 25 μM was then performed and compounds 1, 2, 3, 11 and 21 resulted the most potent. Compounds 1, 2, 3 and 21 did not affect the activa-tion of RhoA protein, while compound 11 partially reduced RhoA-GTP levels. The IC50s for Rac inhibition of these compounds were between 2.9 and 29.1 μM and similar potencies were observed in a cell adhesion assay, a Rac1-dependent cellular event. From these analysis it was selected compound 2 as a most promising inhibitor to test in in-vitro and in-vivo models of atherosclerosis. Compound 2 profoundly affected cytoskeleton organization of cultured human SMCs and inhibited SMC migration in response to PDGF-BB in a concentration dependent manner with an IC50 value of 5.8 µM. More interestingly, incubation of human monocytic cell line THP-1 with Compound 2 (10 µM) completely abrogated their adhesion to cultured human umbilical endothelial cells (HUVEC) indicating a potent anti-inlammatory activity.Taken together, in the present study we identiied a new selective small molecule Rac inhibitor capable to interfere with SMC migra-tion and monocyte-endothelial cell adhesion, two pivotal features of atherogenesis. Further analysis will be carried out to test the effect of compound 2 on spontaneous atherosclerotic plaque de-velopment in apoE-/- mice.Reference1. Ferri N, Corsini A, Bottino P, Clerici F, Contini A, J Med Chem 2009, 52; 4087-4090.EVALUATION OF EFFICACY OF A NEW NUTRICEUTICAL PRODUCT CONTAINING PLANT STEROLS IN BAG (STEROLIP ESI) IN REDUCING CHOLESTEROL LEVELS IN PATIENTS WITH POLYGENIC HYPERCHOLESTEROLEMIAE. Formisano, V. Guido, R. Fresa, L. Cremonini, C. Orlando, S. Bertolini, L. PisciottaDepartment of Internal Medicine, University of GenoaE-mail: salima89@hotmail.it Primary objective was to establish how lipid proile is modiied in patients affected by polygenic hypercholesterolemia after three and six weeks of therapy with Sterolip (a new nutriceutical product in bag containing 1.6 g of plant sterol) with respect to a placebo; secondary objectives were to verify the tolerability of the product, to test the long term eficacy after 12 weeks of treatment, to evalu-ate the response to the therapy in relation with three genetic vari-ants involved in sterol absorption.Methods. We enrolled 60 patients over 18 years of age, affected by polygenic hypercholesterolemia in primary prevention with cardiovascular risk <20% in the next ten years. 30 patients were double-blind randomized with placebo and 30 patients with Ste-rolip. The double blind treatment lasted six weeks at the end of which all patients were treated with Sterolip in open-label for other six weeks. Lipid proile was determined before treatment and ev-ery three weeks. We genotyped all patients for APOE, NPC1L1 c. 816C>G (L272L) and ABCG8 D19H polymorphisms. Results. The parameters that in the treatment group were sig-niicantly reduced compared to the placebo group were total cholesterol (TC) and LDL Cholesterol (LDL-C) at three weeks of treatment (p<0.05). The product was good tolerated. Long term therapy is eficacious only in a few cases with a large interindivid-ual variability. Carriers of G allele of NPC1L1 polimorphism have demonstrated a signiicant more consistent reduction of TC after three and six weeks of treatment in comparison to C allele carriers (p<0.05). Conclusions. In according with data published in literature this study demonstrated a clinically signiicant action of plant sterols af-ter three weeks of treatment. In genetically predisposed individu-als, the therapy may be considered for a more time. INCIDENCE AND SEVERITY OF NONALCOHOLIC FATTY LIVER DISEASE ASSOCIATED WITH IMPAIRED LIPID AND GLUCOSE METABOLISM ARE PREDICTED BY SREBF POLYMORPHISMR. Gambino1, S. Bo1, G. Musso2, S. Pinach1, N. Alemanno1, M. Potenza1, F. Saba1, M. Cassader11Department of Medical Science, University of Turin, Italy; 2Gradenigo Hospital, Turin, ItalyE-mail: roberto.gambino@unito.it Background. Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease, encompasses a histological spec-trum, ranging from simple steatosis (SS) to steatosis plus necro-inlammation (nonalcoholic steatohepatitis, NASH), which can be differentiated only by liver biopsy. While SS has a benign hepato-logical course, NASH can progress to end-stage liver disease. Ste-rol regulatory element-binding factor (SREBF) genes code for key ABSTRACT58nuclear transcription factors regulating lipid homeostasis: sterol regulatory element binding protein (SREBP)-1c regulates hepatic de novo lipogenesis and insulin sensitivity, while sterol regulatory element-binding factor-2 (SREBF-2) codes for SREBP-2, a mas-ter transcriptional regulator of genes involved in cellular choles-terol biosynthesis, uptake, and export. Therefore, SREBF-1c and SREBF-2 may modulate the genetic susceptibility to NAFLD and NASH. Objective. Factors predisposing to non-alcoholic fatty liver dis-ease (NAFLD) and associated cardio-metabolic disorders are unknown. Sterol regulatory element-binding protein (SREBP)-1c and SREBP-2, transcription factors regulating lipogenesis and cholesterol metabolism have been experimentally connected to NAFLD, but no human data exist. In population-based studies, single nucleotide polymorphisms (SNPs) in SREBF-1 gene have been connected to obesity, insulin resistance and T2DM, and the functional SNP rs133291 C/T in the SREBF2 gene has been linked to serum LDL-cholesterol, but there are no human data on the im-pact of these SNPs on the risk of developing NAFLD and associ-ated metabolic abnormalities. We hypothesized SREBF-1c/2 SNPs may not only predispose not only to NAFLD/NASH, but also affect NAFLD-associated cardio-metabolic risk. We aimed at:1) prospectively assessing the role of SREBF-1c/2 SNPs in pro-moting NAFLD development in apparently healthy subjects;2) elucidating mechanisms connecting SREBF-1c/2 to liver in-jury, glucose and lipid homeostasis in established NAFLD. Methods. We followed-up 165 non-obese nondiabetic participants in a population-based study, without NAFLD/metabolic syndrome, characterized for 2 common SREBF-1c and SREBF-2 polymor-phisms, dietary habits, physical activity, adipokines, CRP, and endothelial dysfunction markers. NAFLD developers underwent an OGTT with Minimal Model analysis of glucose homeostasis parameters, and an oral fat tolerance test with measurement of plasma lipoproteins, adipocytes, and hepatocyte apoptosis marker cytokeratin-18 fragments. Results. After 7 years, 29% subjects developed NAFLD and 5% developed diabetes. SREBF-1c and SREBF-2 predicted incident NAFLD; SREBF-2 predicted non-alcoholic steatohepatitis (NASH), diabetes, CRP and endothelial dysfunction markers. In NAFLD, while SREBF-1c predicted histological steatosis and hepatic in-sulin resistance, SREBF-2 predicted progressive liver histology, hepatic/muscle/adipose insulin resistance, pancreatic b-cell dys-function, and an altered fat tolerance: higher postprandial lipemia, cholesterol enrichment of triglyceride-rich lipoproteins and ox-LDLs, HDL-C reduction, adipokine imbalance (lower adiponectin and higher resistin), and higher cytokeratin-18 fragments. Conclusions. SREBF-2 predisposes to NASH and cardio-metabol-ic disorders by affecting glucose homeostasis and dietary fat toler-ance. We showed polymorphisms in genes coding for nuclear tran-scription factor SREBP-2 predict incidence and severity of NAFLD and of associated abnormalities in glucose and lipid metabolism and in adipokine response to dietary fat. Our indings may have relevant implications: from a clinical standpoint, SREBF-1/2 SNPs may be used to select NAFLD patients at higher risk of develop-ing progressive liver disease and cardio-metabolic complications for tight monitoring and experimental treatments. Furthermore, future research should verify whether a genetically-mediated mal-adaptive response to a chronic, daily, repetitive stress like fat inges-tion may link chronic overfeeding to obesity and its complications and to assess whether SREBP-2 pathway modulation may prevent cholesterol lipotoxicity in different tissues more effectively than currently available strategies, which selectively target hepatic cho-lesterol synthesis or intestinal absorption.SMALL DENSE LDL PROFILES IN FAMILIAL COMBINED HYPERLIPIDEMIA AND IN FAMILIAL HYPERCOLESTEROLEMIAM. Gentile, G. Marotta, F. Jossa, M. Sodano, L. Maresca, A. Strazzullo, M. Nunziata, C. Pagano, P. RubbaDepartment of Clinical and Experimental Medicine University “Federico II” Medical School, Naples, ItalyE-mail: margenti@unina.it Introduction. Differences between small dense LDL (sd-LDL) proiles were evaluated in 108 probands with Familial Combined Hyperlipidemia (FCHL), 117 probands with Familial Hypercoles-terolemia (FH) and 146 normolipidemic, normotensive, normo-glicaemic healthy subjects among those consecutively admitted to the outpatient Lipid Clinic of the “Federico II” University of Naples. Methods. LDL particle separation was performed by Lipoprint System: 7 LDL subfractions (LDL 1 to LDL 7) were obtained, mean LDL particle size and LDL score (% of sd-LDL) were calculated. Results. LDL score was signiicantly (p<0.001) higher in FCHL patients as compared to FH patients (21.6±1.3 vs 15.3±1.0 mg/dL) and controls (3.3±5.0 mg/dL); mean LDL size was signiicantly lower (p<0.001) in FCHL patients than FH patients (262.8±0.5 vs 264. ±0.4 Å) and controls (271.1±2.8 mg/dL). In a subsequent analysis we compared the amount of cholesterol in each LDL sub-fractions of the two groups of patients and controls. LDL I and LDL II cholesterol were signiicantly (p<0.001) higher in FH patients as compared to FCHL patients (69.0±1.9 vs 44.4±1.9 mg/dL for LDL I) and controls (41.7±11.5 mg/dL); (69.5±2.0 vs 42.8±1.5 vs 19.1±8.6 mg/dL for LDL II) (FH vs FCHL vs controls). Conclusions. These indings indicate that FCHL patients have LDL score signiicantly higher and mean LDL size signiicantly lower than FH patients and healthy subjects. Small, dense LDL particles have been associated with an increased risk of coronary artery disease. More studies are envisaged to investigate the spe-ciic contribution of LDL subfractions to cardiovascular risk in FH patient. THE IMPROVED BIOCHEMICAL DIAGNOSTICS OF THE LIPID PROFILES IN THE FRAMEWORK OF REGIONAL NETWORK FOR INHERITED LIPID DISORDERS: FIRST REPORTM. Gentile1, F. Rubba2, E. Giancotti2, B. De Simone1, E. La Fata1, M.F. Coppola, S. Panico, P. Rubba11Network regionale Dislipidemie, Dipartimento di Medicina Clinica e Sperimentale, A.O.U. Federico II, Napoli; 2Direzione Medica di Presidio, AOU Federico II, NapoliE-mail: margenti@unina.it Familial combined hyperlipidemia (FCHL) is a severe inherited hyperlipidemia with a high cardiovascular mortality. Affected in-dividuals have elevated cholesterol or trygliceride concentrations or both. Such a lipid proile is frequently associated with an un-favourable decrease in high density lipoprotein concentration, an elevated apolipoprotein B and an increased prevalence of athero-genic, small, dense low-density lipoprotein (sd-LDL) subfractions. Family studies are necessary to establish the diagnosis of FCHL in each patient. Since it is not always possible to get some biochemical data from 

INCIDENCE AND SEVERITY OF NONALCOHOLIC FATTY LIVER DISEASE ASSOCIATED WITH IMPAIRED LIPID AND GLUCOSE METABOLISM ARE PREDICTED BY SREBF POLYMORPHISM.

https://iris.unito.it/bitstream/2318/129172/1/INCIDENCE%20AND%20SEVERITY%20OF%20NONALCOHOLIC%20FATTY%20LIVER%20DISEASE%20ASSOCIATED%20WITH%20IMPAIRED%20LIPID%20AND%20GLUCOSE%20METABOLISM%20ARE%20PREDICTED%20BY%20SREBF%20POLYMORPHISM.pdf

INCIDENCE AND SEVERITY OF NONALCOHOLIC FATTY LIVER DISEASE ASSOCIATED WITH IMPAIRED LIPID AND GLUCOSE METABOLISM ARE PREDICTED BY SREBF POLYMORPHISM.

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