- Email: [email protected]
STAT3 inhibition induces PCSK9 in hepatic cell line: possible involvement in hypertriglyceridemia associated with insulin resistance
e46
Abstracts / Atherosclerosis 241 (2015) e32ee71
Results: At baseline, CRP surprisingly was significantly higher in nonobese subjects (n¼1,367) than obese individuals (n¼364)(0.6±1.5 vs. 0.5±0.8 mg/dl; p Conclusions: From the results of this large 10-year prospective cohort study we conclude that obesity significantly modulates the power of CRP to predict cardiovascular event risk among angiographied coronary patients.
EAS-0012. A DIET LOW IN SUGAR REDUCES THE PRODUCTION OF ATHEROGENIC LIPOPROTEINS IN MEN WITH HIGH LIVER FAT M. Umpleby 1, F. Shojaee-Moradie 1, B. Fielding 1, X. Li 1, C. Isherwood 1, N. Jackson 1, G. Wilinska 2, R. Hovorka 2, J. Bell 3, E.L. Thomas 3, J. Wright 1, G.S. Frost 3, B. Griffin 1. 1 Nutritional Sciences, University of Surrey, Guildford, United Kingdom; 2 Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom; 3 Division of Diabetes Endocrinology and Metabolism, Imperial College London, London, United Kingdom Aim: To determine how dietary sugar promotes the formation of an atherogenic lipoprotein phenotype by studying the effects of high and low sugar diets on lipoprotein kinetics. Methods: Two groups of men at risk of metabolic syndrome, with low liver fat (LLF; <5%) (n¼14) or high liver fat (HLF; >5%) [BAG1] (n¼11), were randomised to a cross-over intervention with high and low sugar diets (HSD; 26% energy or LSD; 6% energy) for 12 weeks. ApoB production (PR) and fractional catabolic rates (FCR) of lipoprotein fractions (VLDL1, VLDL2, IDL, LDL2 and LDL3 apolipoproteinB (apoB)) were measured by constant infusion of 13C-leucine and mathematical modelling. Results: In post-dietary comparisons (LSD v HSD), liver fat was lower after the LSD in both groups (HLF, p¼0.01; LLF, p¼0.008). In LLF men, VLDL1 apoB, TG and cholesterol concentration, LDL3 apoB concentration and VLDL1 apoB PR were lower (all p <0.05) after a LSD whilst VLDL1 apoB FCR and VLDL2, IDL and LDL apoB kinetics were not different. In HLF men, plasma TG was lower (p<0.04), but VLDL1 and VLDL2 apoB kinetics were unchanged after the LSD but IDL apoB, TG and cholesterol concentration, IDL apoB PR and LDL3 apoB PR and FCR were lower (All p¼0.05). Small dense LDL cholesterol and oxidized LDL were lower in both groups after the LSD (HLF: p¼0.02, p¼0.08; LLF: p¼0.02, p<0.02 respectively). Conclusion: Men with HLF and LLF respond differently to dietary sugar. A LSD can reduce the production of atherogenic lipoproteins in men with HLF.
EAS-0143. EFFECT OF METFORMIN ON GLUCOSE AND FATTY ACID UTILIZATION IN BROWN ADIPOSE TISSUE J. Trnovska, V. Skop, H. Malinska, L. Kazdova. Center for experimental medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic Aim: Growing evidence indicates that metformin, in addition to its well-recognized antihyperglycemic properties, also reduces total body and abdominal fat, but the mechanisms are still unclear. Brown adipose tissue (BAT) plays an important role in triglyceride and glucose utilization for thermoregulation and thus could prevent obesity, ectopic fat accumulation, and associated metabolic disturbances. The aim of this study was to investigate if metformin increase glucose and fatty acid utilization in BAT, and ameliorate related parameters of metabolic syndrome. Methods: Male Wistar rats (age: 8 months) were fed a standard diet (SD) or SD enriched by metformin (SD+Mf) in a dose: 300 mg/kg b.wt./day for 4 weeks. Lipolysis, 14C-U-palmitic acid and 14C-U-glucose oxidation and incorporation into lipids were measured in the interscapular BAT ex vivo.
Results: Metformin significantly decreased body weight (-25 %, P<0.001), adiposity (-61 %, P<0.002), serum triglycerides (-48 %, P<0.03) and ectopic accumulation of triglycerides in liver (-72 %, P<0.02), heart (-66 %, P<0.03), aorta (-48 %, P<0.01) and diaphragm (-80 %, P<0.01). Metformin increased lipolysis (+47 %, P<0.01), palmitic acid oxidation (+45 %, P<0.03) and incorporation into BAT lipids (+26 %, P<0.01). There were not significant differences in glucose oxidation between groups but basal (+61 %, P<0.01) and insulin stimulated (+60 %, P<0.01) incorporation of glucose into BAT lipids was higher after metformin treatment. Conclusion: Results indicate that metformin-induced increase of lipid and glucose utilization in BAT may participate in the improvement of metabolic syndrome disorders. Supported by the grant GACR P303/13-04420S
EAS-0149. FAST REGRESSION OF CAROTID INTIMA-MEDIA THICKNESS AND CARDIOVASCULAR RISK FACTORS IN PATIENTS PRE- AND POSTBARIATRIC SURGERY J. Matos-Souza, G. De Rossi, W. Cirillo, W. Nadruz, Jr., O.R. Coelho. Clinical, Faculty of Medical Sciences, Campinas, Brazil Purpose: Obesity is associated with cardiovascular risk factors (CVRFs), such as hypertension, hypertriglyceridemia, and low levels of high-density cholesterol (HDL-C). In obese patients with a body mass index (BMI) of 40 kg/m2 or 35-40 kg/m2 associated with CVRFs, bariatric surgery promove significant weight loss and showed reduction on CVRFs. Carotid intima-media thickness (C-IMT) is widely acept as an indicator of atherosclerosis, and used to be correlated with severals CVRFs. Our objective was to correlate C-IMT with CVRFs before (baseline data) and after surgery, and to observe whether weight loss is followed by a regression of C-IMT. Methods: Fifty four patients who had undergone bariatric surgery participated in this study. Assessments were carried out on the baseline date, and 1, 2, 6, and 12 months after surgery. CVRFs analyzed were: total cholesterol (TC) levels, HDL-C, triglycerides to HDL-C ratio (TG/ HDL-C) and fasting plasma glucose. C-IMT was measured by B-mode ultrasound. Results: One month after surgery, we found a significant reduction in CIMT (p < 0.001), which was significantly correlated with fasting plasma glucose, low-density cholesterol (LDL-C) (p < 0.001), BMI (p < 0.001) and waist circunference (p < 0.05). The reduction in C-IMT is significantly after 2, 6 and 12 months (p<0,001) Conclusion: The impact achieved with bariatric surgery resulted in fast regression of C-IMT. This regression could be observed at 1, 2 and 6 months following surgery, with an sustained benefit at 12 months. This finding was correlated with a reduction in LDL-C levels, fasting plasma glucose, BMI and waist circunference.
EAS-0471. STAT3 INHIBITION INDUCES PCSK9 IN HEPATIC CELL LINE: POSSIBLE INVOLVEMENT IN HYPERTRIGLYCERIDEMIA ASSOCIATED WITH INSULIN RESISTANCE C. Ricci, M. Ruscica, C. Macchi, P. Magni, A. Corsini, N. Ferri. Scienze Farmacologiche e Biomolecolari, University of Milan, Milan, Italy PCSK9 regulates the circulating LDL-cholesterol levels by inducing LDLR degradation. However, PCSK9 levels are positively correlated with insulin resistance, liver steatosis and plasma VLDL-TG concentrations. This evidence suggests that PCSK9 could be implicated in lipid homeostasis. Chronic inflammation, associated with elevated circulating cytokines, and hepatic overexpression of suppressor of cytokine signaling (SOCS) proteins, are major determinants of hypertriglyceridemia associated to insulin resistance. In the present study, we have investigated the role of SOCS3 in the transcriptional regulation of PCSK9 in HepG2 cells. Forced overexpression of SOCS3 determined the abrogation of STAT3
Abstracts / Atherosclerosis 241 (2015) e32ee71
phosphorylation, associated to: 1) induction of fatty-acid synthase mRNA levels (3.59±0.40 fold); 2) activation of SREBP transcriptional activity (1.58±0.15 fold); 3) increase apoB production (3.47±0.09 fold). SOCS3 overexpression also determined an increase of PCSK9 mRNA (7.82±1.73 fold) and protein (2.18±1.13 fold) without significant changes of HMG-CoA reductase, LDLR and cholesterol biosynthesis. Pharmacological inhibition of STAT3 or JAK proteins also induced PCSK9 levels by 2.06±0.75 and 3.30±0.3 fold, respectively. Interestingly, insulin significantly induced STAT3 phosphorylation, fatty-acid synthase and PCSK9 mRNA levels to a similar extent in both control and SOCS3-overexpressing cells, although the overall mRNA levels of PCSK9 and fattyacid synthase were significantly higher in HepG2 SOCS3 cells. In conclusion, we provided evidence that biological and/or pharmacological inhibition of the JAK/STAT pathway increased PCSK9 levels, both in the absence and in the presence of insulin stimulation, a possible determinant of PCSK9 transcription in insulin resistant patients The present work was supported by the grant 2012-0549 from Fondazione Cariplo, ITALY
EAS-0494. ASSOCIATION BETWEEN EARLY ALCOHOLIC STEATOHEPATITIS
ATHEROSCLEROSIS
AND
NON-
E. Dronca 2, D.P. Sampelean 1, I. Para 1, M. N. Leach 1, Grigorescu 1. 1 Department of Internal Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu” Cluj-Napoca, CLUJ-NAPOCA, Romania; 2 Department of Medical Genetics, University of Medicine and Pharmacy “Iuliu Hatieganu” Cluj-Napoca, CLUJ-NAPOCA, Romania Introduction: Non alcoholic liver disease (NAFLD) is closely associated with abdominal obesity, hypertension, dyslipidemia, and type 2 diabetes, which are all features of the metabolic syndrome, a highly pro-atherogenic state. Aim: Our study aimed to assessed whether patients with biopsy proven NASH had an increased cardiovascular (CV) risk evaluated from measured c-IMT than control subjects and to evaluate possible relationships between c-IMT and classical (CV) risk factors and also liver histology. Patients and methods: 50 patients with non-alcoholic steatohepatitis and 30 healthy controls, age and gender matched, were recruited. Lipid profile, liver biochemical markers, insulin level, HOMA IR and carotid intimamedia thickness were assayed. Results: Patients with NASH had a significantly higher c-IMT than control group (0.9 mm vs. 0.6 mm, p<0.001). The prevalence of plaques in subjects with NASH was 7/50 (14.2%) vs. 0/30 (0%) in the control group (p¼0.04).The c-IMT were significantly positively correlated with age, WC,BMI, insulin level ,HOMA-IR, fasting plasma glucose, AST, ALT and lobular inflammation. In multiple logistic analysis, after adjustment for age, gender, smoking, BMI, metabolic syndrome NASH was independent associated with high c-IMT (OR, 13.9; 95%CI, 1.9 to 99, P<0.001). Other independent predictors of c-IMT were HOMAIR (p¼0.006) and age (p¼0.001). Conclusion: NASH is independent associated with subclinical atherosclerosis. The hepatic inflammation could be one of the links between NASH and cardiovascular disease. Carotid intima-media thickness maybe used as an indicator of early atherosclerotic changes in patiens with NASH.
EAS-0551. EPICARDIAL FAT THICKNESS IS AN ECTOPIC FAT ASSOCIATED WITH METABOLIC SYNDROME, SUBCLINICAL ATHEROSCLEROSIS AND MARKERS OF CARDIAC DYSFUNCTION IN THE GENERAL POPULATION A. Baragetti 1, G. Pisano 2, K. Garlaschelli 3, L. Grigore 4, F. Pellegatta 4, G.D. Nora 1, A.L. Fracanzani 2, S. Fargion 2, A.L. Catapano 4. 1 Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; 2 Department of Pathophysiology and Transplantation Metabolic Liver Diseases Research Center Ca' Granda IRCCS Foundation Policlinico Hospital,
e47
University of Milan, Milan, Italy; 3 Center for the Study of Atherosclerosis, Bassini Hospital Cinisello Balsamo, Milan, Italy; 4 Multimedica Hospital, IRCCS - Istituti di Ricovero e Cura a Carattere Scientifico Sesto San Giovanni Italy, Milan, Italy Obesity is associated with Metabolic Syndrome (MetS) and hepatic steatosis represents an ectopic fat localization frequently observed in this condition. Epicardial Fat Thickness (EFT) is a new discovered marker of ectopic fat associated with obesity. To date, it is not clear whether EFT is associated both with subclinical atherosclerotic markers and steatosis degree in the general population. 1,018 subjects (from the PLIC Study) were included, for whom information about clinical, cardio-metabolic and pharmacological profile are available. EFT, aortic calcifications, carotid Intima-Media Thickness (c-IMT) and echocardiographic parameters were determined. Steatosis was defined according to a scoring system and abdominal adiposity by using Dual Xrays Absorbimetry (DEXA). EFT, independently from age, was similar between women and men (4.73 + 0.14 mm vs 4.25 + 0.16 mm respectively, p¼ 0.067); however it was thicker in post-menopausal women (independently from hormone-replacement therapy) (4.76 + 0.16 mm vs 4.07 + 0.16 in age-matched men, p¼ 0.013). EFT increased with determinants of MetS (p < 0.001), dyslipidaemia, ultrasound steatosis degrees (p < 0.001) and with abdominal adiposity. ROC analysis showed that those with MetS presented EFT above 5.2 mm (6.10 mm in women, 4.7 mm in men). EFT was associated with diastolic dysfunction (beta¼ -0.101, p¼ 0.015) and AC (OR¼ 1.067 [1.014-1.123] 95% C.I., p¼ 0.013). The association between EFT and c-IMT weakened as function of steatosis degree. EFT is associated with subclinical atherosclerosis and hepatic steatosis. Our data suggest that EFT determination may represent and additional tool for the stratification of the cardiovascular risk.
EAS-0645. MIR-34A HAS A ROLE IN WEIGHT GAIN, DURING MURINE DIETINDUCED OBESITY C.A. Lavery 1, M. Kurowska-Stolarska 2, I. Donnelly 1, A.H. Baker 1, A.M. Miller 1. 1 Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom; 2 Institute of Infection Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom Aim: With the global obesity epidemic, it is increasingly important to find novel therapies to treat comorbidities, such as dyslipidaemia and atherosclerosis. For example, microRNA-34a has been show to regulate inflammatory cytokine expression in macrophages, the main adipose infiltrate during obesity. We aimed to investigate the role of miR-34a in adipose inflammation and weight gain, in a murine diet-induced obesity model. Methods: Wild type (WT) C57BL/6 mice and miR-34a-/- mice, were fed a normal chow diet (NCD) or high-fat diet (HFD; 0.15% cholesterol, 21% lard) ad libitum, for 24 weeks, in accordance with UK Home Office guidelines. Epididymal adipose tissue was collagenase digested and analysed by FACS. WT and miR-34a-/- bone marrow derived macrophages (BMDM) were cultured in vitro, and gene expression analysed by QPCR. Results: miR-34a-/- mice on HFD were significantly heavier (P¼0.0096) than WT counterparts and exhibited a greater increase in epididymal adipose weight (P¼0.0011). Examination of macrophage phenotypes in epididymal adipose by FACS demonstrated no change in M1 or M2 markers in miR-34a-/- mice on HFD, but a significant increase in macrophage F4/80 expression (P¼0.0288), and decrease of the activation marker, CD69 (P¼0.0107). However, WT and miR-34a-/- BMDM cultures showed no difference in the metabolic and inflammatory genes examined. Conclusions: We have demonstrated that miR-34a has a role in murine weight maintenance, and suggest that macrophages are unlikely to be the main contributor to the adipose phenotype, in miR-34a-/- mice. Further
Abstracts / Atherosclerosis 241 (2015) e32ee71
Results: At baseline, CRP surprisingly was significantly higher in nonobese subjects (n¼1,367) than obese individuals (n¼364)(0.6±1.5 vs. 0.5±0.8 mg/dl; p Conclusions: From the results of this large 10-year prospective cohort study we conclude that obesity significantly modulates the power of CRP to predict cardiovascular event risk among angiographied coronary patients.
EAS-0012. A DIET LOW IN SUGAR REDUCES THE PRODUCTION OF ATHEROGENIC LIPOPROTEINS IN MEN WITH HIGH LIVER FAT M. Umpleby 1, F. Shojaee-Moradie 1, B. Fielding 1, X. Li 1, C. Isherwood 1, N. Jackson 1, G. Wilinska 2, R. Hovorka 2, J. Bell 3, E.L. Thomas 3, J. Wright 1, G.S. Frost 3, B. Griffin 1. 1 Nutritional Sciences, University of Surrey, Guildford, United Kingdom; 2 Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom; 3 Division of Diabetes Endocrinology and Metabolism, Imperial College London, London, United Kingdom Aim: To determine how dietary sugar promotes the formation of an atherogenic lipoprotein phenotype by studying the effects of high and low sugar diets on lipoprotein kinetics. Methods: Two groups of men at risk of metabolic syndrome, with low liver fat (LLF; <5%) (n¼14) or high liver fat (HLF; >5%) [BAG1] (n¼11), were randomised to a cross-over intervention with high and low sugar diets (HSD; 26% energy or LSD; 6% energy) for 12 weeks. ApoB production (PR) and fractional catabolic rates (FCR) of lipoprotein fractions (VLDL1, VLDL2, IDL, LDL2 and LDL3 apolipoproteinB (apoB)) were measured by constant infusion of 13C-leucine and mathematical modelling. Results: In post-dietary comparisons (LSD v HSD), liver fat was lower after the LSD in both groups (HLF, p¼0.01; LLF, p¼0.008). In LLF men, VLDL1 apoB, TG and cholesterol concentration, LDL3 apoB concentration and VLDL1 apoB PR were lower (all p <0.05) after a LSD whilst VLDL1 apoB FCR and VLDL2, IDL and LDL apoB kinetics were not different. In HLF men, plasma TG was lower (p<0.04), but VLDL1 and VLDL2 apoB kinetics were unchanged after the LSD but IDL apoB, TG and cholesterol concentration, IDL apoB PR and LDL3 apoB PR and FCR were lower (All p¼0.05). Small dense LDL cholesterol and oxidized LDL were lower in both groups after the LSD (HLF: p¼0.02, p¼0.08; LLF: p¼0.02, p<0.02 respectively). Conclusion: Men with HLF and LLF respond differently to dietary sugar. A LSD can reduce the production of atherogenic lipoproteins in men with HLF.
EAS-0143. EFFECT OF METFORMIN ON GLUCOSE AND FATTY ACID UTILIZATION IN BROWN ADIPOSE TISSUE J. Trnovska, V. Skop, H. Malinska, L. Kazdova. Center for experimental medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic Aim: Growing evidence indicates that metformin, in addition to its well-recognized antihyperglycemic properties, also reduces total body and abdominal fat, but the mechanisms are still unclear. Brown adipose tissue (BAT) plays an important role in triglyceride and glucose utilization for thermoregulation and thus could prevent obesity, ectopic fat accumulation, and associated metabolic disturbances. The aim of this study was to investigate if metformin increase glucose and fatty acid utilization in BAT, and ameliorate related parameters of metabolic syndrome. Methods: Male Wistar rats (age: 8 months) were fed a standard diet (SD) or SD enriched by metformin (SD+Mf) in a dose: 300 mg/kg b.wt./day for 4 weeks. Lipolysis, 14C-U-palmitic acid and 14C-U-glucose oxidation and incorporation into lipids were measured in the interscapular BAT ex vivo.
Results: Metformin significantly decreased body weight (-25 %, P<0.001), adiposity (-61 %, P<0.002), serum triglycerides (-48 %, P<0.03) and ectopic accumulation of triglycerides in liver (-72 %, P<0.02), heart (-66 %, P<0.03), aorta (-48 %, P<0.01) and diaphragm (-80 %, P<0.01). Metformin increased lipolysis (+47 %, P<0.01), palmitic acid oxidation (+45 %, P<0.03) and incorporation into BAT lipids (+26 %, P<0.01). There were not significant differences in glucose oxidation between groups but basal (+61 %, P<0.01) and insulin stimulated (+60 %, P<0.01) incorporation of glucose into BAT lipids was higher after metformin treatment. Conclusion: Results indicate that metformin-induced increase of lipid and glucose utilization in BAT may participate in the improvement of metabolic syndrome disorders. Supported by the grant GACR P303/13-04420S
EAS-0149. FAST REGRESSION OF CAROTID INTIMA-MEDIA THICKNESS AND CARDIOVASCULAR RISK FACTORS IN PATIENTS PRE- AND POSTBARIATRIC SURGERY J. Matos-Souza, G. De Rossi, W. Cirillo, W. Nadruz, Jr., O.R. Coelho. Clinical, Faculty of Medical Sciences, Campinas, Brazil Purpose: Obesity is associated with cardiovascular risk factors (CVRFs), such as hypertension, hypertriglyceridemia, and low levels of high-density cholesterol (HDL-C). In obese patients with a body mass index (BMI) of 40 kg/m2 or 35-40 kg/m2 associated with CVRFs, bariatric surgery promove significant weight loss and showed reduction on CVRFs. Carotid intima-media thickness (C-IMT) is widely acept as an indicator of atherosclerosis, and used to be correlated with severals CVRFs. Our objective was to correlate C-IMT with CVRFs before (baseline data) and after surgery, and to observe whether weight loss is followed by a regression of C-IMT. Methods: Fifty four patients who had undergone bariatric surgery participated in this study. Assessments were carried out on the baseline date, and 1, 2, 6, and 12 months after surgery. CVRFs analyzed were: total cholesterol (TC) levels, HDL-C, triglycerides to HDL-C ratio (TG/ HDL-C) and fasting plasma glucose. C-IMT was measured by B-mode ultrasound. Results: One month after surgery, we found a significant reduction in CIMT (p < 0.001), which was significantly correlated with fasting plasma glucose, low-density cholesterol (LDL-C) (p < 0.001), BMI (p < 0.001) and waist circunference (p < 0.05). The reduction in C-IMT is significantly after 2, 6 and 12 months (p<0,001) Conclusion: The impact achieved with bariatric surgery resulted in fast regression of C-IMT. This regression could be observed at 1, 2 and 6 months following surgery, with an sustained benefit at 12 months. This finding was correlated with a reduction in LDL-C levels, fasting plasma glucose, BMI and waist circunference.
EAS-0471. STAT3 INHIBITION INDUCES PCSK9 IN HEPATIC CELL LINE: POSSIBLE INVOLVEMENT IN HYPERTRIGLYCERIDEMIA ASSOCIATED WITH INSULIN RESISTANCE C. Ricci, M. Ruscica, C. Macchi, P. Magni, A. Corsini, N. Ferri. Scienze Farmacologiche e Biomolecolari, University of Milan, Milan, Italy PCSK9 regulates the circulating LDL-cholesterol levels by inducing LDLR degradation. However, PCSK9 levels are positively correlated with insulin resistance, liver steatosis and plasma VLDL-TG concentrations. This evidence suggests that PCSK9 could be implicated in lipid homeostasis. Chronic inflammation, associated with elevated circulating cytokines, and hepatic overexpression of suppressor of cytokine signaling (SOCS) proteins, are major determinants of hypertriglyceridemia associated to insulin resistance. In the present study, we have investigated the role of SOCS3 in the transcriptional regulation of PCSK9 in HepG2 cells. Forced overexpression of SOCS3 determined the abrogation of STAT3
Abstracts / Atherosclerosis 241 (2015) e32ee71
phosphorylation, associated to: 1) induction of fatty-acid synthase mRNA levels (3.59±0.40 fold); 2) activation of SREBP transcriptional activity (1.58±0.15 fold); 3) increase apoB production (3.47±0.09 fold). SOCS3 overexpression also determined an increase of PCSK9 mRNA (7.82±1.73 fold) and protein (2.18±1.13 fold) without significant changes of HMG-CoA reductase, LDLR and cholesterol biosynthesis. Pharmacological inhibition of STAT3 or JAK proteins also induced PCSK9 levels by 2.06±0.75 and 3.30±0.3 fold, respectively. Interestingly, insulin significantly induced STAT3 phosphorylation, fatty-acid synthase and PCSK9 mRNA levels to a similar extent in both control and SOCS3-overexpressing cells, although the overall mRNA levels of PCSK9 and fattyacid synthase were significantly higher in HepG2 SOCS3 cells. In conclusion, we provided evidence that biological and/or pharmacological inhibition of the JAK/STAT pathway increased PCSK9 levels, both in the absence and in the presence of insulin stimulation, a possible determinant of PCSK9 transcription in insulin resistant patients The present work was supported by the grant 2012-0549 from Fondazione Cariplo, ITALY
EAS-0494. ASSOCIATION BETWEEN EARLY ALCOHOLIC STEATOHEPATITIS
ATHEROSCLEROSIS
AND
NON-
E. Dronca 2, D.P. Sampelean 1, I. Para 1, M. N. Leach 1, Grigorescu 1. 1 Department of Internal Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu” Cluj-Napoca, CLUJ-NAPOCA, Romania; 2 Department of Medical Genetics, University of Medicine and Pharmacy “Iuliu Hatieganu” Cluj-Napoca, CLUJ-NAPOCA, Romania Introduction: Non alcoholic liver disease (NAFLD) is closely associated with abdominal obesity, hypertension, dyslipidemia, and type 2 diabetes, which are all features of the metabolic syndrome, a highly pro-atherogenic state. Aim: Our study aimed to assessed whether patients with biopsy proven NASH had an increased cardiovascular (CV) risk evaluated from measured c-IMT than control subjects and to evaluate possible relationships between c-IMT and classical (CV) risk factors and also liver histology. Patients and methods: 50 patients with non-alcoholic steatohepatitis and 30 healthy controls, age and gender matched, were recruited. Lipid profile, liver biochemical markers, insulin level, HOMA IR and carotid intimamedia thickness were assayed. Results: Patients with NASH had a significantly higher c-IMT than control group (0.9 mm vs. 0.6 mm, p<0.001). The prevalence of plaques in subjects with NASH was 7/50 (14.2%) vs. 0/30 (0%) in the control group (p¼0.04).The c-IMT were significantly positively correlated with age, WC,BMI, insulin level ,HOMA-IR, fasting plasma glucose, AST, ALT and lobular inflammation. In multiple logistic analysis, after adjustment for age, gender, smoking, BMI, metabolic syndrome NASH was independent associated with high c-IMT (OR, 13.9; 95%CI, 1.9 to 99, P<0.001). Other independent predictors of c-IMT were HOMAIR (p¼0.006) and age (p¼0.001). Conclusion: NASH is independent associated with subclinical atherosclerosis. The hepatic inflammation could be one of the links between NASH and cardiovascular disease. Carotid intima-media thickness maybe used as an indicator of early atherosclerotic changes in patiens with NASH.
EAS-0551. EPICARDIAL FAT THICKNESS IS AN ECTOPIC FAT ASSOCIATED WITH METABOLIC SYNDROME, SUBCLINICAL ATHEROSCLEROSIS AND MARKERS OF CARDIAC DYSFUNCTION IN THE GENERAL POPULATION A. Baragetti 1, G. Pisano 2, K. Garlaschelli 3, L. Grigore 4, F. Pellegatta 4, G.D. Nora 1, A.L. Fracanzani 2, S. Fargion 2, A.L. Catapano 4. 1 Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; 2 Department of Pathophysiology and Transplantation Metabolic Liver Diseases Research Center Ca' Granda IRCCS Foundation Policlinico Hospital,
e47
University of Milan, Milan, Italy; 3 Center for the Study of Atherosclerosis, Bassini Hospital Cinisello Balsamo, Milan, Italy; 4 Multimedica Hospital, IRCCS - Istituti di Ricovero e Cura a Carattere Scientifico Sesto San Giovanni Italy, Milan, Italy Obesity is associated with Metabolic Syndrome (MetS) and hepatic steatosis represents an ectopic fat localization frequently observed in this condition. Epicardial Fat Thickness (EFT) is a new discovered marker of ectopic fat associated with obesity. To date, it is not clear whether EFT is associated both with subclinical atherosclerotic markers and steatosis degree in the general population. 1,018 subjects (from the PLIC Study) were included, for whom information about clinical, cardio-metabolic and pharmacological profile are available. EFT, aortic calcifications, carotid Intima-Media Thickness (c-IMT) and echocardiographic parameters were determined. Steatosis was defined according to a scoring system and abdominal adiposity by using Dual Xrays Absorbimetry (DEXA). EFT, independently from age, was similar between women and men (4.73 + 0.14 mm vs 4.25 + 0.16 mm respectively, p¼ 0.067); however it was thicker in post-menopausal women (independently from hormone-replacement therapy) (4.76 + 0.16 mm vs 4.07 + 0.16 in age-matched men, p¼ 0.013). EFT increased with determinants of MetS (p < 0.001), dyslipidaemia, ultrasound steatosis degrees (p < 0.001) and with abdominal adiposity. ROC analysis showed that those with MetS presented EFT above 5.2 mm (6.10 mm in women, 4.7 mm in men). EFT was associated with diastolic dysfunction (beta¼ -0.101, p¼ 0.015) and AC (OR¼ 1.067 [1.014-1.123] 95% C.I., p¼ 0.013). The association between EFT and c-IMT weakened as function of steatosis degree. EFT is associated with subclinical atherosclerosis and hepatic steatosis. Our data suggest that EFT determination may represent and additional tool for the stratification of the cardiovascular risk.
EAS-0645. MIR-34A HAS A ROLE IN WEIGHT GAIN, DURING MURINE DIETINDUCED OBESITY C.A. Lavery 1, M. Kurowska-Stolarska 2, I. Donnelly 1, A.H. Baker 1, A.M. Miller 1. 1 Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom; 2 Institute of Infection Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom Aim: With the global obesity epidemic, it is increasingly important to find novel therapies to treat comorbidities, such as dyslipidaemia and atherosclerosis. For example, microRNA-34a has been show to regulate inflammatory cytokine expression in macrophages, the main adipose infiltrate during obesity. We aimed to investigate the role of miR-34a in adipose inflammation and weight gain, in a murine diet-induced obesity model. Methods: Wild type (WT) C57BL/6 mice and miR-34a-/- mice, were fed a normal chow diet (NCD) or high-fat diet (HFD; 0.15% cholesterol, 21% lard) ad libitum, for 24 weeks, in accordance with UK Home Office guidelines. Epididymal adipose tissue was collagenase digested and analysed by FACS. WT and miR-34a-/- bone marrow derived macrophages (BMDM) were cultured in vitro, and gene expression analysed by QPCR. Results: miR-34a-/- mice on HFD were significantly heavier (P¼0.0096) than WT counterparts and exhibited a greater increase in epididymal adipose weight (P¼0.0011). Examination of macrophage phenotypes in epididymal adipose by FACS demonstrated no change in M1 or M2 markers in miR-34a-/- mice on HFD, but a significant increase in macrophage F4/80 expression (P¼0.0288), and decrease of the activation marker, CD69 (P¼0.0107). However, WT and miR-34a-/- BMDM cultures showed no difference in the metabolic and inflammatory genes examined. Conclusions: We have demonstrated that miR-34a has a role in murine weight maintenance, and suggest that macrophages are unlikely to be the main contributor to the adipose phenotype, in miR-34a-/- mice. Further