- Email: [email protected]
FGF21 lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown adipose tissues
Abstracts / Atherosclerosis 252 (2016) e236ee264
as monocytes, key drivers of plaque inflammation, have been reported to accumulate remnant cholesterol, enhancing migratory capacity, we assessed the phenotype of circulating monocytes. Methods: We performed 18fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) imaging in patients with familial dysbetalipoproteinemia (FD) compared with matched healthy controls. Furthermore, we performed monocyte characterization studies. Results: We included 14 FD patients (age 61±8, 64% male) and 14 controls (age 58±6, 64% male). FD patients had a significant higher total cholesterol, remnant cholesterol and plasma triglycerides. 18F-FDG uptake in the arterial wall was significantly increased in FD patients compared with controls (carotid target-to-background-ratio: 2,03±0,39 versus 1,62±0,29, p<0.001). Furthermore, monocyte count was significantly increased and characterization showed higher surface expression of adhesion markers CD18, CD11b and CD11c. Assessment of lipid accumulation showed an increase in percentage of monocytes with lipid droplets and a concomitant increase in number of lipid droplets. Conclusions: FD patients have increased arterial wall inflammation and are characterized by an inflammatory phenotype of circulating monocytes, which accumulated larger amounts of lipids. These findings indicate an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to its relationship with increased CVD risk.
EAS16-0663, WORKSHOP 1.2: THERAPEUTIC AND DIAGNOSTIC TARGETING OF THE ARTERIAL WALL. GENE THERAPY REDUCES ANGIOPLASTY INDUCED CORONARY RESTENOSIS IN A HIGH CHOLESTEROL SWINE MODEL D. Agrawal, P. Gunasekar, C. Boosani, V. Swier, M. Radwan, M. Del Core, W. Hunter. Creighton University School of Medicine, Center for Clinical & Translational Science, Omaha, USA Objectives: Interventional procedures including coronary angioplasty (PTCA) induce neointimal hyperplasia and restenosis in coronary arteries. Thus, targeted expression of specific genes in coronary artery smooth muscle cells, which regulate cell proliferation, could prevent neointimal hyperplasia. Here, we report our novel findings on the effect of SOCS3 gene therapy. Methods: Yucatan™ miniature swine were categorized into three groups e control, control-vector and gene therapy group. PTCA was performed in all groups. Swine in the control group received equivalent volume of normal saline, whereas swine in SOCS3 gene therapy group and control vector received about 5x1012 genome copies of AAV2/9 viral particles with or without SOCS3 gene, respectively. Following PTCA, the coronary lumen diameter was measured by optical coherence tomography (OCT) and histomorphometric studies before and six months after gene therapy. Immunopositivity to IL-6, NF-kB, pSTAT-3, SOCS3, and PCNA was examined in thin sections of coronary arteries stained with H&E and Movat’s pentachrome. Results: There was significant decrease in percent stenosis in the swine coronary arteries that underwent SOCS3 gene therapy, compared with control and control vector groups. Protein expression of pSTAT-3, NF-kB, pro-inflammatory cytokine IL-6, and proliferation marker PCNA, as revealed by immunofluorescence staining and Western blotting, was significantly decreased in coronary arteries of SOCS3 gene therapy swine compared to control groups. The histopathological findings correlate with the OCT findings in regard to percent restenosis. Conclusions: The findings support the potential application of SOCS3 gene therapy in preventing intimal hyperplasia and restenosis of coronary arteries following angioplasty.
EAS16-0174, WORKSHOP 1.2: THERAPEUTIC AND DIAGNOSTIC TARGETING OF THE ARTERIAL WALL. SPOTTY CALCIFICATION AS A MARKER OF VULNERABLE PLAQUE:
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NOVEL FINDINGS FROM IN-VIVO STUDY IN SURVIVORS OF CARDIAC ARREST AND IN-VITRO STUDY IN AUTOPTIC SCD PATIENTS J. Pu 1, P. Zhang 2, G.S. Mintz 3, X. Ma 4, B. He 1. 1 Renji Hospital, School of Medicine, Shanghai Jiaotong University, Department of Cardiology, Shanghai, China; 2 University of Maryland, University of Maryland Medical Center, Baltimore, USA; 3 Columbia University, Columbia University Medical Center, Baltimore, USA; 4 Thomas Jefferson University, Thomas Jefferson University Hospital, Philadelphia, USA Objectives: Calcification is a common finding in human atherosclerotic lesion. However, our understanding of calcification in human vessels remains limited. We previously reported that spotty calcification detected by IVUS was often associated with histopathological fibroatheromas (J Am Coll Cardiol, 2014: 6321:2220-33). In the present study, we reported our novel findings on spotty calcification from in-vivo study in survivors of cardiac arrest and in-vitro study in autopsied patients with sudden cardiac death (SCD). Methods: IVUS, OCT and near-infrared spectroscopy (NIRS) were performed in vivo in 153 native lesions in 84 vessels from 62 patients who experienced a documented sudden cardiac arrest but successfully resuscitated, and in vitro in 3,301 vessel segments in 184 coronary specimens from 82 patients at necropsy. Results: IVUS and OCT detected spotty calcification in 88.5% survivors of cardiac arrest, 78.3% of them had spotty calcification in superficial location. The arc of superficial spotty calcification was negatively correlated with lipid core burden index on NIRS, and positively correlated with the thickness of fibrous cap on OCT. In in-vitro study, IVUS and OCT detected spotty calcification in 80.6% SCD patients at necropsy, 84.0 % of them was superficial in location. On pathological analyses, spotty calcification was associated with i) increased inflammation of fibrous cap, ii) increased apoptosis of SMC and necrotic core size, iii) increased oxidative/nitrative stress levels, and iv) increased MMP expression and decreased collagen content in human coronary plaques. Conclusions: Spotty calcification, especially superficial location, is a marker of vulnerable plaque in survivors of cardiac arrest and autopsied patients of SCD.
EAS16-0272, WORKSHOP 2.2: ADIPOSE TISSUE e LIVER AXIS. FGF21 LOWERS PLASMA TRIGLYCERIDES BY ACCELERATING LIPOPROTEIN CATABOLISM IN WHITE AND BROWN ADIPOSE TISSUES C. Schlein 1, S. Talukdar 2, M. Heine 1, A.W. Fischer 1, L.M. Krott 1, S.K. Nilsson 1, M.B. Brenner 2, J. Heeren 1, L. Scheja 1. 1 University Medical Center Hamburg-Eppendorf, Institute for Biochemistry and Molecular Cellbiology, Hamburg, Germany; 2 Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, USA Objectives: FGF21 decreases plasma triglycerides (TGs) in rodents and humans, however, the underlying mechanism(s) are unclear. In the present study, we examined the role of FGF21 in production and disposal of TG-rich lipoproteins (TRL) in mice. Methods: To study the role of FGF21 in lipoprotein and glucose metabolism, recombinant FGF21 protein was injected acutely and chronically. Lipid and glucose organ distribution was investigated by the use of radiolabelled TRL, glucose or fatty acids as well as different genetic mouse models lacking either the fatty acid transporter CD36 or lipoprotein lipase specifically in adipose tissue. VLDL production was studied by i.v. injection of the lipase inhibitor Tyloxapol. Results: Treatment with pharmacological doses of FGF21 acutely reduced plasma non-esterified fatty acids (NEFA), liver TG content and VLDL-TG secretion. In addition, metabolic turnover studies revealed that FGF21 facilitated the catabolism of TRL in white adipose tissue (WAT) and brown adipose tissue (BAT). FGF21-dependent TRL processing was strongly attenuated in CD36-deficient mice and transgenic mice lacking lipoprotein lipase
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Abstracts / Atherosclerosis 252 (2016) e236ee264
in adipose tissues. Notably, insulin resistance in diet-induced obese and ob/ ob mice shifted FGF21 responses from WAT towards energy combusting BAT. Conclusions: FGF21 lowers plasma TG through a dual mechanism; first, by reducing NEFA plasma levels and consequently hepatic VLDL lipidation and second, by increasing CD36 and LPL dependent TRL disposal in WAT and BAT.
sensitivity and hepatic steatosis via downregulation of hepatic FSP27/ Cidec expression independently of sex and diets. Targeting Soat2 may thus be a novel strategy to treat cardiometabolic diseases.
EAS16-0928, WORKSHOP 2.2: ADIPOSE TISSUE e LIVER AXIS. SHORT-TERM COLD EXPOSURE MODULATES HUMAN VLDL AND HDL METABOLISM K. Nahon 1, G. Hoeke 1, L. Bakker 1, D. Drettwan 2, P. Pagel 2, I. Jazet 1, J. e 1, M. Boon 1, P. Rensen 1. 1 Leiden University Medical Center, Internal Berbe Medicine- Division Endocrinology, Leiden, Netherlands; 2 Numares, AG, Regensburg, Germany Objectives: Upon cold activation, brown adipose tissue (BAT) combusts intracellular triglycerides (TG) into heat. Mouse studies showed that BAT consequently internalizes VLDL-TG-derived fatty acids to replenish intracellular TG stores (Hoeke, Circ Res 2016). Since the effect of cold-induced BAT activation on human lipoprotein metabolism remained elusive, we now assessed the effect of short-term mild cold exposure on the lipoprotein profile in men.
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EAS16-0944, WORKSHOP 2.2: ADIPOSE TISSUE e LIVER AXIS. SOAT2 DEPLETION IMPROVES INSULIN SENSITIVITY AND HEPATIC STEATOSIS P. Parini 1, C. Pramfalk 2, O. Ahmed 2, L. Larsson 2, F. Karpe 3, M. Neville 3, M. Eriksson 4. 1 Karolinska Institutet, Dept Laboratory Medicine/Dept Medicine, Stockholm, Sweden; 2 Karolinska Institutet, Dept of Laboratory Medicine, Stockholm, Sweden; 3 University of Oxford, Radcliffe Dept. of Medicine, Oxford, United Kingdom; 4 Karolinska Institutet, Dept of Medicine, Stockholm, Sweden Objectives: Excessive accumulation of triglycerides and cholesteryl esters (CE) inside the hepatocytes (hepatic steatosis) is a prerequisite for the development of nonalcoholic fatty liver disease. The cholesterol esterifying enzyme acyl-Coenzyme A: cholesterol acyltransferase 2 (ACAT2), encoded by the Soat2 gene, is exclusively expressed in enterocytes and hepatocytes and synthesize CE from cholesterol and long-chain fatty acids. Soat2-/mice do not develop atherosclerosis or diet-induced hypercholesterolemia. In this study we aimed to investigate the role of ACAT2 in hepatic steatosis and its potential association with insulin sensitivity by genetic disruption of Soat2 gene. Methods: Wild type and Soat2-/- mice were either fed a high-fat, a highcarbohydrate, or a chow diet. Serum, liver, adipose, and muscle tissues were analyzed. Oral glucose and insulin tolerance tests were performed. Plasma from humans bearing a rare exonic variant was analyzed. Results: Soat2-/- mice fed a high-fat diet for eight weeks developed less hepatic steatosis, were more insulin sensitive, and had lower expressions of hepatic membrane glucose transporter 2 (GLUT2) and fat specific protein 27 (FSP27, named Cidec in humans). Similar findings were present in Soat2-/- mice fed a high-carbohydrate diet for two weeks. Carriers of a rare exonic variant in CIDEC (rs140125102, Pro73Thr) had lower insulin and HOMA-IR compared to non-carriers. Conclusions: Genetic depletion of Soat2 dramatically improves insulin
Methods: 10 lean adolescent white Caucasian males were exposed to a personalized cooling protocol (water cooling; average 9.9 C) for 3 h. Before and after cooling, serum samples were collected for analysis of lipids and lipoprotein composition using 1H-NMR. Results: Mild cold exposure increased TG (+18%; p<0.05) as well as VLDL-C (+8%; p<0.05) and the VLDL particle concentration (+68%; p<0.05), suggesting that cold exposure increases hepatic VLDL production. At the same time, cold exposure increased HDL particle concentration (+9%; p<0.05) as well as HDL-C (+9%; p<0.05), specific for small HDL, and decreased the average HDL size (-0.1 nm), which is consistent with LPL-mediated generation of VLDL surface remnants that attract cholesterol from tissues into the circulation. Conclusions: Short-term cold exposure modulates human lipoprotein metabolism by enhancing hepatic VLDL production as well as LPL-mediated VLDL-TG processing. This is likely a consequence of enhanced uptake of TG-derived fatty acids by BAT, resulting in the generation of surface remnants as precursors of HDL that enhance cholesterol efflux into the circulation.
EAS16-1027, LATE BREAKING: BASIC SCIENCE. FLOW PERTURBATION MEDIATES NEUTROPHIL RECRUITMENT AND POTENTIATES ENDOTHELIAL INJURY VIA TLR2 IN MICE. A NOVEL IN VIVO APPROACH FOR PROBING THE PATHOPHYSIOLOGY OF SUPERFICIAL EROSION G. Franck 1, G. Sausen 1, T. Mawson 1, M. Salinas 2, G. Masson 3, A. Cole 1, M. Beltrami-Moreira 1, Y. Chatzizisis 1, Y. Tesmenitsky 1, E. Swartz 1, G. Sukhova 1, F. Swirski 3, M. Nahrendorf 3, E. Aikawa 2, K. Croce 1, P. Libby 1. 1 Brigham and Women's Hospital, Cardiovascular Medicine, Boston, USA; 2 Brigham and Women’s Hospital, Center for Interdisciplinary Cardiovascular Sciences, Boston, USA; 3 Center for Systems Biology, Massachusetts General Hospital, Boston, USA Objectives: Superficial erosion currently accounts for a third of coronary thrombi in patients with fatal acute coronary syndromes. Yet, mechanisms involved in its initiation remain unclear. Superficial erosion commonly colocalizes with regions of disturbed flow and promotes local loss of endothelial cells (EC), NETosis, and mural thrombosis. Engagement of TLR2, highly expressed by EC in human erosion-prone plaque, could potentiate this process. This study tested those hypotheses in mice. Methods: Apoe-/- mice previously subjected to injury to induce neointima formation underwent flow perturbation, assessed with combined echo/ Doppler interrogation and computational fluid dynamic analysis, produced by placement of cone-shaped adventitial cuffs for 1 or 6h. Treatment with anti-Ly6G or anti-LFA-1 neutralizing antibodies limited neutrophil
as monocytes, key drivers of plaque inflammation, have been reported to accumulate remnant cholesterol, enhancing migratory capacity, we assessed the phenotype of circulating monocytes. Methods: We performed 18fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) imaging in patients with familial dysbetalipoproteinemia (FD) compared with matched healthy controls. Furthermore, we performed monocyte characterization studies. Results: We included 14 FD patients (age 61±8, 64% male) and 14 controls (age 58±6, 64% male). FD patients had a significant higher total cholesterol, remnant cholesterol and plasma triglycerides. 18F-FDG uptake in the arterial wall was significantly increased in FD patients compared with controls (carotid target-to-background-ratio: 2,03±0,39 versus 1,62±0,29, p<0.001). Furthermore, monocyte count was significantly increased and characterization showed higher surface expression of adhesion markers CD18, CD11b and CD11c. Assessment of lipid accumulation showed an increase in percentage of monocytes with lipid droplets and a concomitant increase in number of lipid droplets. Conclusions: FD patients have increased arterial wall inflammation and are characterized by an inflammatory phenotype of circulating monocytes, which accumulated larger amounts of lipids. These findings indicate an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to its relationship with increased CVD risk.
EAS16-0663, WORKSHOP 1.2: THERAPEUTIC AND DIAGNOSTIC TARGETING OF THE ARTERIAL WALL. GENE THERAPY REDUCES ANGIOPLASTY INDUCED CORONARY RESTENOSIS IN A HIGH CHOLESTEROL SWINE MODEL D. Agrawal, P. Gunasekar, C. Boosani, V. Swier, M. Radwan, M. Del Core, W. Hunter. Creighton University School of Medicine, Center for Clinical & Translational Science, Omaha, USA Objectives: Interventional procedures including coronary angioplasty (PTCA) induce neointimal hyperplasia and restenosis in coronary arteries. Thus, targeted expression of specific genes in coronary artery smooth muscle cells, which regulate cell proliferation, could prevent neointimal hyperplasia. Here, we report our novel findings on the effect of SOCS3 gene therapy. Methods: Yucatan™ miniature swine were categorized into three groups e control, control-vector and gene therapy group. PTCA was performed in all groups. Swine in the control group received equivalent volume of normal saline, whereas swine in SOCS3 gene therapy group and control vector received about 5x1012 genome copies of AAV2/9 viral particles with or without SOCS3 gene, respectively. Following PTCA, the coronary lumen diameter was measured by optical coherence tomography (OCT) and histomorphometric studies before and six months after gene therapy. Immunopositivity to IL-6, NF-kB, pSTAT-3, SOCS3, and PCNA was examined in thin sections of coronary arteries stained with H&E and Movat’s pentachrome. Results: There was significant decrease in percent stenosis in the swine coronary arteries that underwent SOCS3 gene therapy, compared with control and control vector groups. Protein expression of pSTAT-3, NF-kB, pro-inflammatory cytokine IL-6, and proliferation marker PCNA, as revealed by immunofluorescence staining and Western blotting, was significantly decreased in coronary arteries of SOCS3 gene therapy swine compared to control groups. The histopathological findings correlate with the OCT findings in regard to percent restenosis. Conclusions: The findings support the potential application of SOCS3 gene therapy in preventing intimal hyperplasia and restenosis of coronary arteries following angioplasty.
EAS16-0174, WORKSHOP 1.2: THERAPEUTIC AND DIAGNOSTIC TARGETING OF THE ARTERIAL WALL. SPOTTY CALCIFICATION AS A MARKER OF VULNERABLE PLAQUE:
e239
NOVEL FINDINGS FROM IN-VIVO STUDY IN SURVIVORS OF CARDIAC ARREST AND IN-VITRO STUDY IN AUTOPTIC SCD PATIENTS J. Pu 1, P. Zhang 2, G.S. Mintz 3, X. Ma 4, B. He 1. 1 Renji Hospital, School of Medicine, Shanghai Jiaotong University, Department of Cardiology, Shanghai, China; 2 University of Maryland, University of Maryland Medical Center, Baltimore, USA; 3 Columbia University, Columbia University Medical Center, Baltimore, USA; 4 Thomas Jefferson University, Thomas Jefferson University Hospital, Philadelphia, USA Objectives: Calcification is a common finding in human atherosclerotic lesion. However, our understanding of calcification in human vessels remains limited. We previously reported that spotty calcification detected by IVUS was often associated with histopathological fibroatheromas (J Am Coll Cardiol, 2014: 6321:2220-33). In the present study, we reported our novel findings on spotty calcification from in-vivo study in survivors of cardiac arrest and in-vitro study in autopsied patients with sudden cardiac death (SCD). Methods: IVUS, OCT and near-infrared spectroscopy (NIRS) were performed in vivo in 153 native lesions in 84 vessels from 62 patients who experienced a documented sudden cardiac arrest but successfully resuscitated, and in vitro in 3,301 vessel segments in 184 coronary specimens from 82 patients at necropsy. Results: IVUS and OCT detected spotty calcification in 88.5% survivors of cardiac arrest, 78.3% of them had spotty calcification in superficial location. The arc of superficial spotty calcification was negatively correlated with lipid core burden index on NIRS, and positively correlated with the thickness of fibrous cap on OCT. In in-vitro study, IVUS and OCT detected spotty calcification in 80.6% SCD patients at necropsy, 84.0 % of them was superficial in location. On pathological analyses, spotty calcification was associated with i) increased inflammation of fibrous cap, ii) increased apoptosis of SMC and necrotic core size, iii) increased oxidative/nitrative stress levels, and iv) increased MMP expression and decreased collagen content in human coronary plaques. Conclusions: Spotty calcification, especially superficial location, is a marker of vulnerable plaque in survivors of cardiac arrest and autopsied patients of SCD.
EAS16-0272, WORKSHOP 2.2: ADIPOSE TISSUE e LIVER AXIS. FGF21 LOWERS PLASMA TRIGLYCERIDES BY ACCELERATING LIPOPROTEIN CATABOLISM IN WHITE AND BROWN ADIPOSE TISSUES C. Schlein 1, S. Talukdar 2, M. Heine 1, A.W. Fischer 1, L.M. Krott 1, S.K. Nilsson 1, M.B. Brenner 2, J. Heeren 1, L. Scheja 1. 1 University Medical Center Hamburg-Eppendorf, Institute for Biochemistry and Molecular Cellbiology, Hamburg, Germany; 2 Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, USA Objectives: FGF21 decreases plasma triglycerides (TGs) in rodents and humans, however, the underlying mechanism(s) are unclear. In the present study, we examined the role of FGF21 in production and disposal of TG-rich lipoproteins (TRL) in mice. Methods: To study the role of FGF21 in lipoprotein and glucose metabolism, recombinant FGF21 protein was injected acutely and chronically. Lipid and glucose organ distribution was investigated by the use of radiolabelled TRL, glucose or fatty acids as well as different genetic mouse models lacking either the fatty acid transporter CD36 or lipoprotein lipase specifically in adipose tissue. VLDL production was studied by i.v. injection of the lipase inhibitor Tyloxapol. Results: Treatment with pharmacological doses of FGF21 acutely reduced plasma non-esterified fatty acids (NEFA), liver TG content and VLDL-TG secretion. In addition, metabolic turnover studies revealed that FGF21 facilitated the catabolism of TRL in white adipose tissue (WAT) and brown adipose tissue (BAT). FGF21-dependent TRL processing was strongly attenuated in CD36-deficient mice and transgenic mice lacking lipoprotein lipase
e240
Abstracts / Atherosclerosis 252 (2016) e236ee264
in adipose tissues. Notably, insulin resistance in diet-induced obese and ob/ ob mice shifted FGF21 responses from WAT towards energy combusting BAT. Conclusions: FGF21 lowers plasma TG through a dual mechanism; first, by reducing NEFA plasma levels and consequently hepatic VLDL lipidation and second, by increasing CD36 and LPL dependent TRL disposal in WAT and BAT.
sensitivity and hepatic steatosis via downregulation of hepatic FSP27/ Cidec expression independently of sex and diets. Targeting Soat2 may thus be a novel strategy to treat cardiometabolic diseases.
EAS16-0928, WORKSHOP 2.2: ADIPOSE TISSUE e LIVER AXIS. SHORT-TERM COLD EXPOSURE MODULATES HUMAN VLDL AND HDL METABOLISM K. Nahon 1, G. Hoeke 1, L. Bakker 1, D. Drettwan 2, P. Pagel 2, I. Jazet 1, J. e 1, M. Boon 1, P. Rensen 1. 1 Leiden University Medical Center, Internal Berbe Medicine- Division Endocrinology, Leiden, Netherlands; 2 Numares, AG, Regensburg, Germany Objectives: Upon cold activation, brown adipose tissue (BAT) combusts intracellular triglycerides (TG) into heat. Mouse studies showed that BAT consequently internalizes VLDL-TG-derived fatty acids to replenish intracellular TG stores (Hoeke, Circ Res 2016). Since the effect of cold-induced BAT activation on human lipoprotein metabolism remained elusive, we now assessed the effect of short-term mild cold exposure on the lipoprotein profile in men.
Ă
EAS16-0944, WORKSHOP 2.2: ADIPOSE TISSUE e LIVER AXIS. SOAT2 DEPLETION IMPROVES INSULIN SENSITIVITY AND HEPATIC STEATOSIS P. Parini 1, C. Pramfalk 2, O. Ahmed 2, L. Larsson 2, F. Karpe 3, M. Neville 3, M. Eriksson 4. 1 Karolinska Institutet, Dept Laboratory Medicine/Dept Medicine, Stockholm, Sweden; 2 Karolinska Institutet, Dept of Laboratory Medicine, Stockholm, Sweden; 3 University of Oxford, Radcliffe Dept. of Medicine, Oxford, United Kingdom; 4 Karolinska Institutet, Dept of Medicine, Stockholm, Sweden Objectives: Excessive accumulation of triglycerides and cholesteryl esters (CE) inside the hepatocytes (hepatic steatosis) is a prerequisite for the development of nonalcoholic fatty liver disease. The cholesterol esterifying enzyme acyl-Coenzyme A: cholesterol acyltransferase 2 (ACAT2), encoded by the Soat2 gene, is exclusively expressed in enterocytes and hepatocytes and synthesize CE from cholesterol and long-chain fatty acids. Soat2-/mice do not develop atherosclerosis or diet-induced hypercholesterolemia. In this study we aimed to investigate the role of ACAT2 in hepatic steatosis and its potential association with insulin sensitivity by genetic disruption of Soat2 gene. Methods: Wild type and Soat2-/- mice were either fed a high-fat, a highcarbohydrate, or a chow diet. Serum, liver, adipose, and muscle tissues were analyzed. Oral glucose and insulin tolerance tests were performed. Plasma from humans bearing a rare exonic variant was analyzed. Results: Soat2-/- mice fed a high-fat diet for eight weeks developed less hepatic steatosis, were more insulin sensitive, and had lower expressions of hepatic membrane glucose transporter 2 (GLUT2) and fat specific protein 27 (FSP27, named Cidec in humans). Similar findings were present in Soat2-/- mice fed a high-carbohydrate diet for two weeks. Carriers of a rare exonic variant in CIDEC (rs140125102, Pro73Thr) had lower insulin and HOMA-IR compared to non-carriers. Conclusions: Genetic depletion of Soat2 dramatically improves insulin
Methods: 10 lean adolescent white Caucasian males were exposed to a personalized cooling protocol (water cooling; average 9.9 C) for 3 h. Before and after cooling, serum samples were collected for analysis of lipids and lipoprotein composition using 1H-NMR. Results: Mild cold exposure increased TG (+18%; p<0.05) as well as VLDL-C (+8%; p<0.05) and the VLDL particle concentration (+68%; p<0.05), suggesting that cold exposure increases hepatic VLDL production. At the same time, cold exposure increased HDL particle concentration (+9%; p<0.05) as well as HDL-C (+9%; p<0.05), specific for small HDL, and decreased the average HDL size (-0.1 nm), which is consistent with LPL-mediated generation of VLDL surface remnants that attract cholesterol from tissues into the circulation. Conclusions: Short-term cold exposure modulates human lipoprotein metabolism by enhancing hepatic VLDL production as well as LPL-mediated VLDL-TG processing. This is likely a consequence of enhanced uptake of TG-derived fatty acids by BAT, resulting in the generation of surface remnants as precursors of HDL that enhance cholesterol efflux into the circulation.
EAS16-1027, LATE BREAKING: BASIC SCIENCE. FLOW PERTURBATION MEDIATES NEUTROPHIL RECRUITMENT AND POTENTIATES ENDOTHELIAL INJURY VIA TLR2 IN MICE. A NOVEL IN VIVO APPROACH FOR PROBING THE PATHOPHYSIOLOGY OF SUPERFICIAL EROSION G. Franck 1, G. Sausen 1, T. Mawson 1, M. Salinas 2, G. Masson 3, A. Cole 1, M. Beltrami-Moreira 1, Y. Chatzizisis 1, Y. Tesmenitsky 1, E. Swartz 1, G. Sukhova 1, F. Swirski 3, M. Nahrendorf 3, E. Aikawa 2, K. Croce 1, P. Libby 1. 1 Brigham and Women's Hospital, Cardiovascular Medicine, Boston, USA; 2 Brigham and Women’s Hospital, Center for Interdisciplinary Cardiovascular Sciences, Boston, USA; 3 Center for Systems Biology, Massachusetts General Hospital, Boston, USA Objectives: Superficial erosion currently accounts for a third of coronary thrombi in patients with fatal acute coronary syndromes. Yet, mechanisms involved in its initiation remain unclear. Superficial erosion commonly colocalizes with regions of disturbed flow and promotes local loss of endothelial cells (EC), NETosis, and mural thrombosis. Engagement of TLR2, highly expressed by EC in human erosion-prone plaque, could potentiate this process. This study tested those hypotheses in mice. Methods: Apoe-/- mice previously subjected to injury to induce neointima formation underwent flow perturbation, assessed with combined echo/ Doppler interrogation and computational fluid dynamic analysis, produced by placement of cone-shaped adventitial cuffs for 1 or 6h. Treatment with anti-Ly6G or anti-LFA-1 neutralizing antibodies limited neutrophil