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Short-term cold exposure modulates human VLDL and HDL metabolism
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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
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