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Dissociation of postprandial clearance of chylomicrons and VLDL1 in MBL deficiency: Role of the innate immune system in postprandial lipemia?
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Abstracts / Atherosclerosis Supplements 9 (2008) 83–102
atherosclerotic status should be taken into account in studies involving postprandial lipemia.
Young Investigator Oral Presentation
Acknowledgment
Dissociation of postprandial clearance of chylomicrons and VLDL1 in MBL deficiency: Role of the innate immune system in postprandial lipemia?
Support for this work was funded in part by Spanish Arteriosclerosis Society with grant # 03/2005.
A. Alipour 1,∗ , A.J.H.H.M. van Oostrom 2 , J.P.H. Van Wijk 3 , C. Verseyden 4 , H.W.M. Plokker 2 , J.W. Jukema 5 , A.J. Rabelink 6 , M. Castro Cabezas 1
doi:10.1016/j.atherosclerosissup.2008.09.406 Chylomicron amyloid-beta in the aetiology of Alzheimer’s disease Ryusuke Takechi (BSc MSc), Susan Galloway (BSc (Hons)), Menuka M. Pallebage-Gamarallage (BSc (Hons)), John Charles Louis Mamo (PhD) ∗ School of Public Health and Australian Technology Network (ATN), Centre for Metabolic Fitness, Curtin University of Technology, Perth, Western Australia, Australia Alzheimer’s disease is characterized by inflammatory proteinaceous comprised principally of the protein amyloidbeta (Abeta). Presently, the origins of cerebral amyloid deposits are controversial, though pivotal for the prevention of Alzheimer’s disease. Recent evidence suggests that in blood, Abeta may serve as a regulating apoprotein of the triglyceride-richlipoproteins and we have found that the synthesis of Abeta in enterocytes and thereafter secretion as part of the chylomicron cascade is regulated by dietary fats. It is our contention that chronically elevated plasma levels of Abeta in response to diets rich in saturated-fats may lead to disturbances within the cerebrovasculature and exaggerated blood-to-brain delivery of circulating Abeta, thereby exacerbating amyloidosis. Consistent with this hypothesis we show that enterocytic Abeta is increased concomitant with apolipoprotein B48. Furthermore, cerebral extravasation of immunoglobulin G, a surrogate marker of plasma proteins is observed in a murine model of Alzheimer’s disease maintained on a saturated-fat diet and there is diminished expression of occludin within the cerebrovasculature, an endothelial tight junction protein. doi:10.1016/j.atherosclerosissup.2008.09.407
1 Department of Internal Medicine, Sint Franciscus Gasthuis,
Rotterdam, The Netherlands 2 Department of Cardiology, Sint Antonius Hospital, Nieuwegein, The Netherlands 3 Department of Internal Medicine, University Medical Center, Utrecht, The Netherlands 4 Research Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands 5 Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands 6 Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands Introduction: Mannose binding lectin (MBL) is one of the three initiators of complement activation of the innate immune system. MBL deficiency has been associated to the development of atherosclerosis. However, the mechanism of this relationship is unclear. Since atherosclerosis, inflammation and postprandial lipemia are linked to the complement system, we studied the effects of MBL deficiency as a model of disturbed complement activation, on the metabolism of postprandial lipoproteins. Methodology: We performed an observational study in 107 volunteers of whom 23 were MBL deficient. Baseline cardiovascular risk factors were determined in all and oral fat loading tests (OFLTs) were carried out in 8 MBL deficient and 14 MBL sufficient subjects. Postprandial lipoprotein responses were calculated as area under the curve. Results: MBL activity in the 23 deficient subjects was (mean ± S.E.M.) 0.22 ± 0.02 mg/L and in MBL sufficient subjects 1.38 ± 0.09 mg/L (P < 0.005). There were no differences in baseline cardiovascular risk factors between MBL deficient and sufficient subjects. The prevalence of coronary artery disease in the families of MBL deficient subjects was significantly higher than in MBL sufficient subjects (50% vs. 15%; P = 0.002). Postprandial plasma TG changes were similar between the groups. Postprandially, MBL deficient subjects had a significant 71% higher VLDL1-apoB100 response and 49% higher VLDL1-TG response compared to MBL sufficient subjects. Interestingly, MBL deficients showed a 61% lower chylomicron-apoB48 response suggesting preferential clearance of apoB48 containing lipoproteins. MBL activity was inversely related to the postprandial VLDL1-TG increase (r = −0.58, P = 0.005). Furthermore, MBL sufficient subjects showed a postprandial C3 increase of 7% at 2 h, whereas this response was absent in MBL deficient subjects.
Abstracts / Atherosclerosis Supplements 9 (2008) 83–102
Conclusions: The atherogenic tendencies of MBL deficient subjects may in part be explained by accumulation of VLDL1 in the context of enhance chylomicron clearance. The postulated mechanism involves impairment of postprandial complement activation.
Acknowledgments This study was supported by research funds from the Department of Internal Medicine of the University Medical Center Utrecht and the Sint Franciscus Gasthuis in Rotterdam, The Netherlands doi:10.1016/j.atherosclerosissup.2008.09.408 Student Power Presentations Sitaglipin treatment attenuates triglyceride rich lipoprotein accumulation in fructose fed syrian gold hamsters C.L. Baker ∗ , M. Naples, J. Hsieh, K. Adeli The Hospital for Sick Children, Toronto, Canada Dipeptidyl peptidase-4 (DPP-4) is the enzyme responsible for the rapid cleavage of the incretin hormone glucagon like peptide-1 (GLP-1). DPP-4 inhibition is a novel therapy used to treat type 2 diabetes. DPP-4 inhibitors such as sitagliptin increase levels of functional GLP-1, thus increasing insulin secretion and decreasing glucagon secretion, ultimately leading to decreased plasma glucose. Recent studies have indicated that GLP-1 treatment can reduce triglyceride uptake from the intestine and DPP-4 inhibition has been linked decreased levels of ApoB containing chylomicrons. In the present study, the DPP-4 inhibitor, sitagliptin was evaluated for its role in triglyceride absorption and chylomicron formation within the fructose fed Syrian gold hamster. Hamsters were fed either chow or high fructose diet (60% fructose) for 31 days, after 10 days of diet treatment; hamsters were dosed daily with sitagliptin (5 mg/kg po.) for the remaining 21 days. Blood was collected at baseline and endpoint to evaluate plasma cholesterol and triglyceride levels. At the end of 31 days hamsters were cannulated via jugular vein and fat loaded with olive oil, blood was collected at 0, 30, 60, 90 and 120 min after fat load and chylomicron accumulation was evaluated. Hamsters fed fructose showed significantly increased levels of plasma triglyceride compared to chow fed hamsters after 31 days, this was shown to be significantly attenuated with sitagliptin treatment (p < 0.05). FPLC analysis showed this decrease in triglyceride was mainly due to decreases in VLDL triglyceride particles. In fructose fed hamsters sitagliptin treatment significantly decreased accumulation of triglyceride rich lipoproteins (TRL) 90 min after fat load (p < 0.05), TRL ApoB was also decreased with sitagliptin treatment. Enterocytes collected from jejunum of fructose fed hamsters showed decreased total ApoB with sitagliptin treatment compared to control cells, cellular ApoB was also decreased
89
in sitagliptin treated hamsters, while secreted ApoB was increased with sitagliptin treatment. In conclusion, sitagliptin treatment is able to attenuate dyslipidemia resulting from ingestion of high fructose diet by decreasing accumulation of plasma triglycerides, particularly VLDL particles. In addition sitagliptin treatment causes decreased accumulation of chylomicrons, which seems to be linked to a decrease in ApoB 48. This indicates that sitagliptin may have a role in controlling dyslipidemia in addition to stimulating insulin release. doi:10.1016/j.atherosclerosissup.2008.09.409 Effect of fatty acids on enterocytic beta-amyloid abundance: Possible aetiology in Alzheimer’s disease S. Galloway 1 , R. Takechi 1 , M.M.S.R. Pallebage1 1 Gamarallage , L. Jian , R.D. Johnsen 2,3 , J.C.L. Mamo 1 1 School
of Public Health and Australian Technology Network (ATN), Centre for Metabolic Fitness, Curtin University of Technology, Perth, Western Australia, Australia 2 Australian Neuromuscular Research Institute, QEII Medical Centre, Perth, Western Australia, Australia 3 Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australia Background: Dietary fatty acids influence the risk of developing Alzheimer’s disease (AD), a condition caused by the deposition of beta-amyloid (A) peptide in the extracellular matrices of the brain. In animal studies, polyunsaturated fatty acid depress, whilst saturated fats exacerbate cerebral amyloidosis, possibly via mechanism related to A production. Approach: Previously, we showed that A abundance in small intestinal enterocytes is regulated by the availability of lipid substrate from diet [1]. A diet rich in saturated fats and cholesterol significantly enhanced enterocytic A whereas fasting completely abolished protein abundance. Non-esterified fatty acids (NEFA’s) differentially regulate chylomicron biogenesis and secretion and there is accumulating evidence that plasma A kinetics reflects postprandial lipoprotein kinetics. It is currently not known whether monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA) and saturated fatty acids (SFA) differentially influence chylomicron associated A metabolism. In part fulfilment of this hypothesis, this study aimed to determine if enterocytic A abundance is differentially regulated by NEFAs. Methodology: Six-week-old female C57BL/6J mouse were placed on diets containing either 20% (w/w) monounsaturated fatty acid (MUFA), polyunsaturated fatty acids (PUFA) or saturated fatty acids (SFA) for 12 weeks. Mice fed a diet containing 4% PUFA served as low-fat controls. Intestinal A and dietary fatty acids was determined using quantitative immunohistochemistry (IHC) or immunofluorescence microscopy (IFM). Results: Mice fed diets enriched in either of the NEFA’s showed increased enterocytic A compared to low-fat mice.
Abstracts / Atherosclerosis Supplements 9 (2008) 83–102
atherosclerotic status should be taken into account in studies involving postprandial lipemia.
Young Investigator Oral Presentation
Acknowledgment
Dissociation of postprandial clearance of chylomicrons and VLDL1 in MBL deficiency: Role of the innate immune system in postprandial lipemia?
Support for this work was funded in part by Spanish Arteriosclerosis Society with grant # 03/2005.
A. Alipour 1,∗ , A.J.H.H.M. van Oostrom 2 , J.P.H. Van Wijk 3 , C. Verseyden 4 , H.W.M. Plokker 2 , J.W. Jukema 5 , A.J. Rabelink 6 , M. Castro Cabezas 1
doi:10.1016/j.atherosclerosissup.2008.09.406 Chylomicron amyloid-beta in the aetiology of Alzheimer’s disease Ryusuke Takechi (BSc MSc), Susan Galloway (BSc (Hons)), Menuka M. Pallebage-Gamarallage (BSc (Hons)), John Charles Louis Mamo (PhD) ∗ School of Public Health and Australian Technology Network (ATN), Centre for Metabolic Fitness, Curtin University of Technology, Perth, Western Australia, Australia Alzheimer’s disease is characterized by inflammatory proteinaceous comprised principally of the protein amyloidbeta (Abeta). Presently, the origins of cerebral amyloid deposits are controversial, though pivotal for the prevention of Alzheimer’s disease. Recent evidence suggests that in blood, Abeta may serve as a regulating apoprotein of the triglyceride-richlipoproteins and we have found that the synthesis of Abeta in enterocytes and thereafter secretion as part of the chylomicron cascade is regulated by dietary fats. It is our contention that chronically elevated plasma levels of Abeta in response to diets rich in saturated-fats may lead to disturbances within the cerebrovasculature and exaggerated blood-to-brain delivery of circulating Abeta, thereby exacerbating amyloidosis. Consistent with this hypothesis we show that enterocytic Abeta is increased concomitant with apolipoprotein B48. Furthermore, cerebral extravasation of immunoglobulin G, a surrogate marker of plasma proteins is observed in a murine model of Alzheimer’s disease maintained on a saturated-fat diet and there is diminished expression of occludin within the cerebrovasculature, an endothelial tight junction protein. doi:10.1016/j.atherosclerosissup.2008.09.407
1 Department of Internal Medicine, Sint Franciscus Gasthuis,
Rotterdam, The Netherlands 2 Department of Cardiology, Sint Antonius Hospital, Nieuwegein, The Netherlands 3 Department of Internal Medicine, University Medical Center, Utrecht, The Netherlands 4 Research Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands 5 Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands 6 Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands Introduction: Mannose binding lectin (MBL) is one of the three initiators of complement activation of the innate immune system. MBL deficiency has been associated to the development of atherosclerosis. However, the mechanism of this relationship is unclear. Since atherosclerosis, inflammation and postprandial lipemia are linked to the complement system, we studied the effects of MBL deficiency as a model of disturbed complement activation, on the metabolism of postprandial lipoproteins. Methodology: We performed an observational study in 107 volunteers of whom 23 were MBL deficient. Baseline cardiovascular risk factors were determined in all and oral fat loading tests (OFLTs) were carried out in 8 MBL deficient and 14 MBL sufficient subjects. Postprandial lipoprotein responses were calculated as area under the curve. Results: MBL activity in the 23 deficient subjects was (mean ± S.E.M.) 0.22 ± 0.02 mg/L and in MBL sufficient subjects 1.38 ± 0.09 mg/L (P < 0.005). There were no differences in baseline cardiovascular risk factors between MBL deficient and sufficient subjects. The prevalence of coronary artery disease in the families of MBL deficient subjects was significantly higher than in MBL sufficient subjects (50% vs. 15%; P = 0.002). Postprandial plasma TG changes were similar between the groups. Postprandially, MBL deficient subjects had a significant 71% higher VLDL1-apoB100 response and 49% higher VLDL1-TG response compared to MBL sufficient subjects. Interestingly, MBL deficients showed a 61% lower chylomicron-apoB48 response suggesting preferential clearance of apoB48 containing lipoproteins. MBL activity was inversely related to the postprandial VLDL1-TG increase (r = −0.58, P = 0.005). Furthermore, MBL sufficient subjects showed a postprandial C3 increase of 7% at 2 h, whereas this response was absent in MBL deficient subjects.
Abstracts / Atherosclerosis Supplements 9 (2008) 83–102
Conclusions: The atherogenic tendencies of MBL deficient subjects may in part be explained by accumulation of VLDL1 in the context of enhance chylomicron clearance. The postulated mechanism involves impairment of postprandial complement activation.
Acknowledgments This study was supported by research funds from the Department of Internal Medicine of the University Medical Center Utrecht and the Sint Franciscus Gasthuis in Rotterdam, The Netherlands doi:10.1016/j.atherosclerosissup.2008.09.408 Student Power Presentations Sitaglipin treatment attenuates triglyceride rich lipoprotein accumulation in fructose fed syrian gold hamsters C.L. Baker ∗ , M. Naples, J. Hsieh, K. Adeli The Hospital for Sick Children, Toronto, Canada Dipeptidyl peptidase-4 (DPP-4) is the enzyme responsible for the rapid cleavage of the incretin hormone glucagon like peptide-1 (GLP-1). DPP-4 inhibition is a novel therapy used to treat type 2 diabetes. DPP-4 inhibitors such as sitagliptin increase levels of functional GLP-1, thus increasing insulin secretion and decreasing glucagon secretion, ultimately leading to decreased plasma glucose. Recent studies have indicated that GLP-1 treatment can reduce triglyceride uptake from the intestine and DPP-4 inhibition has been linked decreased levels of ApoB containing chylomicrons. In the present study, the DPP-4 inhibitor, sitagliptin was evaluated for its role in triglyceride absorption and chylomicron formation within the fructose fed Syrian gold hamster. Hamsters were fed either chow or high fructose diet (60% fructose) for 31 days, after 10 days of diet treatment; hamsters were dosed daily with sitagliptin (5 mg/kg po.) for the remaining 21 days. Blood was collected at baseline and endpoint to evaluate plasma cholesterol and triglyceride levels. At the end of 31 days hamsters were cannulated via jugular vein and fat loaded with olive oil, blood was collected at 0, 30, 60, 90 and 120 min after fat load and chylomicron accumulation was evaluated. Hamsters fed fructose showed significantly increased levels of plasma triglyceride compared to chow fed hamsters after 31 days, this was shown to be significantly attenuated with sitagliptin treatment (p < 0.05). FPLC analysis showed this decrease in triglyceride was mainly due to decreases in VLDL triglyceride particles. In fructose fed hamsters sitagliptin treatment significantly decreased accumulation of triglyceride rich lipoproteins (TRL) 90 min after fat load (p < 0.05), TRL ApoB was also decreased with sitagliptin treatment. Enterocytes collected from jejunum of fructose fed hamsters showed decreased total ApoB with sitagliptin treatment compared to control cells, cellular ApoB was also decreased
89
in sitagliptin treated hamsters, while secreted ApoB was increased with sitagliptin treatment. In conclusion, sitagliptin treatment is able to attenuate dyslipidemia resulting from ingestion of high fructose diet by decreasing accumulation of plasma triglycerides, particularly VLDL particles. In addition sitagliptin treatment causes decreased accumulation of chylomicrons, which seems to be linked to a decrease in ApoB 48. This indicates that sitagliptin may have a role in controlling dyslipidemia in addition to stimulating insulin release. doi:10.1016/j.atherosclerosissup.2008.09.409 Effect of fatty acids on enterocytic beta-amyloid abundance: Possible aetiology in Alzheimer’s disease S. Galloway 1 , R. Takechi 1 , M.M.S.R. Pallebage1 1 Gamarallage , L. Jian , R.D. Johnsen 2,3 , J.C.L. Mamo 1 1 School
of Public Health and Australian Technology Network (ATN), Centre for Metabolic Fitness, Curtin University of Technology, Perth, Western Australia, Australia 2 Australian Neuromuscular Research Institute, QEII Medical Centre, Perth, Western Australia, Australia 3 Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australia Background: Dietary fatty acids influence the risk of developing Alzheimer’s disease (AD), a condition caused by the deposition of beta-amyloid (A) peptide in the extracellular matrices of the brain. In animal studies, polyunsaturated fatty acid depress, whilst saturated fats exacerbate cerebral amyloidosis, possibly via mechanism related to A production. Approach: Previously, we showed that A abundance in small intestinal enterocytes is regulated by the availability of lipid substrate from diet [1]. A diet rich in saturated fats and cholesterol significantly enhanced enterocytic A whereas fasting completely abolished protein abundance. Non-esterified fatty acids (NEFA’s) differentially regulate chylomicron biogenesis and secretion and there is accumulating evidence that plasma A kinetics reflects postprandial lipoprotein kinetics. It is currently not known whether monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA) and saturated fatty acids (SFA) differentially influence chylomicron associated A metabolism. In part fulfilment of this hypothesis, this study aimed to determine if enterocytic A abundance is differentially regulated by NEFAs. Methodology: Six-week-old female C57BL/6J mouse were placed on diets containing either 20% (w/w) monounsaturated fatty acid (MUFA), polyunsaturated fatty acids (PUFA) or saturated fatty acids (SFA) for 12 weeks. Mice fed a diet containing 4% PUFA served as low-fat controls. Intestinal A and dietary fatty acids was determined using quantitative immunohistochemistry (IHC) or immunofluorescence microscopy (IFM). Results: Mice fed diets enriched in either of the NEFA’s showed increased enterocytic A compared to low-fat mice.