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Fibrates and fish oil upregulate the expression of the cholesteryl ester transfer protein (cetp) gene
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Abstracts / Atherosclerosis 235 (2014) e84–e191
substitution Gly185-Cys (G185C), in patients with severe hypertriglyceridemia in association with circulating LPL protein concentrations and activities. Methods: Study subjects were 104 patients with serum triglyceride concentrations over 1000 mg/dl in our hospital. LPL protein concentration and activity were measured 10 minutes after 30 units/kg heparin injection. The apo A-V G185C polymorphism was analyzed by PCR-RFLP. Results: The frequencies of apoA-V G185C in hypertriglyceridemic patients and normolipidemic controls were 58.7 % and 2.3%, respectively. The frequency of apoA-V 185C homozygote and heterozygote was significantly increased in patients with normal level of circulating LPL protein concentrations and activity, compared with those with decreased levels of LPL. Circulating LPL protein concentrations in the patients with apoA-V 185C homozygote were significantly higher than those in the patients with the apoA-V 185G homozygote. Conclusion: An amino acid substitution, G185C in apoA-V possibly causes severe hypertriglyceridemia as a risk factor independent from LPL abnormality. The mutation may accelerate the release of LPL after heparin injection. 32 - Lipases and lipid transfer proteins EAS-0450. FIBRATES AND FISH OIL UPREGULATE THE EXPRESSION OF THE CHOLESTERYL ESTER TRANSFER PROTEIN (CETP) GENE H.C.F. Oliveira, H.F. Raposo, P.R. Patricio, M.C. Simões Structural and Functional Biology, University of Campinas, Campinas, Brazil Objectives: CETP is a plasma protein that reduces HDL-cholesterol levels and may increase atherosclerosis risk. n-3 and n-6 polyunsaturated fatty acids (PUFA) are natural ligands and fibrates are synthetic ligands for PPAR-alpha, a transcription factor that modulates lipid metabolism. In this study, we investigated the effects of PUFA oils and fibrates on the CETP expression. Methods: Hypertriglyceridemic CETP transgenic mice were treated (v.o.) with gemfibrozil, fenofibrate, bezafibrate or vehicle (control), and normolipidemic CETP transgenic mice were treated with fenofibrate or with fish oil (FO, n-3 PUFA rich), corn oil (CO, n-6 PUFA rich) or saline for two weeks. Results: Compared with the control treatment, only fenofibrate significantly diminished triglyceridemia (50%), whereas all fibrates decreased the HDLcholesterol (chol) level. Elevation of the CETP liver mRNA levels and plasma activity was observed in the fenofibrate (53%) and gemfibrozil (75%) groups. Compared with saline, FO reduced the plasma levels of non-esterified fatty acid (NEFA) (26%), total cholesterol (15%) and HDL-cholesterol (20%). Neither of the oil treatments affected the plasma triglyceride levels. Compared with saline, FO increased the plasma adiponectin level and reduced plasma leptin levels, whereas CO increased the leptin levels. FO, but not CO, significantly increased the plasma CETP mass (90%) and activity (23%) as well as increased the liver level of CETP mRNA (28%). Conclusion: In conclusion, fibrates and fish oil, but not corn oil, upregulated CETP expression at both mRNA and protein levels. We propose that these effects may be mediated by the activation of PPARa, which acts on a putative PPAR response element in the CETP gene. 32 - Lipases and lipid transfer proteins EAS-1021. IDENTIFICATION, LIPOPROTEIN PROFILING AND TREATMENT OF PATIENTS WITH LYSOSOMAL ACID LIPASE DEFICIENCY C.R. Pullingera, E. Oestreicher Stocka, R. Tripuranenib, I. Movsesyana, M.J. Malloya, P.H. Frosta, A.G. Quinnb, J.P. Kanea a Cardiovascular Research Institute, University of California San Francisco, San Francisco, USA; b Medical Affairs & Clinical Research, Synageva BioPharma Corp, Lexington, USA
Objectives: To identify previously undiagnosed patients with lysosomal acid lipase (LAL) deficiency (LALD). LALD presents and progresses as a continuum with hepatomegaly, liver damage and fibrosis, and dyslipidemia as prominent common pathologies. Presentation in infants is often called Wolman Disease and in children and adults Cholesteryl Ester Storage Disease (CESD). Recombinant human LAL (sebelipase alfa) therapy has entered clinical trials. LAL is encoded by the LIPA gene, catalyzes the intracellular hydrolysis of lipoprotein cholesteryl esters and triglycerides. LIPA gene defects cause lysosomal accumulation of these lipids. Methods: To improve the identification of LALD, an underappreciated cause of cirrhosis and dyslipidemia, we developed a screening method utilizing DNA samples from the Cardiovascular Research Institute (University of California, San Francisco). Participants, recruited mainly from a tertiary lipid clinic, were identified by lipid profiles and screened for the common disease-causing LIPA exon 8 skipping splice-site mutation (c.894G>A; p.Ser275_Gln298del; rs116928232). Carriers underwent complete LIPA gene sequencing. Results: LIPA gene sequencing of individuals found to be heterozygous for the exon 8 skipping variant revealed a patient, subsequently confirmed to have LALD, with a heterozygous frameshift mutation resulting from deletion of exon 4 (p.Gly77Valfs*17 c.230-106_c.428+541del). A family study revealed a sister with the same genotype and LALD. Genetic, clinical and lipoprotein profiles of these sisters plus six additional family members are presented. Profiles of other LALD patients, some monitored for two decades, are also presented. Conclusion: We propose this LIPA sequencing strategy (detection of the relatively common exon 8 variant followed by complete gene sequencing to detect additional mutations) among individuals with a suggestive clinical phenotype, as a means to improve detection of LALD. 32 - Lipases and lipid transfer proteins EAS-0276. INCREASED ATHEROSCLEROTIC PLAQUE FORMATION IN APOLIPOPROTEIN E – DEFICIENT MICE LACKING MONOACYLGLYCEROL LIPASE N. Vujic, M. Goeritzer, S. Schlager, B. Radovic, D. Kratky Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria Objectives: Monoglyceride lipase (MGL) catalyzes the final step of lipolysis by degrading monoacylglycerol (MG) to glycerol and free fatty acid. MGL also deactivates the endocannabinoid 2-arachidonoyl glycerol (2-AG), which acts as a full agonist on both cannabinoid receptor (CBR) 1 and 2, predominantly expressed in brain and immune cells, respectively. Taking into account the role of MGL in lipolysis and the multiple effects of the cannabinoid system on lipid homeostasis and immunity, the lack of MGL may promote or prevent lipotoxicity and atherosclerosis. Methods: To assess the role of MGL in atherosclerosis development, we generated Apolipoprotein E (ApoE)/MGL double knockout (DKO) mice, challenged them with Western-type diet (WTD) for 9 weeks and performed atheroassays. Results: We found comparable plasma lipid profiles between DKO and ApoE-/- mice upon WTD feeding. However, hepatic cholesterol and triglyceride concentrations as well as VLDL secretion are significantly reduced in DKO animals compared to the controls. Liver mRNA expression of CYP 7A1 is increased and CD36 decreased in DKO compared to ApoE-/- mice. Surprisingly, we found significantly increased plaque size in both en face aortas and aortic valve sections of DKO when compared to ApoE-/- mice. This might be due to increased circulating numbers of lymphocytes and monocytes in these animals. However, the increase in plaque size was only moderately associated with macrophage lesion infiltration and strongly associated with the increase in collagen content, indicating plaque stabilization in DKO mice compared to the controls.
Abstracts / Atherosclerosis 235 (2014) e84–e191
substitution Gly185-Cys (G185C), in patients with severe hypertriglyceridemia in association with circulating LPL protein concentrations and activities. Methods: Study subjects were 104 patients with serum triglyceride concentrations over 1000 mg/dl in our hospital. LPL protein concentration and activity were measured 10 minutes after 30 units/kg heparin injection. The apo A-V G185C polymorphism was analyzed by PCR-RFLP. Results: The frequencies of apoA-V G185C in hypertriglyceridemic patients and normolipidemic controls were 58.7 % and 2.3%, respectively. The frequency of apoA-V 185C homozygote and heterozygote was significantly increased in patients with normal level of circulating LPL protein concentrations and activity, compared with those with decreased levels of LPL. Circulating LPL protein concentrations in the patients with apoA-V 185C homozygote were significantly higher than those in the patients with the apoA-V 185G homozygote. Conclusion: An amino acid substitution, G185C in apoA-V possibly causes severe hypertriglyceridemia as a risk factor independent from LPL abnormality. The mutation may accelerate the release of LPL after heparin injection. 32 - Lipases and lipid transfer proteins EAS-0450. FIBRATES AND FISH OIL UPREGULATE THE EXPRESSION OF THE CHOLESTERYL ESTER TRANSFER PROTEIN (CETP) GENE H.C.F. Oliveira, H.F. Raposo, P.R. Patricio, M.C. Simões Structural and Functional Biology, University of Campinas, Campinas, Brazil Objectives: CETP is a plasma protein that reduces HDL-cholesterol levels and may increase atherosclerosis risk. n-3 and n-6 polyunsaturated fatty acids (PUFA) are natural ligands and fibrates are synthetic ligands for PPAR-alpha, a transcription factor that modulates lipid metabolism. In this study, we investigated the effects of PUFA oils and fibrates on the CETP expression. Methods: Hypertriglyceridemic CETP transgenic mice were treated (v.o.) with gemfibrozil, fenofibrate, bezafibrate or vehicle (control), and normolipidemic CETP transgenic mice were treated with fenofibrate or with fish oil (FO, n-3 PUFA rich), corn oil (CO, n-6 PUFA rich) or saline for two weeks. Results: Compared with the control treatment, only fenofibrate significantly diminished triglyceridemia (50%), whereas all fibrates decreased the HDLcholesterol (chol) level. Elevation of the CETP liver mRNA levels and plasma activity was observed in the fenofibrate (53%) and gemfibrozil (75%) groups. Compared with saline, FO reduced the plasma levels of non-esterified fatty acid (NEFA) (26%), total cholesterol (15%) and HDL-cholesterol (20%). Neither of the oil treatments affected the plasma triglyceride levels. Compared with saline, FO increased the plasma adiponectin level and reduced plasma leptin levels, whereas CO increased the leptin levels. FO, but not CO, significantly increased the plasma CETP mass (90%) and activity (23%) as well as increased the liver level of CETP mRNA (28%). Conclusion: In conclusion, fibrates and fish oil, but not corn oil, upregulated CETP expression at both mRNA and protein levels. We propose that these effects may be mediated by the activation of PPARa, which acts on a putative PPAR response element in the CETP gene. 32 - Lipases and lipid transfer proteins EAS-1021. IDENTIFICATION, LIPOPROTEIN PROFILING AND TREATMENT OF PATIENTS WITH LYSOSOMAL ACID LIPASE DEFICIENCY C.R. Pullingera, E. Oestreicher Stocka, R. Tripuranenib, I. Movsesyana, M.J. Malloya, P.H. Frosta, A.G. Quinnb, J.P. Kanea a Cardiovascular Research Institute, University of California San Francisco, San Francisco, USA; b Medical Affairs & Clinical Research, Synageva BioPharma Corp, Lexington, USA
Objectives: To identify previously undiagnosed patients with lysosomal acid lipase (LAL) deficiency (LALD). LALD presents and progresses as a continuum with hepatomegaly, liver damage and fibrosis, and dyslipidemia as prominent common pathologies. Presentation in infants is often called Wolman Disease and in children and adults Cholesteryl Ester Storage Disease (CESD). Recombinant human LAL (sebelipase alfa) therapy has entered clinical trials. LAL is encoded by the LIPA gene, catalyzes the intracellular hydrolysis of lipoprotein cholesteryl esters and triglycerides. LIPA gene defects cause lysosomal accumulation of these lipids. Methods: To improve the identification of LALD, an underappreciated cause of cirrhosis and dyslipidemia, we developed a screening method utilizing DNA samples from the Cardiovascular Research Institute (University of California, San Francisco). Participants, recruited mainly from a tertiary lipid clinic, were identified by lipid profiles and screened for the common disease-causing LIPA exon 8 skipping splice-site mutation (c.894G>A; p.Ser275_Gln298del; rs116928232). Carriers underwent complete LIPA gene sequencing. Results: LIPA gene sequencing of individuals found to be heterozygous for the exon 8 skipping variant revealed a patient, subsequently confirmed to have LALD, with a heterozygous frameshift mutation resulting from deletion of exon 4 (p.Gly77Valfs*17 c.230-106_c.428+541del). A family study revealed a sister with the same genotype and LALD. Genetic, clinical and lipoprotein profiles of these sisters plus six additional family members are presented. Profiles of other LALD patients, some monitored for two decades, are also presented. Conclusion: We propose this LIPA sequencing strategy (detection of the relatively common exon 8 variant followed by complete gene sequencing to detect additional mutations) among individuals with a suggestive clinical phenotype, as a means to improve detection of LALD. 32 - Lipases and lipid transfer proteins EAS-0276. INCREASED ATHEROSCLEROTIC PLAQUE FORMATION IN APOLIPOPROTEIN E – DEFICIENT MICE LACKING MONOACYLGLYCEROL LIPASE N. Vujic, M. Goeritzer, S. Schlager, B. Radovic, D. Kratky Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria Objectives: Monoglyceride lipase (MGL) catalyzes the final step of lipolysis by degrading monoacylglycerol (MG) to glycerol and free fatty acid. MGL also deactivates the endocannabinoid 2-arachidonoyl glycerol (2-AG), which acts as a full agonist on both cannabinoid receptor (CBR) 1 and 2, predominantly expressed in brain and immune cells, respectively. Taking into account the role of MGL in lipolysis and the multiple effects of the cannabinoid system on lipid homeostasis and immunity, the lack of MGL may promote or prevent lipotoxicity and atherosclerosis. Methods: To assess the role of MGL in atherosclerosis development, we generated Apolipoprotein E (ApoE)/MGL double knockout (DKO) mice, challenged them with Western-type diet (WTD) for 9 weeks and performed atheroassays. Results: We found comparable plasma lipid profiles between DKO and ApoE-/- mice upon WTD feeding. However, hepatic cholesterol and triglyceride concentrations as well as VLDL secretion are significantly reduced in DKO animals compared to the controls. Liver mRNA expression of CYP 7A1 is increased and CD36 decreased in DKO compared to ApoE-/- mice. Surprisingly, we found significantly increased plaque size in both en face aortas and aortic valve sections of DKO when compared to ApoE-/- mice. This might be due to increased circulating numbers of lymphocytes and monocytes in these animals. However, the increase in plaque size was only moderately associated with macrophage lesion infiltration and strongly associated with the increase in collagen content, indicating plaque stabilization in DKO mice compared to the controls.