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The plasma proteome of tangier disease patients reveals perturbations of diabetic and inflammatory pathways
Abstracts / Atherosclerosis 252 (2016) e197ee235
EAS16-0995, INSULIN RESISTANCE, DIABETES, METABOLIC SYNDROME AND OBESITY. THE PLASMA PROTEOME OF TANGIER DISEASE PATIENTS REVEALS PERTURBATIONS OF DIABETIC AND INFLAMMATORY PATHWAYS J. McParland, E. Pashos, D. Rader, M. Cuchel. University of Pennsylvania, Translational Medicine and Human Genetics, Philadelphia, USA Objectives: The ATP-binding cassette transporter 1 (ABCA1) is a membrane protein well known for its role in cholesterol efflux and HDL formation. Recently, ABCA1 has been implicated as playing a key role in other processes, such as insulin secretion and inflammatory response. We sought to further investigate these potential roles through a quantitative proteomics approach. Specifically, we hypothesized that we could detect differential protein signatures in the plasma of Tangier patients that correspond to pathways involved in diabetes and inflammation. Methods: We used SOMAscan® technology (SomaLogic, Boulder, CO, USA) to analyze plasma collected from 5 Tangier disease patients (homozygotes or compound heterozygotes for functional ABCA1 mutations) and 7 normolipidemic controls. We tested for differences in the levels of approximately 1,000 plasma proteins using a nonparametric test (KS). We then performed Ingenuity Canonical Pathway analysis to examine if proteins linked to diabetes and inflammation pathways were significantly more likely to be differentially abundant in the plasma. We corroborated the results using Gene Set Enrichment Analysis (GSEA). Results: We found an enrichment in differentially abundant proteins involved in type II diabetes mellitus signaling (p-value¼0.0002) and inflammatory pathways, such as granulocyte adhesion and diapedesis (pvalue¼2.2*10-12). These results were also corroborated by GSEA, where gene sets corresponding to GO biological processes such as immune response (p-value¼0.008) and inflammatory response (p-value¼0.032) ranked at the top of the enrichment results. Conclusions: The results from this pilot study support the concept that ABCA1 is implicated in pathways affecting immune and inflammatory response and type II diabetes.
EAS16-0562, INSULIN RESISTANCE, DIABETES, METABOLIC SYNDROME AND OBESITY. ROLE OF PCSK9 (PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9) IN OBESITY AND METABOLIC SYNDROME: BEYOND LDLR TARGETING G. Balzarotti 1, G. Tibolla 1, M. Ruscica 1, M. Stramba-Badiale 1, A.L. degli Studi di Milano, Catapano 1, 2, D.G. Norata 1, 2. 1 Universita Dipartimento di Scienze Farmacologiche e Biomolecolari, Milano, Italy; 2 I.R.C.C.S., MultiMedica Hospital, Milano, Italy Objectives: PCSK9, a liver-secreted plasma enzyme, primarily regulates the levels of circulating low-density lipoprotein cholesterol (LDL-C) by enhancing the degradation of the hepatic LDL receptor (LDLR). The emerging importance of PCSK9 inhibition for the treatment of hypercholesterolemia warrants investigation of the physiological role of PCSK9, beyond LDL-C lowering. Indeed, PCSK9 targets additional receptors which could play a critical role in triglyceride-rich lipoproteins (TGRL) metabolism, thus potentially affecting metabolic syndrome and obesity. Methods: Metabolic disfunction was induced in 2-months old PCSK9 KO and WT male mice by feeding them for 20 weeks with a HFD (High Fat Diet) or SFD (Standard Fat Diet). Body weight was measured weekly; fat distribution and glycemia (glucose GTT and insulin ITT tolerance test) was checked at 12 and 20 weeks. Results: As expected, the deletion of PSCK9 resulted in a significant reduction in plasma cholesterol levels (86,1±2,1 mg/dl vs 123,4±5,2 mg/dl and 51,8±12,3 mg/dl vs 79,8±11,0 mg/dl with HFD and SFD respectively, p<0,05), but not in plasma triglyceride levels. Of note, PCSK9 KO mice accumulated significant more visceral adipose tissue than WT littermates (+50%±17% with HFD, p<0,05) with a trend towards increased weight gain. Further assessement of metabolic disfunction development showed that PCSK9 deficiency resulted in impaired glucose tolerance compared to
e223
control mice (Glucose Tolerance Test e Area Under the Curve +40%±9% with HFD, p<0,05), while response to insulin was not. Conclusions: Taken together our data indicate that, under impaired metabolic setting, PCSK9 deficiency results in reduced glucose tolerance and in increased visceral adipose tissue accumulation.
EAS16-0447, INSULIN RESISTANCE, DIABETES, METABOLIC SYNDROME AND OBESITY. DIPEPTIDYL PEPTIDASE-4 INHIBITORS AND PROTECTION AGAINST STROKE: A SYSTEMATIC REVIEW AND META-ANALYSIS F. Barkas, M. Elisaf, V. Tsimihodimos, H. Milionis. School of Medicine University of Ioannina, Internal Medicine, Ioannina, Greece Objectives: Type 2 diabetes (T2M) is associated with an increased risk of stroke and a worse outcome following stroke. Apart from pioglitazone, glucose-lowering modalities have not been shown to protect against stroke. Nonetheless, there is evidence from experimental studies of potential neuroprotective effects with dipeptidyl peptidase-4 (DPP-4) inhibitors, especially if treatment starts before stroke. We aimed to meta-analyze available evidence regarding the risk of stroke in individuals receiving DPP-4 inhibitors. Methods: We conducted a meta-analysis of randomized, placebocontrolled trials involving DPP-4 inhibitors published until December 2015. Included trials reported at least one stroke with a recruitment rate of at least 100 subjects, and a follow-up of 12 weeks. Results: Three multicenter, prospective double-blinded placebocontrolled randomized, clinical trials (mRCTs) assessing cardiovascular outcomes as primary endpoint (SAVOR TIMI-53, EXAMINE and TECOS) with a total of 36,543 subjects, along with 19 small RCTs evaluating the efficacy and safety of gliptins (n¼9,047) were meta-analyzed separately. The pooled analysis of the small prospective trials showed a trend towards a benefit from DDT-4 inhibitors against stroke [odds ratio (OR): 0.640, 95% confidence interval (CI): 0.348-1.177, p¼0.151]. The analysis of mRCTs did not showed any difference in the risk of stroke compared with placebo (OR: 1.032, 95% CI: 0.890-1.197, p¼0.674). Conclusions: The promising data from experimental studies regarding gliptin-associated protective effects against stroke are not supported by available data from clinical trials. EAS16-0382, HYPERTENSION, LIVER AND CHRONIC RENAL DISEASE. PRO-ATHEROGENIC LIPOPROTEIN PROFILE ASSOCIATED WITH WHITE MATTER LESIONS IN CHRONIC KIDNEY DISEASE PATIENTS: A 1H-NMR METABOLOMIC APPROACH 2, M. Vinaixa 1, M. Romeu 3, M. Mun ~ oz 3, M. 1, R. Fuertes 1, C. Cabre N. Amigo 3 4 5 6 1 Giralt , J. Soler , J. Aquilera , M.T. Compte , X. Correig , A. MartínezVea 2. 1 Rovira i Virgili University, Metabolomics Platform DEEEA, Tarragona, Spain; 2 Joan XXIII University Hospital, Nephrology Service, Tarragona, Spain; 3 Rovira i Virgili University, Cellular Pharmacobiology, Reus, Spain; 4 Medical Care Nephrology Center, Hemodialysis, Reus, Spain; 5 Llevant Hospital, Dialysis Center, Tarragona, Spain; 6 Santa Creu de Jesús Hospital, Hemodialysis, Tortosa, Spain Objectives: Nearly half of Chronic Kidney Disease (CKD) patients have white matter lesions (WMLs). Based on hemodynamic similarities, this cerebrorenal connection is considered to involve small vessel disease. Whereas advanced age and hypertension are the most accepted risk factors for WMLs, the role of other risk factors such as plasma lipoproteins is unclear. The aim of this study is to identify a plasmatic lipoprotein profile associated with lesions. Methods: Sixty-three CKD patients were classified into two groups depending on the presence (n¼34) or absence (n¼29) of WMLs (Fazekas classification). Plasma samples were analyzed by 1H-Nuclear Magnetic Resonance (NMR), and the lipoprotein (Liposcale® test), the lipidic and the aqueous metabolite profiles were characterized. Endothelial function parameters, inflammatory and oxidative stress markers were also
EAS16-0995, INSULIN RESISTANCE, DIABETES, METABOLIC SYNDROME AND OBESITY. THE PLASMA PROTEOME OF TANGIER DISEASE PATIENTS REVEALS PERTURBATIONS OF DIABETIC AND INFLAMMATORY PATHWAYS J. McParland, E. Pashos, D. Rader, M. Cuchel. University of Pennsylvania, Translational Medicine and Human Genetics, Philadelphia, USA Objectives: The ATP-binding cassette transporter 1 (ABCA1) is a membrane protein well known for its role in cholesterol efflux and HDL formation. Recently, ABCA1 has been implicated as playing a key role in other processes, such as insulin secretion and inflammatory response. We sought to further investigate these potential roles through a quantitative proteomics approach. Specifically, we hypothesized that we could detect differential protein signatures in the plasma of Tangier patients that correspond to pathways involved in diabetes and inflammation. Methods: We used SOMAscan® technology (SomaLogic, Boulder, CO, USA) to analyze plasma collected from 5 Tangier disease patients (homozygotes or compound heterozygotes for functional ABCA1 mutations) and 7 normolipidemic controls. We tested for differences in the levels of approximately 1,000 plasma proteins using a nonparametric test (KS). We then performed Ingenuity Canonical Pathway analysis to examine if proteins linked to diabetes and inflammation pathways were significantly more likely to be differentially abundant in the plasma. We corroborated the results using Gene Set Enrichment Analysis (GSEA). Results: We found an enrichment in differentially abundant proteins involved in type II diabetes mellitus signaling (p-value¼0.0002) and inflammatory pathways, such as granulocyte adhesion and diapedesis (pvalue¼2.2*10-12). These results were also corroborated by GSEA, where gene sets corresponding to GO biological processes such as immune response (p-value¼0.008) and inflammatory response (p-value¼0.032) ranked at the top of the enrichment results. Conclusions: The results from this pilot study support the concept that ABCA1 is implicated in pathways affecting immune and inflammatory response and type II diabetes.
EAS16-0562, INSULIN RESISTANCE, DIABETES, METABOLIC SYNDROME AND OBESITY. ROLE OF PCSK9 (PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9) IN OBESITY AND METABOLIC SYNDROME: BEYOND LDLR TARGETING G. Balzarotti 1, G. Tibolla 1, M. Ruscica 1, M. Stramba-Badiale 1, A.L. degli Studi di Milano, Catapano 1, 2, D.G. Norata 1, 2. 1 Universita Dipartimento di Scienze Farmacologiche e Biomolecolari, Milano, Italy; 2 I.R.C.C.S., MultiMedica Hospital, Milano, Italy Objectives: PCSK9, a liver-secreted plasma enzyme, primarily regulates the levels of circulating low-density lipoprotein cholesterol (LDL-C) by enhancing the degradation of the hepatic LDL receptor (LDLR). The emerging importance of PCSK9 inhibition for the treatment of hypercholesterolemia warrants investigation of the physiological role of PCSK9, beyond LDL-C lowering. Indeed, PCSK9 targets additional receptors which could play a critical role in triglyceride-rich lipoproteins (TGRL) metabolism, thus potentially affecting metabolic syndrome and obesity. Methods: Metabolic disfunction was induced in 2-months old PCSK9 KO and WT male mice by feeding them for 20 weeks with a HFD (High Fat Diet) or SFD (Standard Fat Diet). Body weight was measured weekly; fat distribution and glycemia (glucose GTT and insulin ITT tolerance test) was checked at 12 and 20 weeks. Results: As expected, the deletion of PSCK9 resulted in a significant reduction in plasma cholesterol levels (86,1±2,1 mg/dl vs 123,4±5,2 mg/dl and 51,8±12,3 mg/dl vs 79,8±11,0 mg/dl with HFD and SFD respectively, p<0,05), but not in plasma triglyceride levels. Of note, PCSK9 KO mice accumulated significant more visceral adipose tissue than WT littermates (+50%±17% with HFD, p<0,05) with a trend towards increased weight gain. Further assessement of metabolic disfunction development showed that PCSK9 deficiency resulted in impaired glucose tolerance compared to
e223
control mice (Glucose Tolerance Test e Area Under the Curve +40%±9% with HFD, p<0,05), while response to insulin was not. Conclusions: Taken together our data indicate that, under impaired metabolic setting, PCSK9 deficiency results in reduced glucose tolerance and in increased visceral adipose tissue accumulation.
EAS16-0447, INSULIN RESISTANCE, DIABETES, METABOLIC SYNDROME AND OBESITY. DIPEPTIDYL PEPTIDASE-4 INHIBITORS AND PROTECTION AGAINST STROKE: A SYSTEMATIC REVIEW AND META-ANALYSIS F. Barkas, M. Elisaf, V. Tsimihodimos, H. Milionis. School of Medicine University of Ioannina, Internal Medicine, Ioannina, Greece Objectives: Type 2 diabetes (T2M) is associated with an increased risk of stroke and a worse outcome following stroke. Apart from pioglitazone, glucose-lowering modalities have not been shown to protect against stroke. Nonetheless, there is evidence from experimental studies of potential neuroprotective effects with dipeptidyl peptidase-4 (DPP-4) inhibitors, especially if treatment starts before stroke. We aimed to meta-analyze available evidence regarding the risk of stroke in individuals receiving DPP-4 inhibitors. Methods: We conducted a meta-analysis of randomized, placebocontrolled trials involving DPP-4 inhibitors published until December 2015. Included trials reported at least one stroke with a recruitment rate of at least 100 subjects, and a follow-up of 12 weeks. Results: Three multicenter, prospective double-blinded placebocontrolled randomized, clinical trials (mRCTs) assessing cardiovascular outcomes as primary endpoint (SAVOR TIMI-53, EXAMINE and TECOS) with a total of 36,543 subjects, along with 19 small RCTs evaluating the efficacy and safety of gliptins (n¼9,047) were meta-analyzed separately. The pooled analysis of the small prospective trials showed a trend towards a benefit from DDT-4 inhibitors against stroke [odds ratio (OR): 0.640, 95% confidence interval (CI): 0.348-1.177, p¼0.151]. The analysis of mRCTs did not showed any difference in the risk of stroke compared with placebo (OR: 1.032, 95% CI: 0.890-1.197, p¼0.674). Conclusions: The promising data from experimental studies regarding gliptin-associated protective effects against stroke are not supported by available data from clinical trials. EAS16-0382, HYPERTENSION, LIVER AND CHRONIC RENAL DISEASE. PRO-ATHEROGENIC LIPOPROTEIN PROFILE ASSOCIATED WITH WHITE MATTER LESIONS IN CHRONIC KIDNEY DISEASE PATIENTS: A 1H-NMR METABOLOMIC APPROACH 2, M. Vinaixa 1, M. Romeu 3, M. Mun ~ oz 3, M. 1, R. Fuertes 1, C. Cabre N. Amigo 3 4 5 6 1 Giralt , J. Soler , J. Aquilera , M.T. Compte , X. Correig , A. MartínezVea 2. 1 Rovira i Virgili University, Metabolomics Platform DEEEA, Tarragona, Spain; 2 Joan XXIII University Hospital, Nephrology Service, Tarragona, Spain; 3 Rovira i Virgili University, Cellular Pharmacobiology, Reus, Spain; 4 Medical Care Nephrology Center, Hemodialysis, Reus, Spain; 5 Llevant Hospital, Dialysis Center, Tarragona, Spain; 6 Santa Creu de Jesús Hospital, Hemodialysis, Tortosa, Spain Objectives: Nearly half of Chronic Kidney Disease (CKD) patients have white matter lesions (WMLs). Based on hemodynamic similarities, this cerebrorenal connection is considered to involve small vessel disease. Whereas advanced age and hypertension are the most accepted risk factors for WMLs, the role of other risk factors such as plasma lipoproteins is unclear. The aim of this study is to identify a plasmatic lipoprotein profile associated with lesions. Methods: Sixty-three CKD patients were classified into two groups depending on the presence (n¼34) or absence (n¼29) of WMLs (Fazekas classification). Plasma samples were analyzed by 1H-Nuclear Magnetic Resonance (NMR), and the lipoprotein (Liposcale® test), the lipidic and the aqueous metabolite profiles were characterized. Endothelial function parameters, inflammatory and oxidative stress markers were also