- Email: [email protected]
Rare mutations in the APOB gene and its role in LDL oxidation
Abstracts / Atherosclerosis 263 (2017) e29ee110
metabolic syndrome (65.1% vs 58.2%, p¼0.043) than ones in hypertriglyceridemia group. Arterial hypertension and smoking were more prevalent in high triglycerides group (arterial hypertension 69% vs. 59.9%, p¼0.007, smoking 39.4% vs. 23.7%, p<0.001) compared to low HDL-C group. Prevalence of insufficient physical activity, diabetes mellitus, obesity and familial history of coronary heart disease had no significant difference between groups. Conclusions: Subjects in low HDL-C group had lower serum glucose as well as healthier diet compared to high triglycerides group. Arterial hypertension and smoking were less prevalent in low HDL-C group while metabolic syndrome was less prevalent in high triglycerides group.
SAG142. PLASMA PCSK9 AND CARDIOVASCULAR EVENTS IN TYPE 2 DIABETES Petra El Khoury1,2, Ronan Roussel3,4,5, Frederic Fumeron4,5, Gilberto Velho5, Marie-Paule Jacob1,4, Gabriel Steg1,4,6,7, L. Potier3,4,5, Youmna Ghaleb1,2,4, Sandy Elbitar1,2,4, Marianne Abifadel1,2, Catherine Boileau1,4,8, Michel Marre3,4,5, Mathilde Varret1,4, Boris Hansel3,4,5. 1 Inserm U1148, Paris, France; 2 Saint Joseph University, Beruth, Lebanon; 3 Aphp, Chu Bichat, Nutrition Dept, Paris, France; 4 Denis Diderot University, Paris 7, Paris, France; 5 Inserm U1138, Paris, France; 6 Aphp, Chu Bichat, Cardiology Dept, Paris, France; 7 NHLI, Imperial College, Royal Brompton Hospital, London, United Kingdom; 8 Aphp, Chu Bichat, Genetic Dept, Paris, France Aim: Cardiovascular (CV) risk of patients with Type 2 Diabetes mellitus (T2DM), especially if associated to kidney damage, is elevated. Plasma concentration of proprotein convertase subtilisin/kexin type 9 (PCSK9), a secreted protein involved in cholesterol metabolism and a target for novel potent lipid-lowering drugs, is associated with incident CV disease (CVD) independently from classical risk factors. However, no data are available on the prognostic value of PCSK9 in T2DM. Our aim was to investigate whether plasma PCSK9 was associated with CV events in patients with T2DM and albuminuria. Methods: The study population was 2912 French participants from the DIABHYCAR trial. During the 6-year follow-up, 647 CV events occurred and 196 people died from a CV cause. Plasma PCSK9 at baseline was measured by an immunofluorescent assay. Results: In adjusted Cox analysis, plasma PCSK9 was associated, independently from classical risk factors including plasma lipid levels, with the incidence of major CV events (MI, stroke/Transient ischemic attack (TIA), CV death); Hazard Ratio (HR) for one-unit of log(PCSK9): 1.26 (1.05-1.53), the incidence of MI, HR: 1.66; (1.05-2.63), and the incidence of all CV events (MI, stroke, TIA, heart failure leading to hospital admission, coronary/peripheral angioplasty or bypass, CV death; HR: 1.22 (1.04-1.44)), but not with the incidence of CV death or with renal outcomes. Conclusions: This study supports the association of plasma PCSK9 with CV outcomes in patients with T2DM and a high CV risk, independently of other cardiometabolic risk factors.
SAG143. SEX-RELATED DIFFERENCES IN HYPERTENSION: CLINICAL, FUNCTIONAL, STRUCTURAL AND BIOCHEMICAL INFLUENCES 1
1
2
1
Maria Suciu , Lavinia Vlaia , Minodora Andor , Vicentiu Vlaia , Mirela Tomescu2, Carmen Cristescu1. 1 Victor Babes University Of Medicine And Pharmacy, Faculty Of Pharmacy, Timisoara, Romania; 2 Victor Babes University Of Medicine And Pharmacy, Faculty Of Medicine, Timisoara, Romania Aim: A reduction in flow-mediated vasodilatation (%FMD) is reflected in endothelial dysfunction and an elevated carotid intima-media thickness (ITM) is a preclinical phenotype of atherosclerosis. The aim of this study was to investigate the differences and the relationship between clinical, biochemical, functional and structural markers of endothelium damage according to sex in essential hypertensive patients with different degrees of endothelial dysfunction (ED). Methods: A total of 995 hypertensive patients were included in a prospective study. We studied clinical and biochemical markers respectively a
e81
functional and structural evaluation. Regression analyses were used to assess the effects and contributions of these factors on ITM and FMD. Results: In the group with severe ED, FMD (6.17±0.85 vs 5.91±1.04), glucose levels (93.66±7.22 vs 91.76±4, 84) and systolic blood pressure (BP) (166.95±11.43 vs 165.20±8.84) were greater in women than in man. Furthermore, plasma high sensitive C-reactive protein (hs-CRP) levels (r ¼ 0.737 vs r ¼ 0.609), systolic (r ¼ 0.817 vs r ¼ 0.734) and diastolic BP (r ¼ 0.752 vs r ¼ 0.627) of women were significantly positively correlated with IMT much better than in men. But in the group with moderate ED, plasma hs-CRP levels (r ¼ -0.829 vs r ¼ -0.702) and systolic BP (r ¼ -0.637 vs r ¼ -0.586) of hypertensive men were negatively correlated with FMD much better than in women. Conclusions: Our results suggest that hypertensive females have better cardiovascular health than males. Their endothelial function and structure is not affected so quickly by the changes of clinical and biological markers.
SAG144. WHY CAN’T MEN BE MORE LIKE WOMEN? FACTORS FAVOUR FEMALE GENDER IN PREVENTION OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE Shamanna Iyengar1, Rajiv Gupta2, Sandhya Ravi3, Manjunath Cn4, Annie S5, Patil Cb6. 1 Manipal Hospital, Department of Cardiology, Bangalore, India; 2 Eterna Heart Care Centre and Research Institute, Jaipur, India; 3 Lotus Research Clinical Academy, Bangalore, India; 4 Sri Jaideva Institute of cardiovascular research and hospital, Bangalore, India; 5 PS Mission Hospital, Ernakulam, India; 6 St Philomena Hospital, Bangalore, India Aim: Coronary artery disease (CAD) exhibits differences between men and women in its epidemiological features, clinical manifestations, treatment and response, due to biological factors and socio-cultural processes. Some of these factors which could potentially influence preventive process in women were analysed in this study. Methods: From a prospective observational registry of coronary artery disease in young ( men < 55 years and women < 65 years of age ), demographic features, coronary risk factors and clinical presentation were compared between men and women Results: Of 997 patients, 283 were women and 714 men. The mean age was 49.1 years for the whole group, 55.1 years for women and 46.6 for men (p<0.001). Women, as compared to men, had greater prevalence of diabetes (62.1 vs 37.1%, p<0.001), hypertension (72.1 vs 40.3%, p<0.0001) and overweight/obesity (60.1 vs 35.2%, p<0.0001), whereas men had greater prevalence of smoking/tobacco use (52.7 vs 3.2%, p<0.0001). Dyslipidemia (13.4% vs 10.6%, p <0.2) was more frequently seen in women. Women presented with non-ST elevation acute coronary syndrome (NSTE-ACS) more often than men ( 42% vs 29.8%). 358 (35.91%) underwent percutaneous coronary intervention, 261 (36.55%) being male and 97 (34.28%) being female patients. 104 (10.43%) underwent coronary bypass surgery Conclusions: Women have more time and more opportunities to practise cardiovascular disease prevention and prevention of progression, as they present with CAD a decade later, have a higher prevalence of correctable atherosclerotic cardiovascular disease risk factors and have more often NSTE-ACS than men. Genomics and GWAS SAG145. RARE MUTATIONS IN THE APOB GENE AND ITS ROLE IN LDL OXIDATION Eleonora Khlebus1, 2, Natalia Shcherbakova1, Ilya Zhanin1, Anastasia Zharikova1, Alexandra Ershova1, Anna Kiseleva1, Sergey Boytsov1, Alexey Meshkov1. 1 National Research Center for Preventive Medicine, Moscow, Russia; 2 Moscow Institute of Physics and Technology (State University), Moscow, Russia Aim: Atherosclerosis represents one of the major problems in the modern medicine and public health. Many studies have demonstrated a relationship between oxidized low-density lipoprotein (oxLDL) and the progression of atherosclerosis. Our work aims to investigate genetic markers
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Abstracts / Atherosclerosis 263 (2017) e29ee110
affecting levels of oxLDL, on incidence/onset of atherosclerosis and atherosclerotic phenotypes in a cohort of 725 patients. Methods: Genotyping was performed using Cardio-Metabo Chip (Illumina). Targeted sequencing was performed with the TargetSeq™ Custom Enrichment Kit (Applied Biosystems, USA) using the SOLiD 5500W system (Applied Biosystems, USA). Alignment and search SNPs were implemented by data analysis tools with the LifeScope™ Genomic Analysis Software. Results: We performed the genome-wide association study (GWAS) and found genetic locus, 2p24-p23, with 14 SNPs in the APOB gene, significantly associated with levels of oxLDL. For analysing ApoB locus we used data for 725 patients from Cardio-Metabo Chip (Illumina) and for 96 patients from targeted sequencing. We identified SNPs and filtered them to narrow the search for the causal variant. So we focused only on nonsynonymous (protein-altering) changes, other variants have been removed from further consideration. To analyze the impact of the cumulative effect of various rare alleles to the level of oxidized LDL we used R package and statistical tests for rare mutations. We have demonstrated the presence of rare mutations in APOB and their relationship to the level of oxidized LDL on the pilot group of participants. Conclusions: Our results may indicate the influence of functional mutations at the level of oxidized LDL.
SAG146. IN SILICO PATIENT STRATIFICATION FOR ATHEROSCLEROSIS Andrew Parton1, Victoria McGilligan1, Maurice O'Kane2, Steven Watterson1. 1 Northern Ireland Centre for Stratified Medicine, Altnagelvin Hospital, Derry/Londonderry, United Kingdom; 2 Department of Clinical Chemistry, Altnagelvin Hospital, Derry/Londonderry, United Kingdom Aim: To study how the dynamics of atherosclerosis differs between population subgroups through development of an in silico platform. Methods: A mathematical model of atherosclerosis has been developed, incorporating the cell types and proteins involved in atheroma formation and describing the dynamics of disease progression. The model adheres to open systems biology standards, SBGN and SBML. Using sequence data from Phase 3 of the 1000 Genomes Project, tertiary (and quaternary) structures have been developed for all proteins involved in this model,. Through Brownian Dynamics simulations of interactions and electrostatic potential comparison, we predict how the dynamics of atherogenesis differs between population subgroups. Results: Our SBML model represents the underlying disease pathophysiology (e.g. Figure 1). A collection of heatmaps have been generated to describe the inherent protein structure variation within the population (e.g. Figure 2), and we are able to show the variation in disease dynamics between population subgroups Conclusions: We have built the first SBGN/SBML compliant computational model of atherosclerosis as a community resource that describes atherogeneic behaviour. We have examined how structures for the proteins involved vary across a patient cohort and demonstrated the varying disease dynamics that result. Ă
SAG147. THE ROLE OF TTC39B IN ATHEROSCLEROSIS AND NON-ALCOHOLIC STEATOHEPATITIS Joanne Hsieh2, Matthew Molusky2, Emi Masahiro Koseki1, Yakushiji2, Marit Westerterp2, Ikuyo Ichi3, Sandra Abramowicz2, Liana Tascau2, Carrie Welch2, Shunichi Takiguchi4, Jahangir Iqbal5, Yasushi Sakata1, Shizuya Yamashita1, Mahmood Hussain5, Daniel Rader4, Alan Tall2. 1 Osaka University-Cardiovascular Medicine, Osaka, Japan; 2 Columbia University-Molecular Medicine, New York, USA; 3 Ochanomizu University, Tokyo, Japan; 4 University of Pennsylvania School of Medicine-Division of Translational Medicine and Human Genetics, Philadelphia, USA; 5 State Univ of New York Health Science Center at Brooklyn-Department of Cell Biology, Brooklyn, USA
Aim: TTC39B was identified in genome wide association studies as a novel gene influencing HDL-cholesterol levels. The aim of this study is to investigate the role of TTC39B in LXR target gene regulation in liver or intestine. Methods: We have investigated Ttc39b deficient mice. Results: We found that intestinal LXR protein, but not mRNA, were increased in chow fed Ttc39b-/- mice, leading enhancement of intestinal Abca1 mRNA and protein and HDL-C levels. When mice were fed with a high fat/high cholesterol/bile salt diet, in addition to intestinal changes, Ttc39b-/- mice or mice with hepatocyte-specific Ttc39b deficiency showed increased hepatic LXR protein and target genes expression (Abcg5/8, Scd1, Elov5 Insig2a and Lpcat3), and these increases were reversed in Lxra-/-Ttc39b-/- mice. Primary enterocytes secreted 50% less particles not containing apoA-1, as well as particles containing apoA-1 by twofold. In the cholesterol absorption study
metabolic syndrome (65.1% vs 58.2%, p¼0.043) than ones in hypertriglyceridemia group. Arterial hypertension and smoking were more prevalent in high triglycerides group (arterial hypertension 69% vs. 59.9%, p¼0.007, smoking 39.4% vs. 23.7%, p<0.001) compared to low HDL-C group. Prevalence of insufficient physical activity, diabetes mellitus, obesity and familial history of coronary heart disease had no significant difference between groups. Conclusions: Subjects in low HDL-C group had lower serum glucose as well as healthier diet compared to high triglycerides group. Arterial hypertension and smoking were less prevalent in low HDL-C group while metabolic syndrome was less prevalent in high triglycerides group.
SAG142. PLASMA PCSK9 AND CARDIOVASCULAR EVENTS IN TYPE 2 DIABETES Petra El Khoury1,2, Ronan Roussel3,4,5, Frederic Fumeron4,5, Gilberto Velho5, Marie-Paule Jacob1,4, Gabriel Steg1,4,6,7, L. Potier3,4,5, Youmna Ghaleb1,2,4, Sandy Elbitar1,2,4, Marianne Abifadel1,2, Catherine Boileau1,4,8, Michel Marre3,4,5, Mathilde Varret1,4, Boris Hansel3,4,5. 1 Inserm U1148, Paris, France; 2 Saint Joseph University, Beruth, Lebanon; 3 Aphp, Chu Bichat, Nutrition Dept, Paris, France; 4 Denis Diderot University, Paris 7, Paris, France; 5 Inserm U1138, Paris, France; 6 Aphp, Chu Bichat, Cardiology Dept, Paris, France; 7 NHLI, Imperial College, Royal Brompton Hospital, London, United Kingdom; 8 Aphp, Chu Bichat, Genetic Dept, Paris, France Aim: Cardiovascular (CV) risk of patients with Type 2 Diabetes mellitus (T2DM), especially if associated to kidney damage, is elevated. Plasma concentration of proprotein convertase subtilisin/kexin type 9 (PCSK9), a secreted protein involved in cholesterol metabolism and a target for novel potent lipid-lowering drugs, is associated with incident CV disease (CVD) independently from classical risk factors. However, no data are available on the prognostic value of PCSK9 in T2DM. Our aim was to investigate whether plasma PCSK9 was associated with CV events in patients with T2DM and albuminuria. Methods: The study population was 2912 French participants from the DIABHYCAR trial. During the 6-year follow-up, 647 CV events occurred and 196 people died from a CV cause. Plasma PCSK9 at baseline was measured by an immunofluorescent assay. Results: In adjusted Cox analysis, plasma PCSK9 was associated, independently from classical risk factors including plasma lipid levels, with the incidence of major CV events (MI, stroke/Transient ischemic attack (TIA), CV death); Hazard Ratio (HR) for one-unit of log(PCSK9): 1.26 (1.05-1.53), the incidence of MI, HR: 1.66; (1.05-2.63), and the incidence of all CV events (MI, stroke, TIA, heart failure leading to hospital admission, coronary/peripheral angioplasty or bypass, CV death; HR: 1.22 (1.04-1.44)), but not with the incidence of CV death or with renal outcomes. Conclusions: This study supports the association of plasma PCSK9 with CV outcomes in patients with T2DM and a high CV risk, independently of other cardiometabolic risk factors.
SAG143. SEX-RELATED DIFFERENCES IN HYPERTENSION: CLINICAL, FUNCTIONAL, STRUCTURAL AND BIOCHEMICAL INFLUENCES 1
1
2
1
Maria Suciu , Lavinia Vlaia , Minodora Andor , Vicentiu Vlaia , Mirela Tomescu2, Carmen Cristescu1. 1 Victor Babes University Of Medicine And Pharmacy, Faculty Of Pharmacy, Timisoara, Romania; 2 Victor Babes University Of Medicine And Pharmacy, Faculty Of Medicine, Timisoara, Romania Aim: A reduction in flow-mediated vasodilatation (%FMD) is reflected in endothelial dysfunction and an elevated carotid intima-media thickness (ITM) is a preclinical phenotype of atherosclerosis. The aim of this study was to investigate the differences and the relationship between clinical, biochemical, functional and structural markers of endothelium damage according to sex in essential hypertensive patients with different degrees of endothelial dysfunction (ED). Methods: A total of 995 hypertensive patients were included in a prospective study. We studied clinical and biochemical markers respectively a
e81
functional and structural evaluation. Regression analyses were used to assess the effects and contributions of these factors on ITM and FMD. Results: In the group with severe ED, FMD (6.17±0.85 vs 5.91±1.04), glucose levels (93.66±7.22 vs 91.76±4, 84) and systolic blood pressure (BP) (166.95±11.43 vs 165.20±8.84) were greater in women than in man. Furthermore, plasma high sensitive C-reactive protein (hs-CRP) levels (r ¼ 0.737 vs r ¼ 0.609), systolic (r ¼ 0.817 vs r ¼ 0.734) and diastolic BP (r ¼ 0.752 vs r ¼ 0.627) of women were significantly positively correlated with IMT much better than in men. But in the group with moderate ED, plasma hs-CRP levels (r ¼ -0.829 vs r ¼ -0.702) and systolic BP (r ¼ -0.637 vs r ¼ -0.586) of hypertensive men were negatively correlated with FMD much better than in women. Conclusions: Our results suggest that hypertensive females have better cardiovascular health than males. Their endothelial function and structure is not affected so quickly by the changes of clinical and biological markers.
SAG144. WHY CAN’T MEN BE MORE LIKE WOMEN? FACTORS FAVOUR FEMALE GENDER IN PREVENTION OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE Shamanna Iyengar1, Rajiv Gupta2, Sandhya Ravi3, Manjunath Cn4, Annie S5, Patil Cb6. 1 Manipal Hospital, Department of Cardiology, Bangalore, India; 2 Eterna Heart Care Centre and Research Institute, Jaipur, India; 3 Lotus Research Clinical Academy, Bangalore, India; 4 Sri Jaideva Institute of cardiovascular research and hospital, Bangalore, India; 5 PS Mission Hospital, Ernakulam, India; 6 St Philomena Hospital, Bangalore, India Aim: Coronary artery disease (CAD) exhibits differences between men and women in its epidemiological features, clinical manifestations, treatment and response, due to biological factors and socio-cultural processes. Some of these factors which could potentially influence preventive process in women were analysed in this study. Methods: From a prospective observational registry of coronary artery disease in young ( men < 55 years and women < 65 years of age ), demographic features, coronary risk factors and clinical presentation were compared between men and women Results: Of 997 patients, 283 were women and 714 men. The mean age was 49.1 years for the whole group, 55.1 years for women and 46.6 for men (p<0.001). Women, as compared to men, had greater prevalence of diabetes (62.1 vs 37.1%, p<0.001), hypertension (72.1 vs 40.3%, p<0.0001) and overweight/obesity (60.1 vs 35.2%, p<0.0001), whereas men had greater prevalence of smoking/tobacco use (52.7 vs 3.2%, p<0.0001). Dyslipidemia (13.4% vs 10.6%, p <0.2) was more frequently seen in women. Women presented with non-ST elevation acute coronary syndrome (NSTE-ACS) more often than men ( 42% vs 29.8%). 358 (35.91%) underwent percutaneous coronary intervention, 261 (36.55%) being male and 97 (34.28%) being female patients. 104 (10.43%) underwent coronary bypass surgery Conclusions: Women have more time and more opportunities to practise cardiovascular disease prevention and prevention of progression, as they present with CAD a decade later, have a higher prevalence of correctable atherosclerotic cardiovascular disease risk factors and have more often NSTE-ACS than men. Genomics and GWAS SAG145. RARE MUTATIONS IN THE APOB GENE AND ITS ROLE IN LDL OXIDATION Eleonora Khlebus1, 2, Natalia Shcherbakova1, Ilya Zhanin1, Anastasia Zharikova1, Alexandra Ershova1, Anna Kiseleva1, Sergey Boytsov1, Alexey Meshkov1. 1 National Research Center for Preventive Medicine, Moscow, Russia; 2 Moscow Institute of Physics and Technology (State University), Moscow, Russia Aim: Atherosclerosis represents one of the major problems in the modern medicine and public health. Many studies have demonstrated a relationship between oxidized low-density lipoprotein (oxLDL) and the progression of atherosclerosis. Our work aims to investigate genetic markers
e82
Abstracts / Atherosclerosis 263 (2017) e29ee110
affecting levels of oxLDL, on incidence/onset of atherosclerosis and atherosclerotic phenotypes in a cohort of 725 patients. Methods: Genotyping was performed using Cardio-Metabo Chip (Illumina). Targeted sequencing was performed with the TargetSeq™ Custom Enrichment Kit (Applied Biosystems, USA) using the SOLiD 5500W system (Applied Biosystems, USA). Alignment and search SNPs were implemented by data analysis tools with the LifeScope™ Genomic Analysis Software. Results: We performed the genome-wide association study (GWAS) and found genetic locus, 2p24-p23, with 14 SNPs in the APOB gene, significantly associated with levels of oxLDL. For analysing ApoB locus we used data for 725 patients from Cardio-Metabo Chip (Illumina) and for 96 patients from targeted sequencing. We identified SNPs and filtered them to narrow the search for the causal variant. So we focused only on nonsynonymous (protein-altering) changes, other variants have been removed from further consideration. To analyze the impact of the cumulative effect of various rare alleles to the level of oxidized LDL we used R package and statistical tests for rare mutations. We have demonstrated the presence of rare mutations in APOB and their relationship to the level of oxidized LDL on the pilot group of participants. Conclusions: Our results may indicate the influence of functional mutations at the level of oxidized LDL.
SAG146. IN SILICO PATIENT STRATIFICATION FOR ATHEROSCLEROSIS Andrew Parton1, Victoria McGilligan1, Maurice O'Kane2, Steven Watterson1. 1 Northern Ireland Centre for Stratified Medicine, Altnagelvin Hospital, Derry/Londonderry, United Kingdom; 2 Department of Clinical Chemistry, Altnagelvin Hospital, Derry/Londonderry, United Kingdom Aim: To study how the dynamics of atherosclerosis differs between population subgroups through development of an in silico platform. Methods: A mathematical model of atherosclerosis has been developed, incorporating the cell types and proteins involved in atheroma formation and describing the dynamics of disease progression. The model adheres to open systems biology standards, SBGN and SBML. Using sequence data from Phase 3 of the 1000 Genomes Project, tertiary (and quaternary) structures have been developed for all proteins involved in this model,. Through Brownian Dynamics simulations of interactions and electrostatic potential comparison, we predict how the dynamics of atherogenesis differs between population subgroups. Results: Our SBML model represents the underlying disease pathophysiology (e.g. Figure 1). A collection of heatmaps have been generated to describe the inherent protein structure variation within the population (e.g. Figure 2), and we are able to show the variation in disease dynamics between population subgroups Conclusions: We have built the first SBGN/SBML compliant computational model of atherosclerosis as a community resource that describes atherogeneic behaviour. We have examined how structures for the proteins involved vary across a patient cohort and demonstrated the varying disease dynamics that result. Ă
SAG147. THE ROLE OF TTC39B IN ATHEROSCLEROSIS AND NON-ALCOHOLIC STEATOHEPATITIS Joanne Hsieh2, Matthew Molusky2, Emi Masahiro Koseki1, Yakushiji2, Marit Westerterp2, Ikuyo Ichi3, Sandra Abramowicz2, Liana Tascau2, Carrie Welch2, Shunichi Takiguchi4, Jahangir Iqbal5, Yasushi Sakata1, Shizuya Yamashita1, Mahmood Hussain5, Daniel Rader4, Alan Tall2. 1 Osaka University-Cardiovascular Medicine, Osaka, Japan; 2 Columbia University-Molecular Medicine, New York, USA; 3 Ochanomizu University, Tokyo, Japan; 4 University of Pennsylvania School of Medicine-Division of Translational Medicine and Human Genetics, Philadelphia, USA; 5 State Univ of New York Health Science Center at Brooklyn-Department of Cell Biology, Brooklyn, USA
Aim: TTC39B was identified in genome wide association studies as a novel gene influencing HDL-cholesterol levels. The aim of this study is to investigate the role of TTC39B in LXR target gene regulation in liver or intestine. Methods: We have investigated Ttc39b deficient mice. Results: We found that intestinal LXR protein, but not mRNA, were increased in chow fed Ttc39b-/- mice, leading enhancement of intestinal Abca1 mRNA and protein and HDL-C levels. When mice were fed with a high fat/high cholesterol/bile salt diet, in addition to intestinal changes, Ttc39b-/- mice or mice with hepatocyte-specific Ttc39b deficiency showed increased hepatic LXR protein and target genes expression (Abcg5/8, Scd1, Elov5 Insig2a and Lpcat3), and these increases were reversed in Lxra-/-Ttc39b-/- mice. Primary enterocytes secreted 50% less particles not containing apoA-1, as well as particles containing apoA-1 by twofold. In the cholesterol absorption study