Abstract 18085: Heparan Sulfate Proteoglycans Only Modestly Affect Postprandial Hepatic Remnant Clearance in Humans

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Geesje M Dallinga-Thie ◽  
Han Levels ◽  
Alinda M Schimmel ◽  
Max Nieuwdorp
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hepatic Clearance ◽  
Tolerance Test ◽  
Retinyl Palmitate ◽  
Diabetic Patients ◽  
Loss Of Function ◽  
Gene Score ◽  
Relative Contribution ◽  
Increased Risk

Introduction and Methods: Elevated circulating levels of Triglyceride-rich Remnant Lipoproteins (TLR) are strongly associated with increased risk for CVD. The hepatic clearance of TRL involves lipoprotein receptors i.e. the low-density lipoprotein receptor (LDLr) and heparin sulfate proteoglycans (HSPG). The relevance of each pathway in humans remains to be established. To further dissect the relative contribution of each of these receptors, we studied postprandial TRL metabolism with an oral fat tolerance test using cream supplemented with retinyl palmitate (RP) in 1) patients with a heterozygous loss-of-function (LOF) variant in LDLR stratified for a low (n=10) or high (n=10) HSPG gene score; 2) patients with heterozygous LOF variants in EXT1 or EXT2 (n=13), characterised by decreased HSPG chains length but normal sulfation pattern, and compared to matched healthy controls (n=13) and 3) diabetic patients (n=29) stratified for a functional SNP in SULF2, that predisposes to lower SULF2 expression and increased 6-O-sulfation of HSPG chains. Results: Postprandial TRL clearance was significantly delayed in patients with FH compared to controls (AUC-RP FH: 1971±190 vs Con: 646±110 nmol/l/h;P<0.0001 and iAUC-TG FH 6.9±1.0 vs Con 3.8±10 mmol/l/h, P<0.05) supporting the important role of LDLr in TRL clearance. No additional effect was observed if the FH group was stratified for HSPG gene score. Also, in patients with LOF variants in EXT, resulting in shorter HSPG chains, no difference in TRL clearance versus controls could be observed. In contrast, improved 6-O-sulfation due to lower hepatic protein expression of SULF2 resulted in improved fasting and postprandial TG levels and significantly lower iAUC-RP (iAUC-TG AA 6.9±1.1 vs GG 4.1±1.2 mmol/l/h P<0.05; AUC-RP AA 97±15 vs GG 15±2 mg/l/h; P<0.001) Conclusion: Our findings clearly indicate an important role for the LDLr in postprandial TRL clearance in humans. In contrast to murine studies, HSPGs do only modestly contribute to hepatic TRL clearance in humans, and implicate that sulfation of HSPG’s is of more relevance for TRL clearance than HSPG chain length.

scholarly journals Evaluation of type-2 diabetes mellitus patients for dyslipidemia in a tertiary care centre

2020 ◽  
Vol 7 (4) ◽  
pp. 586
Author(s):  
Janak G. Chokshi ◽  
Apal P. Gandhi ◽  
Ishvarlal M. Parmar ◽  
Dipen R. Damor
Keyword(s):  
Diabetes Mellitus ◽  
Blood Glucose ◽  
Total Cholesterol ◽  
Plasma Glucose ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Diabetic Patients ◽  
Low Density ◽  
Increased Risk

Background: Diabetes mellitus (DM) is a syndrome consisting of metabolic, vascular and neuropathic components that are interrelated. Diabetes mellitus is associated with a considerably increased risk of premature atherosclerosis, particularly coronary heart disease (CHD) and peripheral arterial disease. Dyslipidemia is a common feature of diabetes. There is an association between atherosclerotic cardiovascular disease and serum cholesterol and triglyceride levels in both type 1 and type 2 diabetes.Methods: The study was done on 50 adult diabetes mellitus (T2) patients from IPD of General Medicine wards at SMS Hospital, Ahmedabad, Gujarat. 50 healthy age and sex matched healthy volunteers were taken as control. They were evaluated for lipid profile i.e., Total Cholesterol (TC),Triglyceride (TG), Low-density lipoprotein (LDL), High density lipoprotein (HDL), Very low density lipoprotein (VLDL) and glycemic status i.e., Fasting blood glucose (FBS), Postprandial 2 hours blood glucose (PP2BS) & Glycosylated haemoglobin(HbA1C).Results: Diabetic cases had statistically highly significant (p<0.001) elevated levels of total Cholesterol, Triglycerides and VLDL as compared to controls. Serum TG, serum TC, LDL-C and VLDL-C had positive correlation with the postprandial plasma glucose, fasting plasma glucose and HbA1c.Conclusions: Significant correlations between HbA1c levels and lipid levels point towards the usefulness of HbA1c for screening high-risk diabetic patients. High TC, TG, LDL-C and HbA1c with normal or low HDL-C is seen in almost all diabetic patients either alone or in combinations.

P5322Oxidized phospholipids on apolipoprotein B-100 among black US adults with and without PCSK9 loss-of-function variants

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Mefford ◽  
S Marcovina ◽  
V Bittner ◽  
M Cushman ◽  
T Brown ◽  
...  
Keyword(s):  
Racial Differences ◽  
Apolipoprotein B ◽  
Population Distribution ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
P Value ◽  
Loss Of Function ◽  
Black Adults ◽  
Lipoprotein A ◽  
Increased Risk

Abstract Background High oxidized phospholipid-apolipoprotein B-100 (OxPL-apoB) levels are associated with an increased risk for coronary heart disease (CHD). Genetic PCSK9 loss-of-function (LOF) variants result in life-long lower levels of LDL-C and lipoprotein(a) and reduced CHD risk, but the association with OxPL-apoB is unknown. Purpose To estimate the association between PCSK9 LOF variants and OxPL-apoB levels among black adults. Methods Genotyping for LOF variants (Y142X and C679X) was conducted for 10,196 black Reasons for Geographic And Racial Differences in Stroke study participants. OxPL-apoB was measured using antibody E06 for all participants with LOF variants (n=241) and randomly selected participants, matched at a 1:3 ratio, without LOF variants (n=723). Low OxPL-apoB was defined as the bottom quartile of the population distribution (<1.6 nM). Prevalence ratios (PR) and 95% confidence intervals (CI) were calculated for the association between PCSK9 LOF variants and low OxPL-apoB levels adjusting for age, sex, and estimated glomerular filtration rate. Results Adults with versus without PCSK9 LOF variants had lower LDL-C and lipoprotein(a) and were less likely to be taking a statin. (Table) A higher proportion of adults with versus without PCSK9 LOF variants had low OxPL-apoB levels (30.3 vs 23.4, p=0.03). After adjustment for covariates, the PR of low OxPL-apoB was increased for participants with compared to without LOF variants (PR 1.31, 95% CI 1.00, 1.72). Characteristics of REGARDS participants PCSK9 loss-of-function variant p-value Yes (n=241) No (n=723) Age, years, mean (SD) 63.7 (9.2) 63.8 (8.6) 0.81 Female, % 61.4 60.6 0.82 Diabetes, % 34.4 27.4 0.04 LDL-C, mg/dL, mean (SD) 85 (32) 118 (37) <0.001 Lp(a), nmol/L, median (25th, 75th percentile) 63.2 (30.4, 119.6) 80.4 (39.7, 138.4) 0.02 Statin use, % 13.3 30.4 <0.001 OxPL-apoB <1.6 nM, % 30.3 23.4 0.03 Abbreviations: LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); LOF, loss-of-function; nM, nanomolar; OxPL-apoB, oxidized phospholipids on apolipoprotein B-100; PCSK9, proprotein convertase subtilisin/kexin type-9; REGARDS, REasons for Geographic And Racial Differences in Stroke; SD, standard deviation. Conclusion Among black adults, PCSK9 LOF variants were associated with lower OxPL-apoB levels. Acknowledgement/Funding Industry/academic collaboration between Amgen Inc., University of Alabama at Birmingham and the Icahn School of Medicine at Mt. Sinai; and U01NS041588

scholarly journals Some determinants of postprandial lipaemia in Nigerian diabetic and non-diabetic subjects

1992 ◽  
Vol 68 (1) ◽  
pp. 153-162 ◽  
Author(s):  
Abayomi O. Akanji ◽  
Anali A. Nzegwu ◽  
E. Olu Agbedana
Keyword(s):  
Glycaemic Control ◽  
Plasma Levels ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Tolerance Test ◽  
Normal Weight ◽  
High Density Lipoproteins ◽  
Diabetic Patients ◽  
Postprandial Lipaemia ◽  
Fasting Plasma

The efficiency of clearance of plasma triacylglycerols (TAG) after fatty meals in non-diabetic Caucasian subjects is believed to determine the plasma level of high-density-lipoproteins-cholesterol (HDL-C). It is unknown if this observation holds in diabetic subjects and in other racial groups. In assessing the factors that determine TAG responses to acute fat loading in a tropical African population with a low prevalence of atherosclerotic disease, twenty (nine obese) non-insulin-dependent diabetic (NIDDM) patients with optimal glycaemic control and twelve (six obese) age-matched non-diabetic subjects were given meals containing 50 g fat (in butter) and 75 g carbohydrate (in white bread) over 15 min in the morning after a 12 h overnight fast. The fasting plasma levels of glucose, TAG, total cholesterol (total-C), HDL-C, low-density-lipoprotein-cholesterol, insulin and glycosylated haemoglobin (HBAlc) were estimated; glucose and TAG levels were also measured postprandially for 8 h at 2 h intervals. Postprandial lipaemia was consistently higher in the diabetic patients (about 50–100% more than values obtained in the non-diabetic subjects, even when corrected for differences in body mass) and correlated positively with age and postprandial glycaemia. This defect in TAG clearance was even worse (by about 50%) when glucose tolerance became further impaired after ten of the diabetic patients stopped oral hypoglycaemic treatment for 1 week and the fat-tolerance test was repeated. In the obese non-diabetic subjects, but not those of normal weight, there were significant negative relationships between the postprandial lipaemia and fasting plasma levels of HDL-C and the HDL-C: total-C ratio, as reported in Caucasians. It is concluded that age and the ambient glucose concentration appear to be the important determinants of the efficiency of TAG clearance in diabetic subjects. This accords with clinical observations of increased atherogenic liability with increasing age and poorer glycaemic control. The determinants in non-diabetic subjects were less defined, indicating that postprandial lipaemia might be influenced by various factors (obesity as shown here) in different subsets of individuals.

scholarly journals Extremely elevated lipoprotein (a) as an independent risk factor for peripheral arterial disease in large patient cohort

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M.R Poudel ◽  
S Kirana ◽  
D Stoyanova ◽  
K.P Mellwig ◽  
D Hinse ◽  
...  
Keyword(s):  
Peripheral Arterial Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Arterial Disease ◽  
P Value ◽  
Lipoprotein A ◽  
Large Patient ◽  
Increased Risk ◽  
Revascularization Therapy ◽  
Peripheral Arterial

Abstract Background Elevated lipoprotein (a) [LP (a)] levels are an independent, genetic, and causal factor for cardiovascular disease and associated with myocardial infarction (MI). Although the association between circulating levels of lipoprotein(a) [Lp(a)] and risk of coronary artery disease (CAD) is well established, its role in risk of peripheral arterial disease (PAD) remains unclear. PAD affects over 236 million individuals and follows ischaemic heart disease (IHD) and cerebrovascular disease (CVD) as the third leading cause of atherosclerotic cardiovascular morbidity worldwide. LP (a) is genetically determined, stable throughout life and yet refractory to drug therapy. While 30 mg/dl is considered the upper normal value for LP (a) in central Europe, extremely high LP (a) levels (&gt;150mg/dl) are rare in the general population. The aim of our study was to analyse the correlation between lipoprotein (a) [LP (a)] levels and an incidence of PAD in high-risk patients. Patients and methods We reviewed the LP (a) concentrations of 52.898 consecutive patients admitted to our cardiovascular center between January 2004 and December 2014. Of these, 579 patients had LP (a) levels above 150 mg/dl (mean 181.45±33.1mg/dl). In the control collective LP (a) was &lt;30mg/dl (n=350). Other atherogenic risk factors in this group were HbA1c 6.58±1.65%, low density lipoprotein (LDL) 141.99±43.76 mg/dl, and body mass index 27.81±5.61. 54.40% were male, 26.07% were smokers, 93.2% had hypertension, and 24% had a family history of cardiovascular diseases. More than 82.6% were under statins. The mean glomerular filtration rate (GFR) was 69.13±24.8 ml/min [MDRD (Modification of Diet in Renal Disease)]. Results 45.00% (n=261) of the patients with LP (a) &gt;150mg/dl had PAD. The prevalence of PAD in patients with LP (a) &lt;30mg/dl in our control collective was 15.8%. (P- Value 0.001). Patients with LP (a) &gt;150mg/dl had a significantly increased risk for PAD (Odds ratio 4.36, 95% CI 2.94–6.72, p: 0.001). 19.1% of patients were re-vascularized by percutaneous angioplasty (PTA) and 7.09% of patients had to undergo peripheral vascular bypass (PVB). Mean LP (a) level in patients with PAD was 182.6±31.61. Conclusion Elevated LP (a) levels above 150 mg/dl are associated with a significantly increased risk of PAD in our collective and it confirms our hypothesis. Over one fourth of these patients had severe PAD and requiring revascularization therapy. We need more prospective studies to confirm our findings. Funding Acknowledgement Type of funding source: None

scholarly journals Long-term fasting improves lipoprotein-associated atherogenic risk in humans

2021 ◽  
Author(s):  
Franziska Grundler ◽  
Dietmar Plonné ◽  
Robin Mesnage ◽  
Diethard Müller ◽  
Cesare R. Sirtori ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Plasma Lipid ◽  
Density Lipoprotein ◽  
Apolipoprotein A1 ◽  
Health Concern ◽  
Low Density ◽  
Lipoprotein Subclasses ◽  
Ldl Particles ◽  
Increased Risk

Abstract Purpose Dyslipidemia is a major health concern associated with an increased risk of cardiovascular mortality. Long-term fasting (LF) has been shown to improve plasma lipid profile. We performed an in-depth investigation of lipoprotein composition. Methods This observational study included 40 volunteers (50% men, aged 32–65 years), who underwent a medically supervised fast of 14 days (250 kcal/day). Changes in lipid and lipoprotein levels, as well as in lipoprotein subclasses and particles, were measured by ultracentrifugation and nuclear magnetic resonance (NMR) at baseline, and after 7 and 14 fasting days. Results The largest changes were found after 14 fasting days. There were significant reductions in triglycerides (TG, − 0.35 ± 0.1 mmol/L), very low-density lipoprotein (VLDL)-TG (− 0.46 ± 0.08 mmol/L), VLDL-cholesterol (VLDL-C, − 0.16 ± 0.03 mmol/L) and low-density lipoprotein (LDL)-C (− 0.72 ± 0.14 mmol/L). Analysis of LDL subclasses showed a significant decrease in LDL1-C (− 0.16 ± 0.05 mmol/L), LDL2-C (− 0.30 ± 0.06 mmol/L) and LDL3-C (− 0.27 ± 0.05 mmol/L). NMR spectroscopy showed a significant reduction in large VLDL particles (− 5.18 ± 1.26 nmol/L), as well as large (− 244.13 ± 39.45 nmol/L) and small LDL particles (− 38.45 ± 44.04 nmol/L). A significant decrease in high-density lipoprotein (HDL)-C (− 0.16 ± 0.04 mmol/L) was observed. By contrast, the concentration in large HDL particles was significantly raised. Apolipoprotein A1 decreased significantly whereas apolipoprotein B, lipoprotein(a), fibrinogen and high-sensitivity C-reactive protein were unchanged. Conclusion Our results suggest that LF improves lipoprotein levels and lipoprotein subclasses and ameliorates the lipoprotein-associated atherogenic risk profile, suggesting a reduction in the cardiovascular risk linked to dyslipidemia. Trial Registration Study registration number: DRKS-ID: DRKS00010111 Date of registration: 03/06/2016 “retrospectively registered”.

scholarly journals 6th Hellenic Congress in Athens, of the Hellenic Atherosclerosis Society, on the 04-06 December 2014 Novel Pharmacologic Treatments of Familial Hypercholesterolaemia

2015 ◽  
Vol 9 (1) ◽  
pp. 73-77
Author(s):  
Athyros VG
Keyword(s):  
Familial Hypercholesterolaemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Automatic Device ◽  
Loss Of Function ◽  
Ldl Apheresis ◽  
Cvd Risk ◽  
Atherosclerosis Risk In Communities ◽  
Lipid Disorder ◽  
Pharmacologic Treatments

Familial hypercholesterolaemia (FH) is the most common inherited monogenic lipid disorder. It is caused by mutations of genes related to low density lipoprotein (LDL) receptors, apolipoprotein B or proprotein convertase subtilisin/kexin type 9 (PCSK9). Homozygous FH (HoFH; 1/400,000 births) is treated by LDL apheresis. Recently lomitapide has been used for the treatment of HoFH as a monotherapy or in addition to LDL apheresis. Heterozygous FH (HeFH), 1/250-1/200 births, is associated with an increased cardiovascular disease (CVD) risk. The main treatment for HeFH has been high doses of high intensity statins plus ezetimibe. However, this is not usually enough to attain LDL-C targets, especially in those with overt CVD or equivalents (LDL-C goal of<70 mg/dl). Data from the Atherosclerosis Risk in Communities study showed that loss of function mutations of PCSK9 were associated with a 28% lower LDL-C level and an 88% reduction in the risk of CVD in blacks, while in whites these numbers were 15% and 47%, respectively. This led to the development of technology to block PCSK9 with monoclonal human antibodies (e.g. evolocumab and alirocumab). These antibodies have been shown in phase II and III trials to be safe and to produce reductions in LDL-C levels by around 60% either as monotherapy or on top of optimal therapy with statins and ezetimibe. These antibodies are administered subcutaneously every 2 weeks with an automatic device. Anti-PCSK9 antibodies are expected to be licensed soon (? in 2015) and are considered by many as “the statins of the 21st century”.

scholarly journals Lipid Profile of Type 2 Diabetic and Hypertensive Patients in the Jamaican Population

2010 ◽  
Vol 2 (01) ◽  
pp. 025-030 ◽  
Author(s):  
Lorenzo Gordon ◽  
Dalip Ragoobirsingh ◽  
Errol Y St A Morrison ◽  
Eric Choo-Kang ◽  
Donovan McGrowder ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Diabetic Patients ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Type 2 Diabetic Patients ◽  
Type 2 Dm ◽  
Type 2 Diabetic

ABSTRACT Aims: Previous studies have shown that diabetes mellitus (DM) increases the risk of cardiovascular diseases in females to a greater extent than in males. In this cross-sectional study, we evaluated the lipid profiles of type 2 diabetic males and females. Materials and Methods: The study included 107 type 2 diabetic patients (41 males and 66 females), and 122 hypertensive type 2 diabetic patients (39 males and 83 females), aged 15 years and older. Total cholesterol (TC), triglycerides (TG), low density lipoprotein-cholesterol (LDL-C), very low density lipoprotein-cholesterol (VLDL-C) and high density lipoprotein-cholesterol (HDL-C) concentrations were assayed for each group using standard biochemical methods. Results: The mean TC, TG, VLDL-C, HDL-C and LDL-C concentrations, TG/HDL and LDL/HDL ratios were higher in type 2 diabetic and hypertensive type 2 diabetic patients compared with non-diabetic, and hypertensive non-diabetic control subjects, although these were not significant (P > 0.05). Hypertensive type 2 diabetic females had significantly higher serum TC (7.42 ± 1.63 mmol/L) than hypertensive non-diabetic males (5.76±1.57 mmol/L; P < 0.05). All the other lipid and lipoprotein parameters except HDL-C were non-significantly higher in females with type 2 DM and those with hypertension and type 2 DM, compared with type 2 diabetic and hypertensive type 2 diabetic males, respectively (P > 0.05). Conclusion: This study demonstrated that dyslipidemia exists in our type 2 diabetic population with greater TC in hypertensive type 2 diabetic females compared with hypertensive type 2 diabetic males. This suggests that hypertensive type 2 diabetic females are exposed more profoundly to risk factors including atherogenic dyslipidemia compared with males.

Abstract 14727: Meteorin-like Glial Cell Differentiation Regulator is a Novel Protein Biomarker of Cardiovascular Outcomes in Patients With Diabetes and Vascular Disease: A TECOS Substudy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Lauren K Truby ◽  
Jessica A Regan ◽  
Maggie Nguyen ◽  
Stephani Giamberardino ◽  
Robert J Mentz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Conditional Logistic Regression ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Specific Protein ◽  
Cardiovascular Outcomes ◽  
Diabetic Patients ◽  
Proteomic Profiling ◽  
Protein Biomarkers ◽  
Novel Protein

Introduction: To date, there are limited data on the potential role of proteomic biomarkers to predict future cardiovascular (CV) events among patients with type 2 diabetes mellitus (DM). Hypothesis: Specific protein biomarkers will be predictive of major adverse CV events (MACE) and incident heart failure hospitalization (HFH) among patients with DM. Methods: Using the Olink aptamer-based platform, we performed proteomic profiling (>700 proteins) on 440 paired cases and matched controls from placebo-assigned participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Cases were defined as having met the primary composite outcome of MACE or incident HFH and matched to controls on baseline prevalent heart failure, coronary artery disease, BMI, hemoglobin A1C, creatinine, low-density lipoprotein cholesterol, fasting status and ejection fraction. Conditional logistic regression was used to determine the association between log-transformed relative protein expression and incident MACE or HFH. False-discovery-rate (FDR) was used to adjust for multiple comparisons. Results: We identified three specific proteins that were significantly associated with prevalent MACE or HFH: METRNL, Notch 3, and ROR1 (OR 2.1, 1.6, 1.7 and q-value 0.01, 0.02, and 0.05 respectively) (Figure 1). METRNL, in particular, performed similarly to the established biomarker NT-proBNP (Figure 1). When MACE and HFH were analyzed separately, METRNL, in particular, remained strongly associated with both outcomes (OR 2.0, p<0.001 and OR 2.7, p=0.05). Conclusions: Three novel protein biomarkers, in particular METRNL (a circulating adipokine that regulates insulin-sensitivity), may identify diabetic patients at high risk for subsequent HF and MACE. Additional studies are needed to replicate these findings and uncover the biologic mechanism linking adipokine signaling and heart failure.

scholarly journals Liver X Receptor Nuclear Receptors Are Transcriptional Regulators of Dendritic Cell Chemotaxis

2018 ◽  
Vol 38 (10) ◽  
Author(s):  
Susana Beceiro ◽  
Attila Pap ◽  
Zsolt Czimmerer ◽  
Tamer Sallam ◽  
Jose A. Guillén ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Low Density Lipoprotein ◽  
Myeloid Cells ◽  
Density Lipoprotein ◽  
Loss Of Function ◽  
Transcriptional Responses ◽  
Cd38 Expression ◽  
The Impact

ABSTRACTThe liver X receptors (LXRs) are ligand-activated nuclear receptors with established roles in the maintenance of lipid homeostasis in multiple tissues. LXRs exert additional biological functions as negative regulators of inflammation, particularly in macrophages. However, the transcriptional responses controlled by LXRs in other myeloid cells, such as dendritic cells (DCs), are still poorly understood. Here we used gain- and loss-of-function models to characterize the impact of LXR deficiency on DC activation programs. Our results identified an LXR-dependent pathway that is important for DC chemotaxis. LXR-deficient mature DCs are defective in stimulus-induced migrationin vitroandin vivo. Mechanistically, we show that LXRs facilitate DC chemotactic signaling by regulating the expression of CD38, an ectoenzyme important for leukocyte trafficking. Pharmacological or genetic inactivation of CD38 activity abolished the LXR-dependent induction of DC chemotaxis. Using the low-density lipoprotein receptor-deficient (LDLR−/−) LDLR−/−mouse model of atherosclerosis, we also demonstrated that hematopoietic CD38 expression is important for the accumulation of lipid-laden myeloid cells in lesions, suggesting that CD38 is a key factor in leukocyte migration during atherogenesis. Collectively, our results demonstrate that LXRs are required for the efficient emigration of DCs in response to chemotactic signals during inflammation.

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