Publications by authors named "Nada A Abumrad"

111 Publications

Lipolytic enzymes and free fatty acids at the endothelial interface.

Atherosclerosis 2021 Jul 28;329:1-8. Epub 2021 May 28.

Department of Medicine, Center for Human Nutrition, Washington University School of Medicine, Saint Louis, MO, USA. Electronic address:

Lipids released from circulating lipoproteins by intravascular action of lipoprotein lipase (LpL) reach parenchymal cells in tissues with a non-fenestrated endothelium by transfer through or around endothelial cells. The actions of LpL are controlled at multiple sites, its synthesis and release by myocytes and adipocytes, its transit and association with the endothelial cell luminal surface, and finally its activation and inhibition by a number of proteins and by its product non-esterified fatty acids. Multiple pathways mediate endothelial transit of lipids into muscle and adipose tissues. These include movement of fatty acids via the endothelial cell fatty acid transporter CD36 and movement of whole or partially LpL-hydrolyzed lipoproteins via other apical endothelial cell receptors such as SR-B1and Alk1. Lipids also likely change the barrier function of the endothelium and operation of the paracellular pathway around endothelial cells. This review summarizes in vitro and in vivo support for the key role of endothelial cells in delivery of lipids and highlights incompletely understood processes that are the focus of active investigation.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.05.018DOI Listing
July 2021

Eruptive xanthoma model reveals endothelial cells internalize and metabolize chylomicrons, leading to extravascular triglyceride accumulation.

J Clin Invest 2021 Jun;131(12)

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA.

Although tissue uptake of fatty acids from chylomicrons is primarily via lipoprotein lipase (LpL) hydrolysis of triglycerides (TGs), studies of patients with genetic LpL deficiency suggest additional pathways deliver dietary lipids to tissues. Despite an intact endothelial cell (EC) barrier, hyperchylomicronemic patients accumulate chylomicron-derived lipids within skin macrophages, leading to the clinical finding eruptive xanthomas. We explored whether an LpL-independent pathway exists for transfer of circulating lipids across the EC barrier. We found that LpL-deficient mice had a marked increase in aortic EC lipid droplets before and after a fat gavage. Cultured ECs internalized chylomicrons, which were hydrolyzed within lysosomes. The products of this hydrolysis fueled lipid droplet biogenesis in ECs and triggered lipid accumulation in cocultured macrophages. EC chylomicron uptake was inhibited by competition with HDL and knockdown of the scavenger receptor-BI (SR-BI). In vivo, SR-BI knockdown reduced TG accumulation in aortic ECs and skin macrophages of LpL-deficient mice. Thus, ECs internalize chylomicrons, metabolize them in lysosomes, and either store or release their lipids. This latter process may allow accumulation of TGs within skin macrophages and illustrates a pathway that might be responsible for creation of eruptive xanthomas.
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http://dx.doi.org/10.1172/JCI145800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203467PMC
June 2021

Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8 T cells in tumors.

Immunity 2021 Jul 7;54(7):1561-1577.e7. Epub 2021 Jun 7.

NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address:

A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8 tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8 TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8 TILs, which also correlated with progressive T cell dysfunction. Cd36 T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8 TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8 T cell dysfunction and serves as a therapeutic avenue for immunotherapies.
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http://dx.doi.org/10.1016/j.immuni.2021.05.003DOI Listing
July 2021

Visceral obesity and insulin resistance associate with CD36 deletion in lymphatic endothelial cells.

Nat Commun 2021 06 7;12(1):3350. Epub 2021 Jun 7.

Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, USA.

Disruption of lymphatic lipid transport is linked to obesity and type 2 diabetes (T2D), but regulation of lymphatic vessel function and its link to disease remain unclear. Here we show that intestinal lymphatic endothelial cells (LECs) have an increasing CD36 expression from lymphatic capillaries (lacteals) to collecting vessels, and that LEC CD36 regulates lymphatic integrity and optimizes lipid transport. Inducible deletion of CD36 in LECs in adult mice (Cd36) increases discontinuity of LEC VE-cadherin junctions in lacteals and collecting vessels. Cd36 mice display slower transport of absorbed lipid, more permeable mesenteric lymphatics, accumulation of inflamed visceral fat and impaired glucose disposal. CD36 silencing in cultured LECs suppresses cell respiration, reduces VEGF-C-mediated VEGFR2/AKT phosphorylation and destabilizes VE-cadherin junctions. Thus, LEC CD36 optimizes lymphatic junctions and integrity of lymphatic lipid transport, and its loss in mice causes lymph leakage, visceral adiposity and glucose intolerance, phenotypes that increase risk of T2D.
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http://dx.doi.org/10.1038/s41467-021-23808-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184948PMC
June 2021

Autoregulation of insulin receptor signaling through MFGE8 and the αvβ5 integrin.

Proc Natl Acad Sci U S A 2021 May;118(18)

Cardiovascular Research Institute, University of California, San Francisco, CA 94158;

The role of integrins, in particular αv integrins, in regulating insulin resistance is incompletely understood. We have previously shown that the αvβ5 integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) regulates cellular uptake of fatty acids. In this work, we evaluated the impact of MFGE8 on glucose homeostasis. We show that acute blockade of the MFGE8/β5 pathway enhances while acute augmentation dampens insulin-stimulated glucose uptake. Moreover, we find that insulin itself induces cell-surface enrichment of MFGE8 in skeletal muscle, which then promotes interaction between the αvβ5 integrin and the insulin receptor leading to dampening of skeletal-muscle insulin receptor signaling. Blockade of the MFGE8/β5 pathway also enhances hepatic insulin sensitivity. Our work identifies an autoregulatory mechanism by which insulin-stimulated signaling through its cognate receptor is terminated through up-regulation of MFGE8 and its consequent interaction with the αvβ5 integrin, thereby establishing a pathway that can potentially be targeted to improve insulin sensitivity.
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http://dx.doi.org/10.1073/pnas.2102171118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106306PMC
May 2021

Endothelial Cell Receptors in Tissue Lipid Uptake and Metabolism.

Circ Res 2021 02 4;128(3):433-450. Epub 2021 Feb 4.

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University Grossman School of Medicine (A.G.C., D.B., I.J.G.).

Lipid uptake and metabolism are central to the function of organs such as heart, skeletal muscle, and adipose tissue. Although most heart energy derives from fatty acids (FAs), excess lipid accumulation can cause cardiomyopathy. Similarly, high delivery of cholesterol can initiate coronary artery atherosclerosis. Hearts and arteries-unlike liver and adrenals-have nonfenestrated capillaries and lipid accumulation in both health and disease requires lipid movement from the circulation across the endothelial barrier. This review summarizes recent in vitro and in vivo findings on the importance of endothelial cell receptors and uptake pathways in regulating FAs and cholesterol uptake in normal physiology and cardiovascular disease. We highlight clinical and experimental data on the roles of ECs in lipid supply to tissues, heart, and arterial wall in particular, and how this affects organ metabolism and function. Models of FA uptake into ECs suggest that receptor-mediated uptake predominates at low FA concentrations, such as during fasting, whereas FA uptake during lipolysis of chylomicrons may involve paracellular movement. Similarly, in the setting of an intact arterial endothelial layer, recent and historic data support a role for receptor-mediated processes in the movement of lipoproteins into the subarterial space. We conclude with thoughts on the need to better understand endothelial lipid transfer for fuller comprehension of the pathophysiology of hyperlipidemia, and lipotoxic diseases such as some forms of cardiomyopathy and atherosclerosis.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.318003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959116PMC
February 2021

Endothelial cell CD36 deficiency prevents normal angiogenesis and vascular repair.

Am J Transl Res 2020 15;12(12):7737-7761. Epub 2020 Dec 15.

Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health New York, NY, USA.

Endothelial cells (ECs) maintain vascular integrity and mediate vascular repair and angiogenesis, by which new blood vessels are formed from pre-existing blood vessels. Hyperglycemia has been shown to increase EC angiogenic potential. However, few studies have investigated effects of fatty acids (FAs) on EC angiogenesis. Cluster of differentiation 36 (CD36) is a FA transporter expressed by ECs, but its role in EC proliferation, migration, and angiogenesis is unknown. We sought to determine if circulating FAs regulate angiogenic function in a CD36-dependent manner. CD36-dependent effects of FAs on EC proliferation and migration of mouse heart ECs (MHECs) and lung ECs (MLECs) were studied. We used both silencing RNA and antisense oligonucleotides to reduce CD36 expression. Oleic acid (OA) did not affect EC proliferation, but significantly increased migration of ECs in wound healing experiments. CD36 knockdown prevented OA-induced increases in wound healing potential. In EC transwell migration experiments, OA increased recruitment and migration of ECs, an effect abolished by CD36 knockdown. Phospho-AMP-activated protein kinase (AMPK) increased in MHECs exposed to OA in a CD36-dependent manner. To test whether CD36 affects angiogenesis, we studied 21-day recovery in post-hindlimb ischemia. EC-specific CD36 knockout mice had reduced blood flow recovery as assessed by laser Doppler imaging. EC content in post-ischemic muscle, assessed from CD31 expression, increased in ischemic muscle of control mice. However, mice with EC-specific CD36 deletion lacked the increase in CD31 and matrix metalloprotease 9 expression observed in controls. EC expression of CD36 and its function in FA uptake modulate angiogenic function and response to ischemia, likely due to reduced activation of the AMPK pathway.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791529PMC
December 2020

A Single Bout of Premeal Resistance Exercise Improves Postprandial Glucose Metabolism in Obese Men with Prediabetes.

Med Sci Sports Exerc 2021 04;53(4):694-703

Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.

Introduction: Prediabetes is a major risk factor for type 2 diabetes and cardiovascular diseases. Although resistance exercise (RE) is recommended for individuals with prediabetes, the effects of RE on postprandial glucose metabolism in this population are poorly understood. Therefore, the purpose of this study was to elucidate how RE affects postprandial glucose kinetics, insulin sensitivity, beta cell function, and glucose oxidation during the subsequent meal in sedentary men with obesity and prediabetes.

Methods: We studied 10 sedentary men with obesity (body mass index, 33 ± 3 kg·m-2) and prediabetes by using a randomized, cross-over study design. After an overnight fast, participants completed either a single bout of whole-body RE (seven exercises, 3 sets of 10-12 repetitions at 80% one-repetition maximum each) or an equivalent period of rest. Participants subsequently completed a mixed meal test in conjunction with an intravenous [6,6-2H2]glucose infusion to determine basal and postprandial glucose rate of appearance (Ra) and disappearance (Rd) from plasma, insulin sensitivity, and the insulinogenic index (a measure of beta cell function). Skeletal muscle biopsies were obtained 90 min postmeal to evaluate pyruvate-supported and maximal mitochondrial respiration. Whole-body carbohydrate oxidation was assessed using indirect calorimetry.

Results: RE significantly reduced the postprandial rise in glucose Ra and plasma glucose concentration. Postprandial insulin sensitivity was significantly greater after RE, whereas postprandial plasma insulin concentration was significantly reduced. RE had no effect on the insulinogenic index, postprandial pyruvate respiration, or carbohydrate oxidation.

Conclusion/interpretation: A single bout of RE has beneficial effects on postprandial glucose metabolism in men with obesity and prediabetes by increasing postprandial insulin sensitivity, reducing the postprandial rise in glucose Ra, and reducing postprandial plasma insulin concentration.
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http://dx.doi.org/10.1249/MSS.0000000000002538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969361PMC
April 2021

Myeloid-specific Asxl2 deletion limits diet-induced obesity by regulating energy expenditure.

J Clin Invest 2020 05;130(5):2644-2656

Department of Pathology and Immunology and.

We previously established that global deletion of the enhancer of trithorax and polycomb (ETP) gene, Asxl2, prevents weight gain. Because proinflammatory macrophages recruited to adipose tissue are central to the metabolic complications of obesity, we explored the role of ASXL2 in myeloid lineage cells. Unexpectedly, mice without Asxl2 only in myeloid cells (Asxl2ΔLysM) were completely resistant to diet-induced weight gain and metabolically normal despite increased food intake, comparable activity, and equivalent fecal fat. Asxl2ΔLysM mice resisted HFD-induced adipose tissue macrophage infiltration and inflammatory cytokine gene expression. Energy expenditure and brown adipose tissue metabolism in Asxl2ΔLysM mice were protected from the suppressive effects of HFD, a phenomenon associated with relatively increased catecholamines likely due to their suppressed degradation by macrophages. White adipose tissue of HFD-fed Asxl2ΔLysM mice also exhibited none of the pathological remodeling extant in their control counterparts. Suppression of macrophage Asxl2 expression, via nanoparticle-based siRNA delivery, prevented HFD-induced obesity. Thus, ASXL2 controlled the response of macrophages to dietary factors to regulate metabolic homeostasis, suggesting modulation of the cells' inflammatory phenotype may impact obesity and its complications.
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http://dx.doi.org/10.1172/JCI128687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190927PMC
May 2020

A single bout of resistance exercise improves postprandial lipid metabolism in overweight/obese men with prediabetes.

Diabetologia 2020 03 23;63(3):611-623. Epub 2019 Dec 23.

Program in Physical Therapy, Washington University, St Louis, Campus Box 8502, 4444 Forest Park Ave., St Louis, MO, 63110, USA.

Aims/hypothesis: Prediabetes is associated with postprandial hypertriacylglycerolaemia. Resistance exercise acutely lowers postprandial plasma triacylglycerol (TG); however, the changes in lipid metabolism that mediate this reduction are poorly understood. The aim of this study was to identify the constitutive metabolic mechanisms underlying the changes in postprandial lipid metabolism after resistance exercise in obese men with prediabetes.

Methods: We evaluated the effect of a single bout of whole-body resistance exercise (seven exercises, three sets, 10-12 repetitions at 80% of one-repetition maximum) on postprandial lipid metabolism in ten middle-aged (50 ± 9 years), overweight/obese (BMI: 33 ± 3 kg/m), sedentary men with prediabetes (HbA >38 but <48 mmol/mol [>5.7% but <6.5%]), or fasting plasma glucose >5.6 mmol/l but <7.0 mmol/l or 2 h OGTT glucose >7.8 mmol/l but <11.1 mmol/l). We used a randomised, crossover design with a triple-tracer mixed meal test (ingested [(C)]tripalmitin, i.v. [U-C]palmitate and [H]glycerol) to evaluate chylomicron-TG and total triacylglycerol-rich lipoprotein (TRL)-TG kinetics. We used adipose tissue and skeletal muscle biopsies to evaluate the expression of genes regulating lipolysis and lipid oxidation, skeletal muscle respirometry to evaluate oxidative capacity, and indirect calorimetry to assess whole-body lipid oxidation.

Results: The single bout of resistance exercise reduced the lipaemic response to a mixed meal in obese men with prediabetes without changing chylomicron-TG or TRL-TG fractional clearance rates. However, resistance exercise reduced endogenous and meal-derived fatty acid incorporation into chylomicron-TG and TRL-TG. Resistance exercise also increased whole-body lipid oxidation, skeletal muscle mitochondrial respiration, oxidative gene expression in skeletal muscle, and the expression of key lipolysis genes in adipose tissue.

Conclusions/interpretation: A single bout of resistance exercise improves postprandial lipid metabolism in obese men with prediabetes, which may mitigate the risk for cardiovascular disease and type 2 diabetes.
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http://dx.doi.org/10.1007/s00125-019-05070-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002271PMC
March 2020

Lipokine 5-PAHSA Is Regulated by Adipose Triglyceride Lipase and Primes Adipocytes for De Novo Lipogenesis in Mice.

Diabetes 2020 03 5;69(3):300-312. Epub 2019 Dec 5.

Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic

Branched esters of palmitic acid and hydroxystearic acid (PAHSA) are anti-inflammatory and antidiabetic lipokines that connect glucose and lipid metabolism. We aimed to characterize involvement of the 5-PAHSA regioisomer in the adaptive metabolic response of white adipose tissue (WAT) to cold exposure (CE) in mice, exploring the cross talk between glucose utilization and lipid metabolism. CE promoted local production of 5- and 9-PAHSAs in WAT. Metabolic labeling of de novo lipogenesis (DNL) using HO revealed that 5-PAHSA potentiated the effects of CE and stimulated triacylglycerol (TAG)/fatty acid (FA) cycling in WAT through impacting lipogenesis and lipolysis. Adipocyte lipolytic products were altered by 5-PAHSA through selective FA re-esterification. The impaired lipolysis in global adipose triglyceride lipase (ATGL) knockout mice reduced free PAHSA levels and uncovered a metabolite reservoir of TAG-bound PAHSAs (TAG estolides) in WAT. Utilization of C isotope tracers and dynamic metabolomics documented that 5-PAHSA primes adipocytes for glucose metabolism in a different way from insulin, promoting DNL and impeding TAG synthesis. In summary, our data reveal new cellular and physiological mechanisms underlying the beneficial effects of 5-PAHSA and its relation to insulin action in adipocytes and independently confirm a PAHSA metabolite reservoir linked to ATGL-mediated lipolysis.
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http://dx.doi.org/10.2337/db19-0494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118252PMC
March 2020

Regulation of lipophagy in NAFLD by cellular metabolism and CD36.

J Lipid Res 2019 04 28;60(4):755-757. Epub 2019 Feb 28.

Center for Human Nutrition, Washington University School of Medicine, Saint Louis, MO 63108.

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http://dx.doi.org/10.1194/jlr.C093674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446712PMC
April 2019

Fatty acid 2-hydroxylation inhibits tumor growth and increases sensitivity to cisplatin in gastric cancer.

EBioMedicine 2019 Mar 7;41:256-267. Epub 2019 Feb 7.

Department of Biochemistry and Molecular Biology, Soochow University Medical College, Suzhou 215123, China; Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO 63110, United States. Electronic address:

Background: Most gastric cancers are diagnosed at an advanced or metastatic stage with poor prognosis and survival rate. Fatty acid 2-hydroxylase (FA2H) with high expression in stomach generates chiral (R)-2-hydroxy FAs ((R)-2-OHFAs) and regulates glucose utilization which is important for cell proliferation and invasiveness. We hypothesized that FA2H impacts gastric tumor growth and could represent a novel target to improve gastric cancer therapy.

Methods: FA2H level in 117 human gastric tumors and its association with tumor growth, metastasis and overall survival were examined. Its roles and potential mechanisms in regulating tumor growth were studied by genetic and pharmacological manipulation of gastric cancer cells in vitro and in vivo.

Findings: FA2H level was lower in gastric tumor tissues as compared to surrounding tissues and associated with clinicopathologic status of patients, which were confirmed by analyses of multiple published datasets. FA2H depletion decreased tumor chemosensitivity, partially due to inhibition of AMPK and activation of the mTOR/S6K1/Gli1 pathway. Conversely, FA2H overexpression or treatment with (R)-2-OHFAs had the opposite effects. In line with these in vitro observations, FA2H knockdown promoted tumor growth with increased level of tumor Gli1 in vivo. Moreover, (R)-2-OHFA treatment significantly decreased Gli1 level in gastric tumors and enhanced tumor chemosensitivity to cisplatin, while alleviating the chemotherapy-induced weight loss in mice.

Interpretation: Our results demonstrate that FA2H plays an important role in regulating Hh signaling and gastric tumor growth and suggest that (R)-2-OHFAs could be effective as nontoxic wide-spectrum drugs to promote chemosensitivity. FUND: Grants of NSF, NIH, and PAPD.
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http://dx.doi.org/10.1016/j.ebiom.2019.01.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441949PMC
March 2019

Endothelial cell CD36 optimizes tissue fatty acid uptake.

J Clin Invest 2018 10 26;128(10):4329-4342. Epub 2018 Jul 26.

Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York, New York, USA.

Movement of circulating fatty acids (FAs) to parenchymal cells requires their transfer across the endothelial cell (EC) barrier. The multiligand receptor cluster of differentiation 36 (CD36) facilitates tissue FA uptake and is expressed in ECs and parenchymal cells such as myocytes and adipocytes. Whether tissue uptake of FAs is dependent on EC or parenchymal cell CD36, or both, is unknown. Using a cell-specific deletion approach, we show that EC, but not parenchymal cell, CD36 deletion increased fasting plasma FAs and postprandial triglycerides. EC-Cd36-KO mice had reduced uptake of radiolabeled long-chain FAs into heart, skeletal muscle, and brown adipose tissue; these uptake studies were replicated using [11C]palmitate PET scans. High-fat diet-fed EC-CD36-deficient mice had improved glucose tolerance and insulin sensitivity. Both EC and cardiomyocyte (CM) deletion of CD36 reduced heart lipid droplet accumulation after fasting, but CM deletion did not affect heart glucose or FA uptake. Expression in the heart of several genes modulating glucose metabolism and insulin action increased with EC-CD36 deletion but decreased with CM deletion. In conclusion, EC CD36 acts as a gatekeeper for parenchymal cell FA uptake, with important downstream effects on glucose utilization and insulin action.
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http://dx.doi.org/10.1172/JCI99315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159965PMC
October 2018

Deciphering the Role of Lipid Droplets in Cardiovascular Disease: A Report From the 2017 National Heart, Lung, and Blood Institute Workshop.

Circulation 2018 07;138(3):305-315

National Institutes of Health/National, Heart, Lung, and Blood Institute, Bethesda, MD (Z.S.G., M.O., L.S.-L., J.C.).

Lipid droplets (LDs) are distinct and dynamic organelles that affect the health of cells and organs. Much progress has been made in understanding how these structures are formed, how they interact with other cellular organelles, how they are used for storage of triacylglycerol in adipose tissue, and how they regulate lipolysis. Our understanding of the biology of LDs in the heart and vascular tissue is relatively primitive in comparison with LDs in adipose tissue and liver. The National Heart, Lung, and Blood Institute convened a working group to discuss how LDs affect cardiovascular diseases. The goal of the working group was to examine the current state of knowledge on the cell biology of LDs, including current methods to study them in cells and organs and reflect on how LDs influence the development and progression of cardiovascular diseases. This review summarizes the working group discussion and recommendations on research areas ripe for future investigation that will likely improve our understanding of atherosclerosis and heart function.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.033704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056021PMC
July 2018

Transfer of Cell-Surface Antigens by Scavenger Receptor CD36 Promotes Thymic Regulatory T Cell Receptor Repertoire Development and Allo-tolerance.

Immunity 2018 05 8;48(5):923-936.e4. Epub 2018 May 8.

Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

The development of T cell tolerance in the thymus requires the presentation of host proteins by multiple antigen-presenting cell (APC) types. However, the importance of transferring host antigens from transcription factor AIRE-dependent medullary thymic epithelial cells (mTECs) to bone marrow (BM) APCs is unknown. We report that antigen was primarily transferred from mTECs to CD8α dendritic cells (DCs) and showed that CD36, a scavenger receptor selectively expressed on CD8α DCs, mediated the transfer of cell-surface, but not cytoplasmic, antigens. The absence of CD8α DCs or CD36 altered thymic T cell selection, as evidenced by TCR repertoire analysis and the loss of allo-tolerance in murine allogeneic BM transplantation (allo-BMT) studies. Decreases in these DCs and CD36 expression in peripheral blood of human allo-BMT patients correlated with graft-versus-host disease. Our findings suggest that CD36 facilitates transfer of mTEC-derived cell-surface antigen on CD8α DCs to promote tolerance to host antigens during homeostasis and allo-BMT.
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http://dx.doi.org/10.1016/j.immuni.2018.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986080PMC
May 2018

Regulation of Insulin Receptor Pathway and Glucose Metabolism by CD36 Signaling.

Diabetes 2018 07 10;67(7):1272-1284. Epub 2018 May 10.

Departments of Medicine and Cell Biology, Washington University in St. Louis, St. Louis, MO

During reduced energy intake, skeletal muscle maintains homeostasis by rapidly suppressing insulin-stimulated glucose utilization. Loss of this adaptation is observed with deficiency of the fatty acid transporter CD36. A similar loss is also characteristic of the insulin-resistant state where CD36 is dysfunctional. To elucidate what links CD36 to muscle glucose utilization, we examined whether CD36 signaling might influence insulin action. First, we show that CD36 deletion specific to skeletal muscle reduces expression of insulin signaling and glucose metabolism genes. It decreases muscle ceramides but impairs glucose disposal during a meal. Second, depletion of CD36 suppresses insulin signaling in primary-derived human myotubes, and the mechanism is shown to involve functional CD36 interaction with the insulin receptor (IR). CD36 promotes tyrosine phosphorylation of IR by the Fyn kinase and enhances IR recruitment of P85 and downstream signaling. Third, pretreatment for 15 min with saturated fatty acids suppresses CD36-Fyn enhancement of IR phosphorylation, whereas unsaturated fatty acids are neutral or stimulatory. These findings define mechanisms important for muscle glucose metabolism and optimal insulin responsiveness. Potential human relevance is suggested by genome-wide analysis and RNA sequencing data that associate genetically determined low muscle CD36 expression to incidence of type 2 diabetes.
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http://dx.doi.org/10.2337/db17-1226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014550PMC
July 2018

Intestinal CD36 and Other Key Proteins of Lipid Utilization: Role in Absorption and Gut Homeostasis.

Compr Physiol 2018 03 26;8(2):493-507. Epub 2018 Mar 26.

Department of Internal Medicine, Center for Human Nutrition, Washington University School of Medicine, St Louis, Missouri, USA.

Several proteins have been implicated in fatty acid (FA) transport by enterocytes including the scavenger receptor CD36 (SR-B2), the scavenger receptor B1 (SR-B1) a member of the CD36 family and the FA transport protein 4 (FATP4). Here, we review the regulation of enterocyte FA uptake and its function in lipid absorption including prechylomicron formation, assembly and transport. Emphasis is given to CD36, which is abundantly expressed along the digestive tract of rodents and humans and has been the most studied. We also address the pleiotropic functions of CD36 that go beyond lipid absorption and metabolism to include recent evidence of its impact on intestinal homeostasis and barrier maintenance. Areas of progress involving contribution of membrane phospholipid remodeling and of cytosolic FA-binding proteins, FABP1 and FABP2 to fat absorption will be covered. © 2018 American Physiological Society. Compr Physiol 8:493-507, 2018.
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http://dx.doi.org/10.1002/cphy.c170026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247794PMC
March 2018

CD36 Modulates Fasting and Preabsorptive Hormone and Bile Acid Levels.

J Clin Endocrinol Metab 2018 05;103(5):1856-1866

Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.

Context: Abnormal fatty acid (FA) metabolism contributes to diabetes and cardiovascular disease. The FA receptor CD36 has been linked to risk of metabolic syndrome. In rodents CD36 regulates various aspects of fat metabolism, but whether it has similar actions in humans is unknown. We examined the impact of a coding single-nucleotide polymorphism in CD36 on postprandial hormone and bile acid (BA) responses.

Objective: To examine whether the minor allele (G) of coding CD36 variant rs3211938 (G/T), which reduces CD36 level by ∼50%, influences hormonal responses to a high-fat meal (HFM).

Design: Obese African American (AA) women carriers of the G allele of rs3211938 (G/T) and weight-matched noncarriers (T/T) were studied before and after a HFM.

Setting: Two-center study.

Participants: Obese AA women.

Intervention: HFM.

Main Outcome Measures: Early preabsorptive responses (10 minutes) and extended excursions in plasma hormones [C-peptide, insulin, incretins, ghrelin fibroblast growth factor (FGF)19, FGF21], BAs, and serum lipoproteins (chylomicrons, very-low-density lipoprotein) were determined.

Results: At fasting, G-allele carriers had significantly reduced cholesterol and glycodeoxycholic acid and consistent but nonsignificant reductions of serum lipoproteins. Levels of GLP-1 and pancreatic polypeptide (PP) were reduced 60% to 70% and those of total BAs were 1.8-fold higher. After the meal, G-allele carriers displayed attenuated early (-10 to 10 minute) responses in insulin, C-peptide, GLP-1, gastric inhibitory peptide, and PP. BAs exhibited divergent trends in G allele carriers vs noncarriers concomitant with differential FGF19 responses.

Conclusions: CD36 plays an important role in the preabsorptive hormone and BA responses that coordinate brain and gut regulation of energy metabolism.
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http://dx.doi.org/10.1210/jc.2017-01982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446573PMC
May 2018

Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis.

Oncogene 2018 04 5;37(17):2285-2301. Epub 2018 Feb 5.

Departments of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, IL, USA.

Ovarian cancer (OvCa) is characterized by widespread and rapid metastasis in the peritoneal cavity. Visceral adipocytes promote this process by providing fatty acids (FAs) for tumour growth. However, the exact mechanism of FA transfer from adipocytes to cancer cells remains unknown. This study shows that OvCa cells co-cultured with primary human omental adipocytes express high levels of the FA receptor, CD36, in the plasma membrane, thereby facilitating exogenous FA uptake. Depriving OvCa cells of adipocyte-derived FAs using CD36 inhibitors and short hairpin RNA knockdown prevented development of the adipocyte-induced malignant phenotype. Specifically, inhibition of CD36 attenuated adipocyte-induced cholesterol and lipid droplet accumulation and reduced intracellular reactive oxygen species (ROS) content. Metabolic analysis suggested that CD36 plays an essential role in the bioenergetic adaptation of OvCa cells in the adipocyte-rich microenvironment and governs their metabolic plasticity. Furthermore, the absence of CD36 affected cellular processes that play a causal role in peritoneal dissemination, including adhesion, invasion, migration and anchorage independent growth. Intraperitoneal injection of CD36-deficient cells or treatment with an anti-CD36 monoclonal antibody reduced tumour burden in mouse xenografts. Moreover, a matched cohort of primary and metastatic human ovarian tumours showed upregulation of CD36 in the metastatic tissues, a finding confirmed in three public gene expression data sets. These results suggest that omental adipocytes reprogram tumour metabolism through the upregulation of CD36 in OvCa cells. Targeting the stromal-tumour metabolic interface via CD36 inhibition may prove to be an effective treatment strategy against OvCa metastasis.
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http://dx.doi.org/10.1038/s41388-017-0093-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920730PMC
April 2018

The Liver as a Hub in Thermogenesis.

Authors:
Nada A Abumrad

Cell Metab 2017 09;26(3):454-455

Medicine and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Manipulating thermogenesis could increase energy expenditure and improve metabolism. Brown fat is a major site of nonshivering thermogenesis, but other tissues, notably muscle and liver, can contribute to cold adaptation. In this issue, Simcox et al. (2017) demonstrate in cold-exposed mice that liver-generated acylcarnitines are required to fuel thermogenesis.
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http://dx.doi.org/10.1016/j.cmet.2017.08.018DOI Listing
September 2017

knockout mice are protected against lithogenic diet-induced gallstones.

J Lipid Res 2017 08 20;58(8):1692-1701. Epub 2017 Jun 20.

Gastroenterology Division, Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO. Electronic address:

The scavenger receptor and multiligand transporter CD36 functions to promote cellular free fatty acid uptake and regulates aspects of both hepatic and intestinal cholesterol metabolism. However, the role of CD36 in regulating canalicular and biliary cholesterol transport and secretion is unknown. Here, we show that germline knockout (KO) mice are protected against lithogenic diet (LD)-induced gallstones compared with congenic (C57BL6/J) controls. KO mice crossed into congenic KO mice (DKO mice) demonstrated protection against LD-induced gallstones, reversing the susceptibility phenotype observed in KO mice. DKO mice demonstrated reduced biliary cholesterol secretion and a shift into more hydrophophilic bile acid species, without changes in either BA pool size or fecal excretion. In addition, we found that the mean and maximum force of gallbladder contraction was increased in germline KO mice, and gallbladder lipid content was reduced compared with wild-type controls. Finally, whereas germline KO mice were protected against LD-induced gallstones, neither liver- nor intestine-specific KO mice were protected. Taken together, our findings show that CD36 plays an important role in modifying gallstone susceptibility in mice, at least in part by altering biliary lipid composition, but also by promoting gallbladder contractility.
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http://dx.doi.org/10.1194/jlr.M077479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538290PMC
August 2017

Variant in a common odorant-binding protein gene is associated with bitter sensitivity in people.

Behav Brain Res 2017 06 6;329:200-204. Epub 2017 May 6.

University of Illinois at Urbana Champaign, Urbana, IL, 61801, USA. Electronic address:

Deeper understanding of signaling mechanisms underlying bitterness perception in people is essential for designing novel and effective bitter blockers, which could enhance nutrition and compliance with orally administered bitter-tasting drugs. Here we show that variability in a human odorant-binding protein gene, OBPIIa, associates with individual differences in bitterness perception of fat (oleic acid) and of a prototypical bitter stimulus, 6-n-propylthiouracil (PROP), suggesting a novel olfactory role in the modulation of bitterness sensitivity.
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http://dx.doi.org/10.1016/j.bbr.2017.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534261PMC
June 2017

Kidney triglyceride accumulation in the fasted mouse is dependent upon serum free fatty acids.

J Lipid Res 2017 06 12;58(6):1132-1142. Epub 2017 Apr 12.

Division of Endocrinology, Diabetes, and Metabolism, New York University School of Medicine, New York, NY

Lipid accumulation is a pathological feature of every type of kidney injury. Despite this striking histological feature, physiological accumulation of lipids in the kidney is poorly understood. We studied whether the accumulation of lipids in the fasted kidney are derived from lipoproteins or NEFAs. With overnight fasting, kidneys accumulated triglyceride, but had reduced levels of ceramide and glycosphingolipid species. Fasting led to a nearly 5-fold increase in kidney uptake of plasma [C]oleic acid. Increasing circulating NEFAs using a β adrenergic receptor agonist caused a 15-fold greater accumulation of lipid in the kidney, while mice with reduced NEFAs due to adipose tissue deficiency of adipose triglyceride lipase had reduced triglycerides. Cluster of differentiation () mRNA increased 2-fold, and angiopoietin-like 4 (), an LPL inhibitor, increased 10-fold. Fasting-induced kidney lipid accumulation was not affected by inhibition of LPL with poloxamer 407 or by use of mice with induced genetic LPL deletion. Despite the increase in CD36 expression with fasting, genetic loss of CD36 did not alter fatty acid uptake or triglyceride accumulation. Our data demonstrate that fasting-induced triglyceride accumulation in the kidney correlates with the plasma concentrations of NEFAs, but is not due to uptake of lipoprotein lipids and does not involve the fatty acid transporter, CD36.
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http://dx.doi.org/10.1194/jlr.M074427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454509PMC
June 2017

Pleiotropic physiological roles of PPARs and fatty acids: A tribute to Paul Grimaldi.

Biochimie 2017 May;136:1-2

Institut National de la Santé et de la Recherche Médicale UMR-S 1124, Université Paris Descartes, Faculté des Sciences Fondamentales et Biomédicales, Pharmacologie Toxicologie et Signalisation Cellulaire, 45 rue des Saints Pères, 75006 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.biochi.2017.03.016DOI Listing
May 2017

HIV infection does not prevent the metabolic benefits of diet-induced weight loss in women with obesity.

Obesity (Silver Spring) 2017 04 28;25(4):682-688. Epub 2017 Feb 28.

Center for Human Nutrition, Washington University School of Medicine, St Louis, Missouri, USA.

Objective: To test the hypothesis that HIV infection impairs the beneficial effects of weight loss on insulin sensitivity, adipose tissue inflammation, and endoplasmic reticulum (ER) stress.

Methods: A prospective clinical trial evaluated the effects of moderate diet-induced weight loss on body composition, metabolic function, and adipose tissue biology in women with obesity who were HIV-seronegative (HIV-) or HIV-positive (HIV+). Body composition, multiorgan insulin sensitivity (assessed by using a two-stage hyperinsulinemic-euglycemic clamp procedure with stable isotopically labeled tracer infusions), and adipose tissue expression of markers of inflammation, autophagy, and ER stress were evaluated in 8 HIV- and 20 HIV+ women with obesity before and after diet-induced weight loss of 6% to 8%.

Results: Although weight loss was not different between groups (∼7.5%), the decrease in fat-free mass was greater in HIV+ than HIV- subjects (-4.4 ± 0.7% vs. -1.7 ± 1.0%, P < 0.05). Weight loss improved insulin sensitivity in adipose tissue (suppression of palmitate rate of appearance [Ra]), liver (suppression of glucose Ra), and muscle (glucose disposal) similarly in both groups. Weight loss did not affect adipose tissue expression of markers of inflammation or ER stress in either group.

Conclusions: Moderate diet-induced weight loss improves multiorgan insulin sensitivity in HIV+ women to the same extent as women who are HIV-. However, weight loss causes a greater decline in fat-free mass in HIV+ than HIV- women.
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http://dx.doi.org/10.1002/oby.21793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373981PMC
April 2017

CD36 deficiency impairs the small intestinal barrier and induces subclinical inflammation in mice.

Cell Mol Gastroenterol Hepatol 2017 Jan;3(1):82-98

Department of Medicine, Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA.

Background & Aims: CD36 has immuno-metabolic actions and is abundant in the small intestine on epithelial, endothelial and immune cells. We examined the role of CD36 in gut homeostasis using mice null for CD36 (CD36KO) and with CD36 deletion specific to enterocytes (Ent-CD36KO) or endothelial cells (EC-CD36KO).

Methods: Intestinal morphology was evaluated using immunohistochemistry and electron microscopy (EM). Intestinal inflammation was determined from neutrophil infiltration and expression of cytokines, toll-like receptors and COX-2. Barrier integrity was assessed from circulating lipopolysaccharide (LPS) and dextran administered intragastrically. Epithelial permeability to luminal dextran was visualized using two photon microscopy.

Results: The small intestines of CD36KO mice fed a chow diet showed several abnormalities including extracellular matrix (ECM) accumulation with increased expression of ECM proteins, evidence of neutrophil infiltration, inflammation and compromised barrier function. EM showed shortened desmosomes with decreased desmocollin 2 expression. Systemically, leukocytosis and neutrophilia were present together with 80% reduction of anti-inflammatory Ly6C monocytes. Bone marrow transplants supported the primary contribution of non-hematopoietic cells to the inflammatory phenotype. Specific deletion of endothelial but not of enterocyte CD36 reproduced many of the gut phenotypes of germline CD36KO mice including fibronectin deposition, increased interleukin 6, neutrophil infiltration, desmosome shortening and impaired epithelial barrier function.

Conclusions: CD36 loss results in chronic neutrophil infiltration of the gut, impairs barrier integrity and systemically causes subclinical inflammation. Endothelial cell CD36 deletion reproduces the major intestinal phenotypes. The findings suggest an important role of the endothelium in etiology of gut inflammation and loss of epithelial barrier integrity.
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http://dx.doi.org/10.1016/j.jcmgh.2016.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217470PMC
January 2017

Higher chylomicron remnants and LDL particle numbers associate with CD36 SNPs and DNA methylation sites that reduce CD36.

J Lipid Res 2016 12 11;57(12):2176-2184. Epub 2016 Oct 11.

Department of Medicine, Center for Human Nutrition Washington University School of Medicine, St. Louis, MO 63110

Cluster of differentiation 36 (CD36) variants influence fasting lipids and risk of metabolic syndrome, but their impact on postprandial lipids, an independent risk factor for cardiovascular disease, is unclear. We determined the effects of SNPs within a ∼410 kb region encompassing CD36 and its proximal and distal promoters on chylomicron (CM) remnants and LDL particles at fasting and at 3.5 and 6 h following a high-fat meal (Genetics of Lipid Lowering Drugs and Diet Network study, n = 1,117). Five promoter variants associated with CMs, four with delayed TG clearance and five with LDL particle number. To assess mechanisms underlying the associations, we queried expression quantitative trait loci, DNA methylation, and ChIP-seq datasets for adipose and heart tissues that function in postprandial lipid clearance. Several SNPs that associated with higher serum lipids correlated with lower adipose and heart CD36 mRNA and aligned to active motifs for PPARγ, a major CD36 regulator. The SNPs also associated with DNA methylation sites that related to reduced CD36 mRNA and higher serum lipids, but mixed-model analyses indicated that the SNPs and methylation independently influence CD36 mRNA. The findings support contributions of CD36 SNPs that reduce adipose and heart CD36 RNA expression to inter-individual variability of postprandial lipid metabolism and document changes in CD36 DNA methylation that influence both CD36 expression and lipids.
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http://dx.doi.org/10.1194/jlr.P065250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321222PMC
December 2016

Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits.

Am J Hum Genet 2016 Jul 23;99(1):8-21. Epub 2016 Jun 23.

Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA 98195, USA.

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.
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http://dx.doi.org/10.1016/j.ajhg.2016.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005438PMC
July 2016
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