A Common CD36 Variant Influences Endothelial Function and Response to Treatment with Phosphodiesterase 5 Inhibition

Shibao, Cyndya A.; Celedonio, Jorge E; Ramirez, Claudia E.; Arnold, Amy C.; Choi, Leena; Okamoto, Luis E.; Gamboa, Alfredo; Biaggioni, Italo; Abumrad, Naji N.; Abumrad, Nada A.

doi:10.1210/jc.2016-1294

Cited by 21 publications

(22 citation statements)

References 41 publications

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“…CD36 deficiency has a relatively high frequency in populations of African and Asian ancestry, and single nucleotide polymorphisms that reduce CD36 level are relatively common 58 . Carriers of the minor allele (G) of coding single nucleotide polymorphism rs3211938 (∼20% of African Americans) have ∼50% reduction of CD36 expression, and this associates with increased endothelial stiffness and with an altered nitric oxide–cyclic guanosine monophosphate pathway 59 . Our preliminary data show increased blood levels of activated neutrophils in these subjects, suggesting presence of subclinical inflammation (data not shown).…”

Section: Discussionmentioning

confidence: 99%

CD36 Deficiency Impairs the Small Intestinal Barrier and Induces Subclinical Inflammation in Mice

Cifarelli

Ivanov

Son

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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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 Ly6Clow 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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Section: Discussionmentioning

confidence: 99%

CD36 Deficiency Impairs the Small Intestinal Barrier and Induces Subclinical Inflammation in Mice

Cifarelli

Ivanov

Son

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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“…The participants were divided in two groups based on the CD36 rs3211938 genotype. Individuals homozygous for the major allele (T/T) have normal CD36 expression while those carrying the minor allele G (G/T) have ~50% reduced CD36 expression in monocytes and platelets (18,41,42). No subjects were homozygous (G/G) in the cohort studied.…”

Section: Resultsmentioning

confidence: 99%

“…Genomic DNA was extracted from peripheral blood with a salting-out precipitation (Gentra Puregene) and CD36 SNP rs3211938 was detected using a pre-designed TaqMan SNP Genotyping Assay (Applied Biosystems) on a 7900HT instrument. Presence of the G allele reduces CD36 expression by 50% as previously determined by western blot analysis of monocyte and platelet CD36 protein using anti-CD36 antibody (FA6–152, Abcam) with human b-actin antibody (SC47778, Santa Cruz) bound by goat antimouse IgG (Li-COR Biosciences) as loading control (18,41,42).…”

Section: Methodsmentioning

confidence: 92%

“…The SNP inserts a stop codon and results in a truncated protein that is degraded. Partial (~50%) CD36 protein deficiency is observed in subjects carrying the G allele (G/T) of rs3211938 (41,42) and complete CD36 deficiency is observed in subjects homozygous for the G allele (G/G) (18). Recruited study participants at Vanderbilt University had African ancestry based on 4 grandparents.…”

Section: Methodsmentioning

confidence: 99%

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CD36 Modulates Fasting and Preabsorptive Hormone and Bile Acid Levels

Shibao

Celedonio

Tamboli

et al. 2018

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…Asian individuals with CD36 deficiency have abnormalities of fasting and postprandial plasma lipid levels (44,81,105,172). In African Americans, SNPs in the CD36 gene associate with higher plasma FA (137) and altered TAG and cholesterol (92) and many influence metabolic syndrome risk (38,93). In Caucasians, common polymorphisms (40%−50% incidence) associate with high plasma FA and increased risk of diabetes-linked cardiovascular disease (95).…”

Section: Chylomicron Formationmentioning

confidence: 99%

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

Cifarelli

Abumrad

2018

Comprehensive Physiology

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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.

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A Common CD36 Variant Influences Endothelial Function and Response to Treatment with Phosphodiesterase 5 Inhibition

Abstract: The data document influence of a common genetic variant on susceptibility to endothelial dysfunction and its response to sildenafil treatment.

Cited by 21 publications

References 41 publications

CD36 Deficiency Impairs the Small Intestinal Barrier and Induces Subclinical Inflammation in Mice

CD36 Deficiency Impairs the Small Intestinal Barrier and Induces Subclinical Inflammation in Mice

CD36 Modulates Fasting and Preabsorptive Hormone and Bile Acid Levels

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

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