Platelet CD36 deficiency is present in 2.6% of Arabian individuals and can cause NAIT and platelet refractoriness

Abstract Background Acetaminophen (APAP) overdose causes hepatotoxicity and even acute liver failure. Recent studies indicate that sterile inflammation and innate immune cells may play important roles in damage-induced hepatocytes regeneration and liver repair. The scavenger receptor CD36 has its crucial functions in sterile inflammation. However, the roles of CD36 in APAP induced acute liver injury remain unclear and warrant further investigation. Methods WT C57BL/6 J and CD36−/− mice were intraperitoneally injected with APAP (300 mg/kg) after fasting for 16 h. Liver injury was evaluated by serum alanine aminotransferase (ALT) level and liver tissue hematoxylin and eosin (H&E) staining. Liver inflammatory factor expression was determined by real-time polymerase chain reaction (PCR). The protein adducts forming from the metabolite of APAP and the metabolism enzyme cytochrome P450 2E1 (CYP2E1) levels were measured by Western blot. Liver infiltrating macrophages and neutrophils were characterized by flow cytometry. RNA sequencing and Western blot were used to evaluate the effect of damage-associated molecular patterns (DAMP) molecule high mobility group B1 (HMGB1) on WT and CD36−/− macrophages. Moreover, PP2, a Src kinase inhibitor, blocking CD36 signaling, was applied in APAP model. Results The expression of CD36 was increased in the liver of mice after APAP treatment. Compared with WT mice, APAP treated CD36−/− mice show less liver injury. There was no significant difference in APAP protein adducts and CYP2E1 expression between these two strains. However, reduced pro-inflammatory factor mRNA expression and serum IL-1β level were observed in APAP treated CD36−/− mice as well as infiltrating macrophages and neutrophils. Moreover, CD36 deficiency impaired the activation of c-Jun N-terminal kinase (JNK) caused by APAP. Interestingly, the lack of CD36 reduced the activation of extracellular regulated protein kinases (Erk) and v-akt murine thymoma viral oncogene homolog (Akt) induced by HMGB1. RNA transcription sequencing data indicated that HMGB1 has a different effect on WT and CD36−/− macrophages. Furthermore, treatment with PP2 attenuated APAP induced mouse liver injury. Conclusion Our data demonstrated that CD36 deficiency ameliorated APAP-induced acute liver injury and inflammatory responses by decreasing JNK activation. CD36 might serve as a new target to reduce acute liver injury.

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Th-P15:82 Pitavastatin improved postprandial hypertriglyceridemia caused by the accelerated intestinal lipid absorption in CD36 deficiency

Atherosclerosis Supplements ◽

10.1016/s1567-5688(06)82042-8 ◽

2006 ◽

Vol 7 (3) ◽

pp. 510

Author(s):

D. Masuda ◽

K. Hirano ◽

Y. Tochino ◽

T. Kuwasako ◽

C. Ikegami ◽

...

Keyword(s):

Lipid Absorption ◽

Cd36 Deficiency ◽

Postprandial Hypertriglyceridemia

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Abstract 7: LPA/PKD-1-HDAC7-FoxO1 Signaling-mediated Endothelial CD36 Transcriptional Repression and Proarteriogenic Reprogramming

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.7 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Bin Ren ◽

Brad Best ◽

Devi Ramakrishnan ◽

Brian Walcott ◽

Peter Storz ◽

...

Keyword(s):

Endothelial Cells ◽

Transcriptional Repression ◽

Gene Array ◽

Branching Morphogenesis ◽

Gene Profiling ◽

Molecular Signature ◽

Cd36 Deficiency ◽

Angiogenesis Assay ◽

Thrombotic Diseases

Background: CD36 is a scavenger and antiangiogenic receptor that plays an important role in athero-thrombotic diseases, diabetes and cancer and contributes to obesity. Lysophosphatidic acid (LPA), a bioactive phospholipid signaling mediator, abolishes endothelial cell responses to antiangiogenic proteins containing thrombospondin type 1 homology domains by down-regulating endothelial CD36 transcription via protein kinase PKD-1 signaling. However, the precise mechanism as to how angiogenic signaling is integrated to regulate endothelial specific CD36 transcription remain unknown. Hypothesis: LPA represses CD36 transcription through PKD-1-mediated formation of a nuclear transcriptional complex in endothelial cells. Methods: Microvascular endothelial cells expressing CD36 were used for studying signaling and CD36 transcription by real time RT-qPCR, Western blotting, co-immunoprecipitation or avidin-biotin-conjugated DNA-binding assay; angiogenesis gene array was used for angiogenic gene profiling in response to LPA exposure. Spheroid-based angiogenesis assay, in vivo Matrigel assay and tumor angiogenesis model in CD36 deficiency and wild type mice were established to elucidate mechanisms of angiogenic signaling. Results: CD36 transcriptional repression involved PKD-1 signaling mediated formation of FoxO1-HDAC7 complex in the nucleus of endothelial cells. Unexpectedly, turning off CD36 transcription initiated reprogramming MVECs to express ephrin B2, a critical “molecular signature” involved in angiogenesis and arteriogenesis, and increased phosphorylation of Erk1/2, the MAP kinase important in arterial differentiation. PKD-1 signaling was also shown in tumor endothelium of Lewis lung carcinomas, along with low CD36 expression or CD36 deficiency. Angiogenic branching morphogenesis and in vivo angiogenesis were dependent on PKD-1 signaling. Conclusion: LPA/PKD1-HDAC7-FoxO1 signaling axis regulates endothelial CD36 transcription and mediates silencing of the antiangiogenic switch, resulting in proarteriogenic reprogramming. Targeting this signaling cascade could be a novel approach for cancer, diabetes, athero-thrombotic diseases and obesity.

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Abstract P132: Increased Cardiovascular Parasympathetic Tone in African Americans With CD36 Partial Deficiency

Hypertension ◽

10.1161/hyp.70.suppl_1.p132 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Shahram Ejtemaei Mehr

Keyword(s):

Heart Rate ◽

Fatty Acid ◽

African Americans ◽

Heart Function ◽

Taste Perception ◽

Acid Uptake ◽

High Fat ◽

Cd36 Deficiency ◽

Parasympathetic Tone ◽

Fat Meal

Cardiovascular disease is the leading cause of death among African Americans (AA). Reduced parasympathetic tone as measured by high frequency heart rate variability (HF RRI ) predicts cardiovascular mortality. HF RRI is reduced after a high fat meal through caveolar sequestration of muscarinic M2 receptors. The fatty acid translocase CD36 is a protein abundant in the myocardium and important for heart function and lipid metabolism. CD36 plasma membrane localization and function in fatty acid uptake is modulated by its interaction with caveolin. One in four AAs are G-allele carriers for CD36 SNP rs3211938 resulting in ~50% decreased CD36 expression. CD36 deficiency also reduces fat taste perception, which might lead to higher fat intake to reach taste saturation. We tested the hypothesis that obese AAs with partial CD36 deficiency have altered parasympathetic tone during fasting and after a high-fat meal. We recruited 13 G-allele carriers and 39 non-carriers. Subjects were matched by age (P=0.820), BMI (P=0.751), and blood pressure (P=0.701). There was a trend towards reduction in heart rate in carriers (P=0.07). Baseline HF RRI was elevated in G carriers (557.1 [251 to 942] vs. 224 [95 to 655] ms 2 , P=0.046). Eleven subjects received a high-fat meal (700 Cal/m 2 BSA, 80% fat). HF RRI was measured at baseline and 30, 60, 120, 240 minutes after meal. Non-carriers (n=4) showed a time-dependent decline in the percent change in HF RRI (-23, -32, -70, -84, respectively). In G-allele carriers (N=6), the decline in HF RRI (21, -11, -61, -70 min) was attenuated. Conclusion: AAs with partial CD36 deficiency have enhanced fasting parasympathetic tone and a blunted response to a high fat meal.

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CD36 mediates long-chain fatty acid transport in human myocardium: Complete myocardial accumulation defect of radiolabeled long-chain fatty acid analog in subjects with CD36 deficiency

Lipid Binding Proteins within Molecular and Cellular Biochemistry ◽

10.1007/978-1-4615-4929-1_15 ◽

1999 ◽

pp. 129-135

Author(s):

Shuichi Nozaki ◽

Takao Tanaka ◽

Shizuya Yamashita ◽

Koichi Sohmiya ◽

Tohru Yoshizumi ◽

...

Keyword(s):

Fatty Acid ◽

Chain Fatty Acid ◽

Human Myocardium ◽

Fatty Acid Transport ◽

Acid Transport ◽

Long Chain Fatty Acid ◽

Cd36 Deficiency ◽

Acid Analog ◽

Long Chain

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CD36 Deficiency Rescues Lipotoxic Cardiomyopathy

Circulation Research ◽

10.1161/01.res.0000264104.25265.b6 ◽

2007 ◽

Vol 100 (8) ◽

pp. 1208-1217 ◽

Cited By ~ 168

Author(s):

John Yang ◽

Nandakumar Sambandam ◽

Xianlin Han ◽

Richard W. Gross ◽

Michael Courtois ◽

...

Keyword(s):

Cd36 Deficiency ◽

Lipotoxic Cardiomyopathy

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Identification of molecular defects in a subject with type I CD36 deficiency

Blood ◽

10.1182/blood.v83.12.3545.3545 ◽

1994 ◽

Vol 83 (12) ◽

pp. 3545-3552 ◽

Cited By ~ 41

Author(s):

H Kashiwagi ◽

Y Tomiyama ◽

S Kosugi ◽

M Shiraga ◽

RH Lipsky ◽

...

Keyword(s):

Genomic Dna ◽

Stop Codon ◽

Type I ◽

Molecular Defects ◽

Cdna Sequences ◽

Cd36 Deficiency ◽

Translation Stop Codon ◽

Polymerase Chain ◽

Exon 4 ◽

Splice Junctions

Abstract We performed a molecular analysis of a subject whose platelets and monocytes did not express any cell surface CD36 (designated as a type I CD36 deficiency). Amplification of the 5′ half of platelet and monocyte CD36cDNA (corresponding to nucleotide [nt] 191–1009 of the published CD36 cDNA sequence [Oquendo et al, Cell, 58:95, 1989]) showed that two different-sized CD36 cDNAs existed. One cDNA was of predicted normal size, whereas the other was about 150 bp smaller than that predicted for normal CD36 cDNA. Amplification of the 3′ region of CD36 cDNA (nt 962–1714) in this subject showed only normal-sized CD36 cDNA. Cloning and nt sequence analysis of the cDNAs showed that the smaller sized CD36 cDNA had 161-bp deletion (from nt 331 to 491), and a dinucleotide deletion starting at nt position 539. The same dinucleotide deletion was also detected in the normal sized CD36 cDNA. Both deletions caused a frameshift leading to the appearance of a translation stop codon. RNA blot analysis and quantitative assay using the reverse transcription- polymerase chain reaction (RT-PCR) showed that the CD36 transcripts in both platelets and monocytes were greatly reduced. Comparison of the determined cDNA sequences with the genomic DNA sequence for the human CD36 gene showed that the dinucleotide deletion was located in exon 5, and that the 161-bp deletion corresponded to a loss of exon 4. PCR- based analysis using genomic DNA showed that this subject was homozygous for the dinucleotide deletion in exon 5. Except for the dinucleotide deletion, we could not find any abnormalities around exon 3, 4, and 5 including the splice junctions. These results suggested that the deletions in CD36 mRNA were likely to be responsible for instability of the transcripts, and the dinucleotide deletion in exon 5 might affect the splicing of exon 4.

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