Glucose-Dependent Insulinotropic Polypeptide Suppresses Foam Cell Formation of Macrophages through Inhibition of the Cyclin-Dependent Kinase 5-CD36 Pathway

Glucose-dependent insulinotropic polypeptide (GIP) has been reported to have an atheroprotective property in animal models. However, the effect of GIP on macrophage foam cell formation, a crucial step of atherosclerosis, remains largely unknown. We investigated the effects of GIP on foam cell formation of, and CD36 expression in, macrophages extracted from GIP receptor-deficient (Gipr−/−) and Gipr+/+ mice and cultured human U937 macrophages by using an agonist for GIP receptor, [D-Ala2]GIP(1–42). Foam cell formation evaluated by esterification of free cholesterol to cholesteryl ester and CD36 gene expression in macrophages isolated from Gipr+/+ mice infused subcutaneously with [D-Ala2]GIP(1–42) were significantly suppressed compared with vehicle-treated mice, while these beneficial effects were not observed in macrophages isolated from Gipr−/− mice infused with [D-Ala2]GIP(1–42). When macrophages were isolated from Gipr+/+ and Gipr−/− mice, and then exposed to [D-Ala2]GIP(1–42), similar results were obtained. [D-Ala2]GIP(1–42) attenuated ox-LDL uptake of, and CD36 gene expression in, human U937 macrophages as well. Gene expression level of cyclin-dependent kinase 5 (Cdk5) was also suppressed by [D-Ala2]GIP(1–42) in U937 cells, which was corelated with that of CD36. A selective inhibitor of Cdk5, (R)-DRF053 mimicked the effects of [D-Ala2]GIP(1–42) in U937 cells. The present study suggests that GIP could inhibit foam cell formation of macrophages by suppressing the Cdk5-CD36 pathway via GIP receptor.

AGE-RAGE Axis Stimulates Oxidized LDL Uptake into Macrophages through Cyclin-Dependent Kinase 5-CD36 Pathway via Oxidative Stress Generation

Advanced glycation end products (AGEs) are localized in macrophage-derived foam cells within atherosclerotic lesions, which could be associated with the increased risk of atherosclerotic cardiovascular disease under diabetic conditions. Although foam cell formation of macrophages has been shown to be enhanced by AGEs, the underlying molecular mechanism remains unclear. Since cyclin-dependent kinase 5 (Cdk5) is reported to modulate inflammatory responses in macrophages, we investigated whether Cdk5 could be involved in AGE-induced CD36 gene expression and foam cell formation of macrophages. AGEs significantly increased Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and Cdk5 and CD36 gene expression in U937 human macrophages, all of which were inhibited by DNA aptamer raised against RAGE (RAGE-aptamer). Cdk5 and CD36 gene expression levels were correlated with each other. An antioxidant, N-acetyl-l-cysteine, mimicked the effects of RAGE-aptamer on AGE-exposed U937 cells. A selective inhibitor of Cdk5, (R)-DRF053, attenuated the AGE-induced Dil-ox-LDL uptake and CD36 gene expression, whereas anti-CD36 antibody inhibited the Dil-ox-LDL uptake but not Cdk5 gene expression. The present study suggests that AGEs may stimulate ox-LDL uptake into macrophages through the Cdk5–CD36 pathway via RAGE-mediated oxidative stress.

The Impact of Ag Nanoparticles and CdTe Quantum Dots on Expression and Function of Receptors Involved in Amyloid-β Uptake by BV-2 Microglial Cells

Microglial cells clear the brain of pathogens and harmful debris, including amyloid-β (Aβ) deposits that are formed during Alzheimer’s disease (AD). We studied the expression of Msr1, Ager and Cd36 receptors involved in Aβ uptake and expression of Cd33 protein, which is considered a risk factor in AD. The effect of silver nanoparticles (AgNP) and cadmium telluride quantum dots (CdTeQD) on the expression of the above receptors and Aβ uptake by microglial cells was investigated. Absorption of Aβ and NP was confirmed by confocal microscopy. AgNP, but not CdTeQD, caused a decrease in Aβ accumulation. By using a specific inhibitor—polyinosinic acid—we demonstrated that Aβ and AgNP compete for scavenger receptors. Real-time PCR showed up-regulation of Cd33 and Cd36 gene expression after treatment with CdTeQD for 24 h. Analysis of the abundance of the receptors on the cell surface revealed that AgNP treatment significantly reduced the presence of Msr1, Cd33, Ager and Cd36 receptors (6 and 24 h), whereas CdTeQD increased the levels of Msr1 and Cd36 (24 h). To summarize, we showed that AgNP uptake competes with Aβ uptake by microglial cells and consequently can impair the removal of the aggregates. In turn, CdTeQD treatment led to the accumulation of proinflammatory Cd36 protein on the cell surface.

Transcriptome and metabolome analysis of crGART, a novel cell model of de novo purine synthesis deficiency: Alterations in CD36 expression and activity

ABSTRACTIn humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). 5-PRA is extremely unstable under physiological conditions and is unlikely to accumulate in the absence of GART activity. Recently, a HeLa cell line null mutant for GART was constructed via CRISPR-Cas9 mutagenesis. This cell line, crGART, is an important cellular model of DNPS inactivation that does not accumulate DNPS pathway intermediates. In the current study, we characterized the crGART versus HeLa transcriptomes in purine-supplemented and purine-depleted growth conditions. We observed multiple transcriptome changes and discuss pathways and ontologies particularly relevant to Alzheimer disease and Down syndrome. We also report initial analysis of the Cluster of Differentiation (CD36) gene, which is highly expressed in crGART versus HeLa.

CD36 Polymorphism (rs1761667) Was Associated with Fatty Liver in a Japanese Population

Objectives Nonalcohol fatty liver disease (NAFLD) is one of the considerable health problems in the world. NAFLD is a representative phenotype in the liver reflecting individual's lifestyle. Previous studies suggested that a single nucleotide polymorphism (SNP) in the CD36 gene was associated with dietary fat intake and fat metabolism. Therefore, we hypothesized that this SNP may be associated with fatty liver (FL) and NAFLD. We conducted this cross-sectional study to examine the association between two CD36 polymorphisms (rs1761667 and rs1527483) and FL and NAFLD in a Japanese population. Methods A total of 525 local residents participated in the health check-up in Yakumo town, Hokkaido, Japan. This cross-sectional study was conducted based on clinical information collected in this health check-up. Among all participants, 57 people were excluded due to the inadequate informed consent, clinical history of liver disease. Genotyping of two polymorphisms in the CD36 gpgbrkkene was performed by using the PCR-CTPP method. Ultrasound examination was performed by four qualified ultrasonographers. In this present, NAFLD was defined as 1) presence of FL and 2) a daily alcohol consumption <10 g in women and <20 g in men. Multivariable regression analysis was performed after adjusting for age, sex, waist circumference, medicine for dyslipidemia. Results The mean age of participants was 63.4 (10.0). The minor allele frequency of rs1761667 and rs1527483 was 0.26 and 0.21, respectively. The presence of FL and NAFLD was 90 (19.2%) and 67 (14.3%), respectively. Multiple regression analyses showed a significant association between rs1761667 and presence of FL (P = 0.04), and FL grade (P = 0.03). However, rs1761667 was not significantly associated with NAFLD (P = 0.11). No significant associations were found between rs1527483 and FL and NAFLD. Conclusions A polymorphism (rs1761667) in the CD36 gene was associated with the presence of FL, but we did not find a significant association between this SNP and NAFLD. Funding Sources This study was supported by the Mishima Kaiun Memorial Foundation.

CD36 gene polymorphism -31118 G > A (rs1761667) is associated with overweight and obesity but not with fat preferences in Mexican children

CD36 glycoprotein is a candidate receptor involved in the gustatory detection of lipids and emerging evidence has suggested that genetic variations in CD36 may modulate the oral perception threshold to fatty acids. Here, we analyzed the association of -31118 G > A polymorphism in CD36 gene with nutritional status and preferences for fatty foods in Mexican children. Genotyping of SNP rs1761667 was performed in school-age children (n = 63) in addition to sensory tests evaluating the preference and satisfaction score assigned to oil-based sauces of different fatty acid composition. The G allele was associated with high BMI z-score in children (OR = 2.43, 95% (CI 1.02–5.99); p = 0.02) but CD36 genotypes (AA, GA, and GG) did not show significant association with the preference and satisfaction scores assigned to oil-based sauces. The BMI z-score showed no association with the preference to oil-based sauces; however, children with normal weight gave higher satisfaction scores to sauces with a high content of unsaturated fatty acids than to sauces rich in saturated fatty acids (0.56 ± 1.26 vs. 0.06 ± 1.22; p = 0.02). Therefore, the G allele of -31118 G > A SNP in CD36 gene is associated with overweight and obesity in Mexican children but do not appear to modulate the preferences and satisfaction scores to fat.