Search

Background: Genetic epidemiological evidence for the kidney function traits in East Asian populations, including Japanese, remain still relatively unclarified. Especially, the number of genome-wide association studies (GWASs) for kidney traits reported still remains limited, and the sample size of each independent study is relatively small. Given the genetic variability between ancestries/ethnicities, implementation of GWAS with sufficiently large sample sizes in specific population of Japanese is considered meaningful. Methods: We conducted the GWAS meta-analyses of kidney traits by leveraging the GWAS summary data of the representative large genome cohort studies with about 200,000 Japanese participants (n = 202,406 for estimated glomerular filtration rate [eGFR] and n = 200,845 for serum creatinine [SCr]). Results: In the present GWAS meta-analysis, we identified 110 loci with 169 variants significantly associated with eGFR (on chromosomes 1–13 and 15–22; P < 5 × 10−8), whereas we also identified 112 loci with 176 variants significantly associated with SCr (on chromosomes 1–22; P < 5 × 10−8), of which one locus (more than 1 Mb distant from known loci) with one variant (CD36 rs146148222 on chromosome 7) for SCr was considered as the truly novel finding. Conclusion: The present GWAS meta-analysis of the largest genome cohort studies in Japanese subjects provided some original genomic loci associated with kidney function, which may contribute to the possible development of personalized prevention of kidney diseases based on genomic information in the near future.

Previous studies have shown that variations in the CD36 gene may affect phenotypes associated with fat metabolism as the CD36 protein facilitates the transport of fatty acids to the mitochondria for oxidation. However, no previous study has tested whether variations in the CD36 gene are associated with sports performance. We investigated the genotypic and allelic distribution of the single-nucleotide polymorphism (SNP) rs1761667 in the CD36 gene in elite Moroccan athletes (cyclists and hockey players) in comparison with healthy non-athletes of the same ethnic origin. Forty-three Moroccan elite male athletes (nineteen cyclists and twenty-four field hockey players) belonging to the national teams of their respective sports (athlete group) were compared to twenty-eight healthy, active, male university students (control group). Genotyping of the CD36 rs1761667 (G>A) SNP was performed via polymerase chain reaction (PCR) and Sanger sequencing. A chi-square (χ2) test was used to assess the Hardy–Weinberg equilibrium (HWE) and to compare allele and genotype frequencies in the "athlete" and "control" groups. The genotypic distribution of the CD36 rs1761667 polymorphism was similar in elite athletes (AA: 23.81, AG: 59.52, and GG: 16.67%) and controls (AA: 19.23, AG: 69.23, and GG: 11.54%; χ2 = 0.67, p = 0.71). However, the genotypic distribution of the CD36 rs1761667 polymorphism was different between cyclists (AA: 0.00, AG: 72.22, and GG: 27.78%) and hockey players (AA: 41.67, AG: 50.00, and GG: 8.33%; χ2 = 10.69, p = 0.004). Specifically, the frequency of the AA genotype was significantly lower in cyclists than in hockey players (p = 0.02). In terms of allele frequency, a significant difference was found between cyclists versus field hockey players (χ2 = 7.72, p = 0.005). Additionally, there was a predominance of the recessive model in cyclists over field hockey players (OR: 0.00, 95% CI: 0.00–0.35, p = 0.002). Our study shows a significant difference between cyclists and field hockey players in terms of the genotypic and allelic frequency of the SNP rs1761667 of the CD36 gene. This divergence suggests a probable association between genetic variations in the CD36 gene and the type of sport in elite Moroccan athletes. [ABSTRACT FROM AUTHOR]

The pregnane X receptor (PXR) is a nuclear receptor that can be activated by numerous drugs and xenobiotic chemicals. PXR thereby functions as a xenobiotic sensor to coordinately regulate host responses to xenobiotics by transcriptionally regulating many genes involved in xenobiotic metabolism. We have previously reported that PXR has pro-atherogenic effects in animal models, but how PXR contributes to atherosclerosis development in different tissues or cell types remains elusive. In this study, we generated an LDL receptor-deficient mouse model with myeloid-specific PXR deficiency (PXRΔMyeLDLR-/-) to elucidate the role of macrophage PXR signaling in atherogenesis. The myeloid PXR deficiency did not affect metabolic phenotypes and plasma lipid profiles, but PXRΔMyeLDLR-/- mice had significantly decreased atherosclerosis at both aortic root and brachiocephalic arteries compared with control littermates. Interestingly, the PXR deletion did not affect macrophage adhesion and migration properties, but reduced lipid accumulation and foam cell formation in the macrophages. PXR deficiency also led to decreased expression of the scavenger receptor CD36 and impaired lipid uptake in macrophages of the PXRΔMyeLDLR-/- mice. Further, RNA-Seq analysis indicated that treatment with a prototypical PXR ligand affects the expression of many atherosclerosis-related genes in macrophages in vitro. These findings reveal a pivotal role of myeloid PXR signaling in atherosclerosis development and suggest that PXR may be a potential therapeutic target in atherosclerosis management.

Understanding how natural selection acts on the genome and contributes to the process of speciation is a primary aim of the study of evolution. Here we used natural variation in two subspecies of the Guadeloupean anole (Anolis marmoratus ssp.), from the island of Guadeloupe in the Lesser Antilles, to explore the genomic basis of adaptation and speciation in Anolis lizards. These subspecies inhabit distinct ecological environments and display marked differences in adult male color and pattern. We sequenced the complete genomes of 20 anoles, 10 from each subspecies, at 1.4× coverage. We used genome‐wide scans of population differentiation, allele frequency spectrum, and linkage disequilibrium to characterize the genomic architecture within and between the subspecies. While most of the genome was undifferentiated, we observed five large divergent regions. Within these regions we identified blocks, 5 kb pairs in length, enriched for fixed single nucleotide polymorphisms. These blocks encompass 97 genes, two of which are candidate pigmentation genes. One is melanophilin (mlph), which helps transport melanosomes within melanocytes. The other is a cluster of differentiation 36 (cd36), which regulates carotenoid pigment sequestration. We used high‐pressure liquid chromatography to confirm that carotenoid pigments are significantly more abundant in the conspicuous orange‐pigmented skin of male A. m. marmoratus suggesting that cd36 may be regulating pigment deposition in this tissue. We identified for the first time a carotenoid gene that is a potential target of divergent sexual selection and may be contributing to the early stages of speciation in Anolis lizards. [ABSTRACT FROM AUTHOR]

Abstract Background Aging‐associated frailty has been connected to low‐grade chronic inflammation and also to progressive monocytic activation. CD36 (cluster of differentiation 36, platelet glycoprotein 4 or fatty acid translocase) has been shown to induce the expression of pro‐inflammatory cytokines and to activate macrophage connected inflammation. This study aims to examine whether the expression of CD36 is up‐regulated among frail older adults. Methods The demographic data, Fried Frailty Index, metabolic and inflammatory parameters of our observational study were obtained from the comprehensive geriatric assessment programme of a hospital‐based outpatient department. The mRNA isolated from the peripheral blood mononuclear cells (PBMCs) was used to determine the levels of CD36, tumour necrosis factor alpha (TNF‐α), and CXC chemokine ligand‐10 (CXCL10) mRNAs with real‐time polymerase chain reaction (PCR). Results A total of 189 older adults (58% female) were included in the analysis, and the mean age was 77.19 ± 6.12 years. The numbers of participants who fitted in the groups of robust, pre‐frail, and frail were 46, 106, and 37, respectively. Our data showed that CD36 mRNA expression levels in PBMCs were the highest in the frail group (1.25 ± 0.53 in robust, 2.13 ± 1.02 in pre‐frail, and 2.78 ± 1.15 in frail group, P

Cluster of differentiation 36 (CD36) belongs to the B2 receptors of the scavenger receptor class B family, which is comprised of single-chain secondary transmembrane glycoproteins. It is present in a variety of cell types, including monocytes, macrophages, microvascular endothelial cells, adipocytes, hepatocytes, platelets, skeletal muscle cells, kidney cells, cardiomyocytes, taste bud cells, and a variety of other cell types. CD36 can be localized on the cell surface, mitochondria, endoplasmic reticulum, and endosomes, playing a role in lipid accumulation, oxidative stress injury, apoptosis, and inflammatory signaling. Recent studies have found that CD36 is expressed in a variety of ocular cells, including retinal pigment epithelium (RPE), retinal microvascular endothelial cells, retinal ganglion cells (RGC), Müller cells, and photoreceptor cells, playing an important role in eye diseases, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma. Therefore, a comprehensive understanding of CD36 function and downstream signaling pathways is of great significance for the prevention and treatment of eye diseases. This article reviews the molecular characteristics, distribution, and function of scavenger receptor CD36 and its role in ophthalmology in order to deepen the understanding of CD36 in eye diseases and provide new ideas for treatment strategies. [ABSTRACT FROM AUTHOR]

The pregnane X receptor (PXR) is a nuclear receptor that can be activated by numerous drugs and xenobiotic chemicals. PXR thereby functions as a xenobiotic sensor to coordinately regulate host responses to xenobiotics by transcriptionally regulating many genes involved in xenobiotic metabolism. We have previously reported that PXR has pro-atherogenic effects in animal models, but how PXR contributes to atherosclerosis development in different tissues or cell types remains elusive. In this study, we generated an LDL receptor-deficient mouse model with myeloid-specific PXR deficiency (PXRΔMyeLDLR−/−) to elucidate the role of macrophage PXR signaling in atherogenesis. The myeloid PXR deficiency did not affect metabolic phenotypes and plasma lipid profiles, but PXRΔMyeLDLR−/− mice had significantly decreased atherosclerosis at both aortic root and brachiocephalic arteries compared with control littermates. Interestingly, the PXR deletion did not affect macrophage adhesion and migration properties, but reduced lipid accumulation and foam cell formation in the macrophages. PXR deficiency also led to decreased expression of the scavenger receptor CD36 and impaired lipid uptake in macrophages of the PXRΔMyeLDLR−/− mice. Further, RNA-Seq analysis indicated that treatment with a prototypical PXR ligand affects the expression of many atherosclerosis-related genes in macrophages in vitro. These findings reveal a pivotal role of myeloid PXR signaling in atherosclerosis development and suggest that PXR may be a potential therapeutic target in atherosclerosis management.

Nonalcoholic fatty liver disease (NAFLD) can lead to hepatocellular carcinoma (HCC). The level of the transcription factor SOX2 correlates with HCC progression, but its role in fat accumulation remains unclear. Here, a high‐fat diet, with and without fructose, significantly upregulated SOX2 in murine liver tissue. Treatment with free fatty acids (FFAs) and fructose upregulated SOX2 in murine FL83B hepatocytes. SOX2 overexpression or knockdown regulated triglyceride synthesis and lipid accumulation after FFA stimulation. CD36, a fatty acid transporter, and Yes‐associated protein (YAP), a downstream molecule of the Hippo signaling pathway, were upregulated by FFA/fructose in vivo and in vitro. Transcriptional regulation of CD36 by SOX2 suggested the involvement of CD36 in SOX2‐mediated hepatic steatosis. Thus, SOX2 may be a target to prevent NAFLD development. [ABSTRACT FROM AUTHOR]

[Display omitted] Hepatic steatosis is a critical factor in the development of nonalcoholic steatohepatitis (NASH). Sesamin (Ses), a functional lignan isolated from Sesamum indicum , possesses hypolipidemic, liver-protective, anti-hypertensive, and anti-tumor properties. Ses has been found to improve hepatic steatosis, but the exact mechanisms through which Ses achieves this are not well understood. In this study, we observed the anti-hepatic steatosis effects of Ses in palmitate/oleate (PA/OA)-incubated primary mouse hepatocytes, AML12 hepatocytes, and HepG2 cells, as well as in high-fat, high-cholesterol diet-induced NASH mice. RNA sequencing analysis revealed that cluster of differentiation 36 (CD36), a free fatty acid (FA) transport protein, was involved in the Ses-mediated inhibition of hepatic fat accumulation. Moreover, the overexpression of CD36 significantly increased hepatic steatosis in both Ses-treated PA/OA-incubated HepG2 cells and NASH mice. Furthermore, Ses treatment suppressed insulin-induced de novo lipogenesis in HepG2 cells, which was reversed by CD36 overexpression. Mechanistically, we found that Ses ameliorated NASH by inhibiting CD36-mediated FA uptake and upregulation of lipogenic genes, including FA synthase, stearoyl-CoA desaturase 1, and sterol regulatory element-binding protein 1. The findings of our study provide novel insights into the potential therapeutic applications of Ses in the treatment of NASH. [ABSTRACT FROM AUTHOR]

The heart faces the challenge of adjusting the rate of fatty acid uptake to match myocardial demand for energy provision at any given moment, avoiding both too low uptake rates, which could elicit an energy deficit, and too high uptake rates, which pose the risk of excess lipid accumulation and lipotoxicity. The transmembrane glycoprotein cluster of differentiation 36 (CD36), a scavenger receptor (B2), serves many functions in lipid metabolism and signaling. In the heart, CD36 is the main sarcolemmal lipid transporter involved in the rate-limiting kinetic step in cardiac lipid utilization. The cellular fatty acid uptake rate is determined by the presence of CD36 at the cell surface, which is regulated by subcellular vesicular recycling from endosomes to the sarcolemma. CD36 has been implicated in dysregulated fatty acid and lipid metabolism in pathophysiological conditions, particularly high-fat diet-induced insulin resistance and diabetic cardiomyopathy. Thus, in conditions of chronic lipid overload, high levels of CD36 are moved to the sarcolemma, setting the heart on a route towards increased lipid uptake, excessive lipid accumulation, insulin resistance, and eventually contractile dysfunction. Insight into the subcellular trafficking machinery of CD36 will provide novel targets to treat the lipid-overloaded heart. A screen for CD36-dedicated trafficking proteins found that vacuolar-type H+-ATPase and specific vesicle-associated membrane proteins, among others, were uniquely involved in CD36 recycling. Preliminary data suggest that these proteins may offer clues on how to manipulate myocardial lipid uptake, and thus could be promising targets for metabolic intervention therapy to treat the failing heart.

Fatty acid translocase cluster of differentiation (CD36) is a multifunctional membrane protein that facilitates the uptake of long-chain fatty acids. Lipophagy is autophagic degradation of lipid droplets. Accumulating evidence suggests that CD36 is involved in the regulation of intracellular signal transduction that modulates fatty acid storage or usage. However, little is known about the relationship between CD36 and lipophagy. In this study, we found that increased CD36 expression was coupled with decreased autophagy in the livers of mice treated with a high-fat diet. Overexpressing CD36 in HepG2 and Huh7 cells inhibited autophagy, while knocking down CD36 expression induced autophagy due to the increased autophagosome formation in autophagic flux. Meanwhile, knockout of CD36 in mice increased autophagy, while the reconstruction of CD36 expression in CD36-knockout mice reduced autophagy. CD36 knockdown in HepG2 cells increased lipophagy and β-oxidation, which contributed to improving lipid accumulation. In addition, CD36 expression regulated autophagy through the AMPK pathway, with phosphorylation of ULK1/Beclin1 also involved in the process. These findings suggest that CD36 is a negative regulator of autophagy, and the induction of lipophagy by ameliorating CD36 expression can be a potential therapeutic strategy for the treatment of fatty liver diseases through attenuating lipid overaccumulation.

Pathological accumulations of amyloid-beta (Aβ) peptide are found in retina early in Alzheimer's disease, yet its effects on retinal neuronal structure remain unknown. To investigate this, we injected fibrillized Aβ1-42 protein into the eye of adult C57BL/6 J mice and analyzed the retina, optic nerve (ON), and the superior colliculus (SC), the primary retinal target in mice. We found that retinal Aβ exposure stimulated microglial activation and retinal ganglion cell (RGC) loss as early as 1-week post-injection. Pathology was not limited to the retina, but propagated into other areas of the central nervous system. Microgliosis spread throughout the retinal projection (retina, ON, and SC), with multiplex protein quantitation demonstrating an increase in endogenously produced Aβ in the ON and SC corresponding to the injected retinas. Surprisingly, this pathology spread to the opposite side, with unilateral Aβ eye injections driving increased Aβ levels, neuroinflammation, and RGC death in the opposite, un-injected retinal projection. As Aβ-mediated microglial activation has been shown to propagate Aβ pathology, we also investigated the role of the Aβ-binding microglial scavenger receptor CD36 in this pathology. Transgenic mice lacking the CD36 receptor were resistant to Aβ-induced inflammation and RGC death up to 2 weeks following exposure. These results indicate that Aβ pathology drives regional neuropathology in the retina and does not remain isolated to the affected eye, but spreads throughout the nervous system. Further, CD36 may serve as a promising target to prevent Aβ-mediated inflammatory damage.

Cluster of differentiation 36 (CD36) is a scavenger receptor (SR), recognizing diverse extracellular ligands in various types of mammalian cells. Long-chain fatty acids (FAs), which are important constituents of phospholipids and triglycerides, also utilize CD36 as a predominant membrane transporter, being incorporated from the circulation across the plasma membrane in several cell types, including cardiac and skeletal myocytes and adipocytes. CD36 is localized in intracellular vesicles as well as the plasma membrane, and its distribution is modulated by extracellular stimuli. Herein, we aimed to clarify the molecular basis of insulin-stimulated translocation of CD36, which leads to the enhanced uptake of long-chain FAs, in adipocytes. To this end, we developed a novel exofacial epitope-tagged reporter to specifically detect cell surface-localized CD36. By employing this reporter, we demonstrate that the small GTPase Rac1 plays a pivotal role in insulin-stimulated translocation of CD36 to the plasma membrane in 3T3-L1 adipocytes. Additionally, phosphoinositide 3-kinase and the protein kinase Akt2 are shown to be involved in the regulation of Rac1. Downstream of Rac1, another small GTPase RalA directs CD36 translocation. Collectively, these results suggest that CD36 is translocated to the plasma membrane by insulin through mechanisms similar to those for the glucose transporter GLUT4 in adipocytes. • A reporter assay for the plasma membrane translocation of CD36 has been established. • Insulin-stimulated uptake of fatty acids is dependent on Rac1 in adipocytes. • Insulin-stimulated translocation of CD36 is dependent on Rac1 in adipocytes. • RalA has been implicated in the regulation of CD36 translocation downstream of Rac1. • Phosphoinositide 3-kinase and Akt2 regulate Rac1 in adipocyte insulin signaling. [ABSTRACT FROM AUTHOR]

• Clearance of Plasmodium-infected erythrocytes depends on phagocytosis by macrophages with CD36 as the adhesion molecule. • Certain single nucleotide variants of PCSK9 presumably affect its capability of regulating CD36 degradation and expression. • Malaria is hence hypothesized to be the pathogen-driven selective pressure for the designated PCSK9 variants. • These PCSK9 polymorphisms might also influence the prognosis of cancer patients on account of the tumor-promoting role of CD36. Genetic polymorphism of proprotein convertase subtilisin/kexin type 9 (PCSK9), identified as single nucleotide variant (SNV), when locating at the Cys-His rich domain (CHRD), for example, E670G and I474V, is herein hypothesized to affect the domain's binding affinity to cluster of differentiation 36 (CD36), which plays a major role in the phagocytosis of Plasmodium parasitized erythrocytes, and thus bringing on divergent susceptibility to malaria, with supporting evidence coming from epidemiologic studies of Malian children infected by malaria and population genetic comparison of European-Americans and African-Americans whose ancestors originated in the land ravaged by malaria. Starting from this proposal, the hypothesis extends further to the possible influence of PCSK9 CHRD SNVs on the development, therapeutic effects, and prognosis of cancer based on recently discovered roles of CD36 in tumour biology. It is hoped that more laboratory, epidemiology, and computation analyses in the near future can prove the whole speculation and broaden our knowledge about the physiology of PCSK9. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are the leading cause of death worldwide, with the majority of the cases being heart failure due to myocardial infarction. Research on cardiovascular diseases is currently underway, particularly on atherosclerosis prevention, to reduce the risk of myocardial infarction. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been reported to play a role in lipid metabolism, by enhancing low-density lipoprotein (LDL) receptor degradation. Therefore, PCSK9 inhibitors have been developed and found to successfully decrease LDL plasma levels. Recent experimental studies have also implicated PCSK9 in platelet activation, having a key role during atherosclerosis progression. Although numerous studies have addressed the role of PCSK9 role in controlling hypercholesterolemia, studies and discussions exploring its involvement in platelet activation are still limited. Hence, here, we address our current understanding of the pathophysiological process involved in atherosclerosis-induced myocardial infarction (MI) through platelet activation and highlight the molecular mechanisms used by PCSK9 in regulating platelet activation. Undoubtedly, a deeper understanding of the relationship between platelet activation and the underlying molecular mechanisms of PCSK9 in the context of MI progression will provide a new strategy for developing drugs that selectively inhibit the most relevant pathways in cardiovascular disease progression.

The widely expressed transmembrane glycoprotein, cluster of differentiation 36 (CD36), a scavenger receptor class B protein (SR-B2), serves many functions in lipid metabolism and signaling. Here, we review CD36's role in facilitating cellular long-chain fatty acid uptake across the plasma membrane, particularly in heart and skeletal muscles. CD36 acts in concert with other membrane proteins, such as peripheral plasma membrane fatty acid-binding protein, and is an intracellular docking site for cytoplasmic fatty acid-binding protein. The cellular fatty-acid uptake rate is governed primarily by the presence of CD36 at the cell surface, which is regulated by the subcellular vesicular recycling of CD36 from endosomes to the plasma membrane. CD36 has been implicated in dysregulated fatty acid and lipid metabolism in pathophysiological conditions, particularly in high-fat diet-induced insulin resistance and diabetic cardiomyopathy. Current research is exploring signaling pathways and vesicular trafficking routes involving CD36 to identify metabolic targets to manipulate the cellular utilization of fatty acids. Because of its rate-controlling function in the use of fatty acids in the heart and muscle, CD36 would be a preferable target to protect myocytes against lipotoxicity. Despite a poor understanding of its mechanism of action, CD36 has emerged as a pivotal membrane protein involved in whole-body lipid homeostasis.

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 [14C]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 (Cd)36 mRNA increased 2-fold, and angiopoietin-like 4 (Angptl4), 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.

A major challenge in taste research is to overcome the flavour imperfections in food products and to build nutritious strategies to combat against obesity as well as other related metabolic syndromes. The field of molecular taste research and chemical senses has contributed to an enormous development in understanding the taste receptors and mechanisms of taste perception. Accordingly, the development of taste-modifying compounds or taste modulators that alter the perception of basic taste modalities has gained significant prominence in the recent past. The beneficial aspects of these substances are overwhelming while considering their potential taste-modifying properties. The objective of the present review is to provide an impression about the taste-modulating compounds and their distinctive taste-modifying properties with reference to their targets and proposed mechanisms of action. The present review also makes an effort to discuss the basic mechanism involved in oro-gustatory taste perception as well as on the effector molecules involved in signal transduction downstream to the activation of taste receptors. [ABSTRACT FROM AUTHOR]

Y-box protein 1 (YB1) is a key regulator of inflammatory mediators. However, the roles of YB1 in oxidized low-density lipoprotein (ox-LDL)-induced macrophage inflammation and lipid uptake remain less understood. Thus, we explored the roles of YB1 in ox-LDL-induced macrophage inflammation and lipid uptake and its underlying molecular mechanisms. An ox-LDL-induced atherosclerosis (AS) model was used in this study. Western blotting, RT-PCR, immunofluorescence, ELISA, dil-ox-LDL staining, a dual-luciferase reporter assay, RNA-binding protein immunoprecipitation (RIP) and in vivo experiments were used to detect each target. ox-LDL downregulates YB1 expression in THP-1-derived macrophages and human monocyte-derived macrophages (hMDMs) via the NF-κB pathway. Downregulation of YB1 is facilitated by lipid uptake in macrophages, and CD36 is involved in this process. Furthermore, YB1 suppresses CD36 protein levels by directly binding to the coding sequence of the CD36 gene to promote CD36 mRNA decay but does not affect its mRNA transcription. Additionally, YB1 knockdown enhances the inflammatory response and lipid deposition via the NF-κB pathway in vivo. ox-LDL decreases YB1 expression in macrophages, resulting in enhanced inflammatory responses by affecting NF-κB and facilitating lipid uptake by promoting scavenger receptor CD36 mRNA decay. Image 1 • YB1 plays a critical role in the progression of AS. • YB1 inhibits inflammatory response in ox-LDL-treated macrophages by affecting NF-κB pathway. • YB1 inhibits lipid uptake by promoting scavenger receptor CD36 mRNA decay. [ABSTRACT FROM AUTHOR]

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.

Objective: To elucidate the protective effects of rice bran water extract on the expression of endothelial nitric oxide synthase (eNOS), nuclear factor-kappa B (NF-κB), and a cluster of differentiation 36 (CD36) in the vasculature of high-fat diet-fed rats. Methods: Male Sprague-Dawley rats were divided into three groups. Group I served as control, Group II was treated with high-fat diet, and Group III was treated with high-fat diet and rice bran water extract at 2205 mg/kg/day. After four weeks, the metabolic parameters, malondialdehyde as a marker of oxidative stress, and histological features of the aorta were evaluated. The levels of transcripts and proteins in aorta were determined by real-time PCR and Western blot analysis, respectively. Results: In comparison with the Group II, rice bran water extract administration resulted in a significant reduction in body weight, visceral fat tissue weights, blood glucose levels, and serum total-cholesterol and free fatty acid levels in Group III. Serum triglyceride levels tended to decrease in the Group III. Also, rice bran water extract administration obviously decreased malondialdehyde levels in both serum and aorta. Interestingly, rice bran water extract treatment demonstrated a significant up-regulation of eNOS expression and down-regulation of NF-κB p65 and CD36 expressions. Nonetheless, all groups showed normal histology of aorta. Conclusions: Rice bran water extract exhibited vasoprotective effects in the high-fat diet-induced obesity condition by modulating the expression of eNOS, NF-κB, and CD36 and metabolic parameters.

The ability of mesenchymal stromal cells (MSCs) to differentiate into adipocytes provides a cellular model of human origin to study adipogenesis in vitro. One of the major challenges in studying adipogenesis is the lack of tools to identify and monitor the differentiation of various subpopulations within the heterogeneous pool of MSCs. Cluster of differentiation (CD)36 plays an important role in the formation of intracellular lipid droplets, a key characteristic of adipocyte differentiation/maturation. The objective of this study was to develop a reproducible quantitative method to study adipocyte differentiation by comparing two lipophilic dyes [Nile Red (NR) and Bodipy 493/503] in combination with CD36 surface marker staining. We identified a subpopulation of adipose-derived stromal cells that express CD36 at intermediate/high levels and show that combining CD36 cell surface staining with neutral lipid-specific staining allows us to monitor differentiation of adipose-derived stromal cells that express CD36intermediate/high during adipocyte differentiation in vitro. The gradual increase of CD36intermediate/high/NRpositive cells during the 21 day adipogenesis induction period correlated with upregulation of adipogenesis-associated gene expression.

This study was designed to explore the protective effect of D4F, an apoA-I mimetic peptide, on oxidized LDL (ox-LDL)-induced endoplasmic reticulum (ER) stress-CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) pathway-mediated apoptosis in macrophages. Our results showed that treating apoE knockout mice with D4F decreased the serum ox-LDL level and apoptosis in atherosclerotic lesions with concomitant downregulation of cluster of differentiation 36 (CD36) and inhibition of ER stress. In vitro, D4F inhibited macrophage-derived foam cell formation. Furthermore, like ER stress inhibitor 4-phenylbutyric acid (PBA), D4F inhibited ox-LDL- or tunicamycin (TM, an ER stress inducer)-induced reduction in cell viability and increase in lactate dehydrogenase leakage, caspase-3 activation, and apoptosis. Additionally, like PBA, D4F inhibited ox-LDL- or TM-induced activation of ER stress response as assessed by the reduced nuclear translocation of activating transcription factor 6 and the decreased phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2α, as well as the downregulation of glucose-regulated protein 78 and CHOP. Moreover, D4F mitigated ox-LDL uptake by macrophages and CD36 upregulation induced by ox-LDL or TM. These data indicate that D4F can alleviate the formation and apoptosis of macrophage-derived foam cells by suppressing CD36-mediated ox-LDL uptake and subsequent activation of the ER stress-CHOP pathway.

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease and a secreted protein which increases cholesterol levels in plasma via inducing degradation of low-density lipoprotein receptor (LDLR). Cluster of differentiation 36 (CD36) is a member of a family of cell surface proteins in many cells. CD36 is known as fatty acid translocase (FAT) because it imports fatty acids inside cells and participate in triglyceride storage. It has been suggested that PCSK9 regulates CD36 in some tissues. Methods Data and serum levels of TSH, FT4, lipid profile and PCSK9 and the expression of CD36 on monocytes from 40 new untreated patients with subclinical hypothyroidism (SH) and 40 age- sex- and BMI-matched euthyroid controls were analyzed in a cross-sectional study. Then the relationships between these parameters were examined. Results Patients with SH had higher TSH, FT4, total cholesterol (TC) and triglyceride (TG) Low-density lipoprotein (LDL) and PCSK9 levels than controls. There were significant and positive correlations between serum TSH levels and lipid parameters except HDL-C. PCSK9 had a significant and negative correlation with FT4. No significant correlation could be found in relation to PCSK9 and CD36. Conclusions PCSK9 inhibitors are used to reduce blood cholesterol levels as drugs. If it will be proven that PCSK9 can induce CD36 degradation, taking these drugs may have unwanted side effects. This study showed that serum PCSK9 and lipid profile levels increase in patients with subclinical hypothyroidism and there is no relationship between PCSK9 and CD36 in these patients. Highlights • Lipid profile levels increase in patients with subclinical hypothyroidism. • There is a negative association between thyroid function and PCSK9 levels in patients with subclinical hypothyroidism. • Low levels of FT4 in subclinical hypothyroidism may increase cholesterol through the PCSK9 pathway. • There was no significant correlation between PCSK9 and the percentage of CD36 presence on the monocytes surface in patients with subclinical hypothyroidism. [ABSTRACT FROM AUTHOR]

Abstract Increased G protein-coupled receptor kinase (GRK)2 is central to heart failure (HF) pathogenesis, via desensitization of β-adrenergic receptors and loss of contractile reserve. Since GRK2 has been shown to compromise fatty acid (FA) oxidation, this kinase may link metabolic and contractile defects in HF. The aim of this study was to investigate the mechanistic role of GRK2 in FA metabolism and bioenergetics in the heart. For that purpose, we measured FA uptake and cluster of differentiation (CD)36 expression, phosphorylation, and ubiquitination in mice with cardiac-specific overexpression of GRK2 (TgGRK2) or expression of its c-terminus (GRK2 inhibitor- TgβARKct) or in global heterozygous GRK2 knockout (GRK2+/−) mice. Cellular bioenergetics were also measured in isolated cardiomyocytes following adenoviral delivery of exogenous GRK2, βARKct, or short hairpin GRK2 (shGRK2). Additionally, CD36 expression and phosphorylation were evaluated following transverse aortic constriction (TAC) in wild type (WT) and GRK2+/− mice. Our results show a 33% ± 0.81 reduction in FA uptake rate, accompanied by 51% ± 0.17 lower CD36 protein, and 70% ± 0.23 and 69% ± 0.18 increases in CD36 phosphorylation and ubiquitination, respectively, in the TgGRK2 mice. Moreover, an in vitro kinase assay suggests that GRK2 directly phosphorylates CD36. In isolated cardiomyocytes, GRK2 overexpression induced a 26% ± 2.21 decrease in maximal respiration, which was enhanced (20% ± 4.02–5.14) with inhibition of the kinase. Importantly, in hearts with systolic dysfunction, notable reductions in CD36 mRNA and protein, as well as a significant increase in CD36 phosphorylation were normalized in the GRK2+/− mice post-TAC. Thus, we propose that GRK2 up-regulation in HF is, at least partly, responsible for reduced FA uptake and oxidation and may be a nodal link between metabolic and contractile defects. Highlights • Elevated GRK2, as in HF, induces phosphorylation and ubiquitination of CD36. • GRK2 mediates CD36 downregulation and compromises FA uptake rate and energetics. • Knockout of GRK2 rescues CD36 phosphorylation and downregulation in HF. • GRK2 likely contributes to reduced CD36 and FA uptake/oxidation in HF. • Targeting GRK2 may restore primary contractile and energetic defects in HF. [ABSTRACT FROM AUTHOR]

Fatty acid translocase/cluster of differentiation 36 (FAT/CD36) functions as a membrane long-chain fatty acid transporter in various tissues in land animals. Not much is known about the CD36 molecule in teleost fish. Therefore, we studied CD36 in grass carp ( Ctenopharyngodon idella, ciCD36). The full-length complementary DNA sequence of ciCD36 was 1976 bp, with an ORF of 468 amino acids, which had high sequence similarity to the CD36 of common carp. The messenger RNA (mRNA) expression of ciCD36 was high in the intestine, heart, liver, visceral tissue, and brain, but absent in the kidney. The protein expression of ciCD36 was high in the brain, intestine, liver, heart, muscle, eye, visceral tissue, gonad, and gill, but not in the kidney. Four groups of grass carp (16 tanks) were fed three times daily to satiation with 17.2 kJ gross energy/g diet (control, CON), 19.4 kJ gross energy/g diet (more energy supplied by proteins, HP), 19.9 kJ gross energy/g diet (more energy supplied by fat, HF), and 19.1 kJ gross energy/g diet (more energy supplied by carbohydrate, HC) for 11 weeks, respectively. At the end of the feeding experiment, the fish were fasted for 48 h, and the brain, heart, intestine, and liver were sampled and designated as the 0-h samples. The fish were then fed a single meal of the above four diets, and these tissues were collected at 8- and 24-h intervals after refeeding to analyze ciCD36 mRNA and protein expression levels. The results showed that at the transcriptional and translational levels, ciCD36 expression was significantly affected by refeeding time and the different diets ( P < 0.05), and the regulation of its transcription in different tissues varied. At the translational level, the protein expression levels decreased in the CON and HC groups, and increased in the HP and HF groups after refeeding. The results indicated that ciCD36 has a modulatory role in the adaptation to dietary high energy in grass carp. Translational regulation might be responsible for the observed variations in ciCD36 expression. [ABSTRACT FROM AUTHOR]

Cluster of differentiation 36 (CD36) is a membrane glycoprotein receptor capable of binding and transporting fatty acid. Nogo-B regulates the metabolism of fatty acids in the liver and affects the development of liver cancer. To date, it remains unclear whether the interaction between CD36 and Nogo-B affects the proliferation and migration of breast cancer cells. In the current study, we aimed to determine whether the interference of CD36 and Nogo-B affects the proliferation and migration of triple-negative breast cancer (TNBC) cells. The results showed that inhibition of CD36 or Nogo-B alone can inhibit the proliferation and migration of TNBC cells, and the inhibitory effect was more pronounced when CD36 and Nogo-B were inhibited simultaneously. Meanwhile, it was found that inhibition of CD36 and Nogo-B expression can inhibit the expression of Vimentin, B-cell lympoma-2 (BCL2) and proliferating cell nuclear antigen (PCNA). In vivo , knockdown of CD36 or Nogo-B in E0771 cells reduced its tumorigenic ability, which was further enhanced by knockdown of CD36 and Nogo-B simultaneously. Mechanistically, inhibition of CD36 and Nogo-B expression can decrease fatty acid binding protein 4 (FABP4) and fatty acid transport protein 4 (FATP4) expression. Moreover, overexpression of CD36 and Nogo-B-induced cell proliferation was attenuated by FABP4 siRNA, indicating that inhibition of CD36 and Nogo-B expression could inhibit the absorption and transport of fatty acids, thereby inhibiting the proliferation and migration of TNBC. Furthermore, inhibition of CD36 and Nogo-B expression activated the P53-P21-Rb signaling pathway which contributed to the CD36 and Nogo-B-inhibited proliferation and migration of TNBC. Taken together, the results suggest that inhibition of CD36 and Nogo-B can reduce the proliferation and migration of TNBC, which provides new targets for the development of drugs against TNBC.

Modulation of the cluster of differentiation-36 receptor (CD36) has proven promising for dampening pro-inflammatory macrophage signaling. For example, azapeptides (e.g., 1 and 2) bind CD36 selectively with high affinity, mitigate Toll-like receptor (TLR) agonist-induced overproduction of nitric oxide (NO), and reduce pro-inflammatory cytokine and chemokine production in macrophages. Moreover, semicarbazides 1 and 2 inhibit microvascular sprouting mediated through CD36 in the choroid explant. Seeking a selective CD36 modulator that mediated inflammation without influencing neovascularization, a set of azasulfurylpeptides (e.g., 3a–e) were synthesized in which the semicarbazide was replaced by an N-aminosulfamide residue using a novel solid-phase approach. Notably, azasulfurylpeptide 3c diminished selectively CD36-mediated TLR-2-triggered inflammatory response without affecting neovascularization. Subtle chemical modification at the peptide backbone from a carbonyl to a sulfuryl residue has had a selective effect on biological activity providing a valuable probe for studying CD36 chemical biology.

Foam cell formation, which is caused by imbalanced cholesterol influx and efflux by macrophages, plays a vital role in the occurrence and development of atherosclerosis. Humanin (HN), a mitochondria-derived peptide, can prevent the production of reactive oxygen species and death of human aortic endothelial cells exposed to oxidized low-density lipoprotein (ox-LDL) and has a protective effect on patients with in early atherosclerosis. However, the effects of HN on the regulation of cholesterol metabolism in RAW 264.7 macrophages are still unknown. This study was designed to investigate the role of [Gly14]-humanin (HNG) in lipid uptake and cholesterol efflux in RAW 264.7 macrophages. Flow cytometry and live cell imaging results showed that HNG reduced Dil-ox-LDL accumulation in the RAW 264.7 macrophages. A similar result was obtained for lipid accumulation by measuring cellular cholesterol content. Western blot analysis showed that ox-LDL treatment upregulated not only the protein expression of CD36 and LOX-1, which mediate ox-LDL endocytosis, but also ATP-binding cassette (ABC) transporter A1 and ABCG1, which mediate ox-LDL exflux. HNG pretreatment inhibited the upregulation of CD36 and LOX-1 levels, prompting the upregulation of ABCA1 and ABCG1 levels induced by ox-LDL. Therefore we concluded that HNG could inhibit ox-LDL-induced macrophage-derived foam cell formation, which occurs because of a decrease in lipid uptake and an increase in cholesterol efflux from macrophage cells. [ABSTRACT FROM AUTHOR]

Oxidized low density lipoprotein (oxLDL)-induced apoptosis of macrophages contributes to the formation of atherosclerotic plaques. R-spondin 2 (Rspo2), a member of the cysteine-rich secreted proteins, has been shown to be involved in the oncogenesis of several types of cancer. It has also been found to be abundantly expressed among the four R-spondin members in macrophages. The present study was performed to determine whether Rspo2 is involved in the ox-LDL-induced apoptosis of macrophages. It was identified that Rspo2 inhibited oxLDL-induced apoptosis in the presence of endoplasmic reticulum (ER) stress activator using flow cytometry. In addition, Rspo2 was observed to suppress oxLDL-induced ER stress and reactive oxygen species production as demonstrated by western blotting. Furthermore, analysis of the role of Rspo2 in macrophage lipid uptake identified that Rspo2 negatively regulated the Dil-oxLDL uptake by inhibiting the expression of cluster of differentiation (CD)36, through the transcription factor, peroxisome proliferator-activated receptor (PPAR)-γ. The manipulation of Rspo2 had a direct effect on PPAR-γ nuclear translocation. In addition, chromatin immunoprecipitation analysis revealed that Rspo2 manipulation led to regulation of the direct binding between PPAR-γ and CD36. In conclusion, Rspo2 was found to have a negative regulatory effect during oxLDL-induced macrophage apoptosis by regulating lipid uptake. [ABSTRACT FROM AUTHOR]

Objective To elucidate the protective effects of rice bran water extract on the expression of endothelial nitric oxide synthase (eNOS), nuclear factor-kappa B (NF-κB), and a cluster of differentiation 36 (CD36) in the vasculature of high-fat diet-fed rats. Methods Male Sprague-Dawley rats were divided into three groups. Group I served as control, Group II was treated with high-fat diet, and Group III was treated with high-fat diet and rice bran water extract at 2 205 mg/kg/day. After four weeks, the metabolic parameters, malondialdehyde as a marker of oxidative stress, and histological features of the aorta were evaluated. The levels of transcripts and proteins in aorta were determined by real-time PCR and Western blot analysis, respectively. Results In comparison with the Group II, rice bran water extract administration resulted in a significant reduction in body weight, visceral fat tissue weights, blood glucose levels, and serum total-cholesterol and free fatty acid levels in Group III. Serum triglyceride levels tended to decrease in the Group III. Also, rice bran water extract administration obviously decreased malondialdehyde levels in both serum and aorta. Interestingly, rice bran water extract treatment demonstrated a significant up-regulation of eNOS expression and down-regulation of NF-κB p65 and CD36 expressions. Nonetheless, all groups showed normal histology of aorta. Conclusions Rice bran water extract exhibited vasoprotective effects in the high-fat diet-induced obesity condition by modulating the expression of eNOS, NF-κB, and CD36 and metabolic parameters. [ABSTRACT FROM AUTHOR]

Cluster of differentiation 36 (CD36) is involved in the development of atherosclerosis by enhancing macrophage endocytosis of oxidized low-density lipoproteins and foam cell formation. Soluble CD36 (sCD36) was found to be elevated in type 2 diabetic patients and possibly acted as a marker of insulin resistance and atherosclerosis. In young subjects, sCD36 was associated with cardiovascular risk factors including obesity and hypertriglyceridemia. The present study was conducted to further investigate the association between plasma sCD36 and cardiovascular risk factors among middle-aged patients with metabolic syndrome (MetS) and healthy controls. sCD36 concentrations were determined by enzyme-linked immunosorbent assays (ELISA) for 41 patients with MetS and 36 healthy controls. Data for other variables were obtained from patient medical records. sCD36 concentrations were relatively low compared to the majority of other studies and were not significantly different between the MetS group and controls (P=0.17). sCD36 was also not correlated with age, body mass index, glucose, lipid profile, serum electrolytes and blood counts. sCD36 was not significantly different between subjects with obesity, hyperglycemia, dyslipidemia, hypertension or cardiovascular disease, and those without these abnormalities (P>0.05). The inconsistency between results reported in the present study and other studies may be unique to the study population or be a result of the lack of a reliable standardized method for determining absolute sCD36 concentrations. However, further investigations are required to assess CD36 tissue expression in the study population and to assess the accuracy of various commercially available sCD36 ELISA kits. Thus, the availability of a standardized simple sCD36 ELISA that could be performed in any basic laboratory would be more favorable to the specialized flow cytometry methods that detect CD36+ microparticles if it was to be used as a biomarker. [ABSTRACT FROM AUTHOR]

The article discusses a study that determined the effects of naringenin on skin inflammation, proinflammatory cytokines and macrophage polarization shifts of pathways M1 to M2 in atopic dermatitis (AD) NC/Nga mouse model. Findings discussed include decrease in dermatitis score of naringenin treatment group, and naringenin treatment to have attenuated changes such as hyperkeratosis, parakeratosis, acanthosis/spongosis and infiltrated mast cells in AD mice skin.

Background: Advanced glycation end products (AGEs) are diabetic metabolic toxic products that cannot be ignored. N ε -(carboxymethyl)lysine (CML), a component of AGEs, could increase macrophage lipid uptake, promote foam cell formation, and thereby accelerate atherosclerosis. The receptor for AGEs (RAGE) and cluster of differentiation 36 (CD36) were the receptors of CML. However, it is still unknown whether RAGE and CD36 play key roles in CML-promoted lipid uptake., Aim: Our study aimed to explore the role of RAGE and CD36 in CML-induced mac-rophage lipid uptake., Methods: In this study, we examined the effect of CML on lipid uptake by Raw264.7 macrophages. After adding 10 mmol/L CML, the lipid accumulation in macro-phages was confirmed by oil red O staining. Expression changes of CD36 and RAGE were detected with immunoblotting and quantitative real-time polymerase chain reaction. The interaction between CML with CD36 and RAGE was verified by immunoprecipitation. We synthesized a novel N-succinimidyl-4- 18 F-fluorobenzoate-CML radioactive probe. Radioactive receptor-ligand binding assays were performed to test the binding affinity between CML with CD36 and RAGE. The effects of blocking CD36 or RAGE on CML-promoting lipid uptake were also detected., Results: The study revealed that CML significantly promoted lipid uptake by macro-phages. Immunoprecipitation and radioactive receptor-ligand binding assays indicated that CML could specifically bind to both CD36 and RAGE. CML had a higher affinity for CD36 than RAGE. ARG82, ASN71, and THR70 were the potential interacting amino acids that CD36 binds to CML Anti-CD36 and anti-RAGE could block the uptake of CML by macrophages. The lipid uptake promotion effect of CML was significantly attenuated after blocking CD36 or RAGE., Conclusion: Our results suggest that the binding of CML with CD36 and RAGE promotes macrophage lipid uptake., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Numerous nuclear receptors including farnesoid X receptor, liver X receptor, peroxisome proliferator-activated receptors, pregnane X receptor, hepatic nuclear factors have been extensively studied within the context of non-alcoholic fatty liver disease (NAFLD). Following the first description of the Aryl hydrocarbon Receptor (AhR) in the 1970s and decades of research which unveiled its role in toxicity and pathophysiological processes, the functional significance of AhR in NAFLD has not been completely decoded. Recently, multiple research groups have utilized a plethora of in vitro and in vivo models that mimic NAFLD pathology to investigate the functional significance of AhR in fatty liver disease. This review provides a comprehensive account of studies describing both the beneficial and possible detrimental role of AhR in NAFLD. A plausible reconciliation for the paradox indicating AhR as a 'double-edged sword' in NAFLD is discussed. Finally, understanding AhR ligands and their signaling in NAFLD will facilitate us to probe AhR as a potential drug target to design innovative therapeutics against NAFLD in the near future., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

The effect of cluster of differentiation (CD)36 on regulatory T cells (T reg ) was investigated in gonadal (GN) adipose tissues and mesenteric lymph nodes (MLN) of wild-type (WT) and CD36 deficient (CD36 −/− ) mice kept on standard fat (SFD, lean) or on high fat diet (HFD, obese). GN adipose tissue mass was smaller, but MLN size larger for obese CD36 −/− versus obese WT mice. Overall, the reduction of T reg cells in GN adipose tissue and MLN after a HFD is much more prominent in WT than CD36 −/− mice. Moreover, CD36 −/− mice may be protected against obesity-related chronic inflammation. [ABSTRACT FROM AUTHOR]

Ceramide synthase 2 (CerS2) null mice cannot synthesize very-long acyl chain (C22–C24) ceramides resulting in significant alterations in the acyl chain composition of sphingolipids. We now demonstrate that hepatic triacylglycerol (TG) levels are reduced in the liver but not in the adipose tissue or skeletal muscle of the CerS2 null mouse, both before and after feeding with a high fat diet (HFD), where no weight gain was observed and large hepatic nodules appeared. Uptake of both BODIPY-palmitate and [ 3 H]-palmitate was also abrogated in the hepatocytes and liver. The role of a number of key proteins involved in fatty acid uptake was examined, including FATP5, CD36/FAT, FABPpm and cytoplasmic FABP1. Levels of FATP5 and FABP1 were decreased in the CerS2 null mouse liver, whereas CD36/FAT levels were significantly elevated and CD36/FAT was also mislocalized upon insulin treatment. Moreover, treatment of hepatocytes with C22–C24-ceramides down-regulated CD36/FAT levels. Infection of CerS2 null mice with recombinant adeno-associated virus (rAAV)-CerS2 restored normal TG levels and corrected the mislocalization of CD36/FAT, but had no effect on the intracellular localization or levels of FATP5 or FABP1. Together, these results demonstrate that hepatic fatty acid uptake via CD36/FAT can be regulated by altering the acyl chain composition of sphingolipids. [ABSTRACT FROM AUTHOR]

The antidiabetic intestinal L cell hormone glucagon-like peptide-1 (GLP-1) enhances glucose-dependent insulin secretion and inhibits gastric emptying. GLP-1 secretion is stimulated by luminal oleic acid (OA), which crosses the cell membrane by an unknown mechanism. We hypothesized that L cell fatty acid transport proteins (FATPs) are essential for OA-induced GLP-1 release. Therefore, the murine GLUTag L cell model was used for immunoblotting, [3H]OA uptake assay, and GLP-1 secretion assay as determined by radioimmunoassay following treatment with OA ± phloretin, sulfo-N-succinimidyl oleate, or siRNA against FATP4. FATP4-/- and cluster-of-differentiation 36 (CD36)-/- mice received intraileal OA, and plasma GLP-1 was measured by sandwich immunoassay. GLUTag cells were found to express CD36, FATP1, FATP3, and FATP4. The cells demonstrated specific 3H[OA] uptake that was dose-dependently inhibited by 500 and 1,000 μM unlabeled OA (P < 0.001). Cell viability was not altered by treatment with OA. Phloretin and sulfo-N-succinimidyl oleate, inhibitors of protein-mediated transport and CD36, respectively, also decreased [3H]OA uptake, as did knockdown of FATP4 by siRNA transfection (P < 0.05- 0.001). OA dose-dependently increased GLP-1 secretion at 500 and 1,000 μM (P < 0.001), whereas phloretin, sulfo-N-succinimidyl oleate, and FATP4 knockdown decreased this response (P < 0.05- 0.01). FATP4-/- mice displayed lower plasma GLP-1 at 60 min in response to intraileal OA (P < 0.05), whereas, unexpectedly, CD36-/- mice displayed higher basal GLP-1 levels (P < 0.01) but a normal response to intraileal OA. Together, these findings demonstrate a key role for FATP4 in OA-induced GLP-1 secretion from the murine L cell in vitro and in vivo, whereas the precise role of CD36 remains unclear. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the clinical significance of anti-angiogenic receptor cluster of differentiation 36 (CD36) in serum of patients with SSc.Methods. We studied 47 SSc patients (28 with lcSSC and 19 with dcSSC) and 38 age- and gender-matched healthy controls. Demographic, clinical, autoantibodies and serological data were prospectively assessed. Peripheral vascular affection was classified into mild, moderate, severe or end-stage based on a vascular severity scale. Soluble CD36 (sCD36) serum levels were measured using ELISA.Results. Serum sCD36 levels were significantly higher in patients with SSc compared with healthy controls (P = 0.045). When the patients were divided into clinical subsets, sCD36 was higher in lcSSc than in healthy controls (P = 0.03). Levels of sCD36 were found to be positively correlated with pulmonary artery systolic pressure (PASP) and negatively correlated with percentage diffusing lung capacity for carbon monoxide (DLCO). In the multivariate analysis, 50% of the variation of sCD36 levels could be explained by elevated PASP (0.000), telangiectasias (0.026) and increasing vascular severity (P = 0.003).Conclusion. Serum sCD36 levels were higher in SSc patients (particularly the limited subset) than in healthy controls and were found to be correlated with PASP and vascular severity. We conclude that sCD36 may be a marker for elevated PASP and vascular involvement in SSc. To confirm our results we propose that larger scale, multicentre studies with longer evaluation periods are needed. [ABSTRACT FROM PUBLISHER]

Cardiovascular diseases are the leading cause of death worldwide, with the majority of the cases being heart failure due to myocardial infarction. Research on cardiovascular diseases is currently underway, particularly on atherosclerosis prevention, to reduce the risk of myocardial infarction. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been reported to play a role in lipid metabolism, by enhancing low-density lipoprotein (LDL) receptor degradation. Therefore, PCSK9 inhibitors have been developed and found to successfully decrease LDL plasma levels. Recent experimental studies have also implicated PCSK9 in platelet activation, having a key role during atherosclerosis progression. Although numerous studies have addressed the role of PCSK9 role in controlling hypercholesterolemia, studies and discussions exploring its involvement in platelet activation are still limited. Hence, here, we address our current understanding of the pathophysiological process involved in atherosclerosis-induced myocardial infarction (MI) through platelet activation and highlight the molecular mechanisms used by PCSK9 in regulating platelet activation. Undoubtedly, a deeper understanding of the relationship between platelet activation and the underlying molecular mechanisms of PCSK9 in the context of MI progression will provide a new strategy for developing drugs that selectively inhibit the most relevant pathways in cardiovascular disease progression. [ABSTRACT FROM AUTHOR]