CD36 Overexpression Research Articles

PDK4-Deficiency Reprograms Intrahepatic Glucose and Lipid Metabolism to Facilitate Liver Regeneration in Mice.

Liver regeneration requires intrahepatic and extrahepatic metabolic reprogramming to meet the high hepatic bioenergy demand for liver cell repopulation. This study aims to elucidate how pyruvate dehydrogenase kinase 4 (PDK4), a critical regulator of glucose and lipid metabolism, coordinates metabolic regulation with efficient liver growth. We found that hepatic Pdk4 expression was elevated after two‐thirds partial hepatectomy (PHx). In Pdk4 −/− PHx mice, the liver/body weight ratio was more rapidly restored, accompanied by more aggressive hepatic DNA replication; however, Pdk4 −/− mice developed more severe hypoglycemia. In Pdk4 −/− PHx livers, the pro‐regenerative insulin signaling was potentiated, as demonstrated by early peaking of the phosphorylation of insulin receptor, more remarkable induction of the insulin receptor substrate proteins, IRS1 and IRS2, and more striking activation of Akt. The hepatic up‐regulation of CD36 contributed to the enhanced transient regeneration‐associated steatosis in Pdk4 −/− PHx mice. Notably, CD36 overexpression in mice promoted the recovery of liver/body weight ratio and elevated intrahepatic adenosine triphosphate after PHx. CD36 expression was transcriptionally suppressed by FOXO1 (forkhead box protein O1), which was stabilized and translocated to the nucleus following AMPK (adenosine monophosphate–activated protein kinase) activation. PHx remarkably induced AMPK activation, which became incompetent to respond in Pdk4 −/− livers. Moreover, we defined that PDK4‐regulated AMPK activation directly depended on intracellular adenosine monophosphate in vitro and in regenerative livers. Conclusion: PDK4 inhibition reprograms glucose and lipid metabolism to promote liver regeneration by enhancing hepatic insulin/Akt signaling and activating an AMPK/FOXO1/CD36 regulatory axis of lipid. These findings may lead to potential therapeutic strategies to prevent hepatic insufficiency and liver failure.

CD36 promotes the epithelial\u2013mesenchymal transition and metastasis in cervical cancer by interacting with TGF-\u03b2

BackgroundAccumulating evidence indicates that CD36 initiates metastasis and correlates with an unfavorable prognosis in cancers. However, there are few reports regarding the roles of CD36 in initiation and metastasis of cervical cancer.MethodsUsing immunohistochemistry, we analyzed 133 cervical cancer samples for CD36 protein expression levels, and then investigated the correlation between changes in its expression and clinicopathologic parameters. The effect of CD36 expression on the epithelial–mesenchymal transition (EMT) in cervical cancer cells was evaluated by Western immunoblotting analysis. In vitro invasion and in vivo metastasis assays were also used to evaluate the role of CD36 in cervical cancer metastasis.ResultsIn the present study, we confirmed that CD36 was highly expressed in cervical cancer samples relative to normal cervical tissues. Moreover, overexpression of CD36 promoted invasiveness and metastasis of cervical cancer cells in vitro and in vivo, while CD36 knockdown suppressed proliferation, migration, and invasiveness. We demonstrated that TGF-β treatment attenuated E-cadherin expression and enhanced the expression levels of CD36, vimentin, slug, snail, and twist in si-SiHa, si-HeLa, and C33a–CD36 cells, suggesting that TGF-β synergized with CD36 on EMT via active CD36 expression. We also observed that the expression levels of TGF-β in si-SiHa cells and si-HeLa cells were down-regulated, whereas the expression levels of TGF-β were up-regulated in C33a–CD36 cells. These results imply that CD36 and TGF-β interact with each other to promote the EMT in cervical cancer.ConclusionsOur findings suggest that CD36 is likely to be an effective target for guiding individualized clinical therapy of cervical cancer.

Abstract 4375: Overexpression of CD36 promotes colorectal cancer cell proliferation via upregulation of survivin

Abstract Altered fatty acid metabolism has is a hallmark of cancer and continues to be a potential target for therapeutic intervention in cancer. Fatty Acid Translocase (CD36), a multifunctional glycoprotein, has been shown to have an important role in fatty acid metabolism as a fatty acid transporter. Fatty Acid Synthase (FASN), a critical enzyme involved in de novo lipogenesis, has been shown to be upregulated and associated with a poor prognosis in many cancers including colorectal cancer (CRC). However, the role of CD36 in CRC as well as its relation to de novo fatty acid synthesis is not understood. The purpose of our study was: (i) to determine the functional importance of CD36 in CRC and (ii) investigate potential relationships between CD36 and FASN expression in CRC cells. METHODS. Expression of CD36 and FASN was assessed by immunohistochemistry (IHC) using a CRC TMA with 2 sets of tissues: (i) Primary tumors with matched normal colon tissue; [n=56]; (ii) primary and metastatic tumors (liver [n=12] and lung metastasis [n=5]) with matched normal colon. Cellular proliferation was assessed in control and CD36 shRNA knockdown CRC cells, and in primary CRC cells established from patient derived xenografts treated with CD36 inhibitor Sulfo-N-succinimidyl oleate (SSO) in combination with FASN inhibitor TVB-3664. CD36 knockdown was confirmed by qRT-PCR. Expression of pro-survival and apoptotic markers was assessed via western blot in CD36 knockdown and overexpression CRC cells, as well as CD36+ and CD36- isogenic cells. CD36 localization was assessed via confocal imaging. RESULTS. We found that CD36 is overexpressed in primary tumors as compared to normal colon mucosa and its expression positively correlates with expression of FASN. Cellular proliferation was significantly reduced when CD36 was inhibited by SSO and a further reduction in proliferation was observed when SSO treatment was combined with TVB-3664. Knockdown and chemical inhibition of CD36 decreased expression of survivin, a member of the inhibitor of apoptosis (IAP) family of proteins, which was shown to promote cancer cell survival in many tumor types. Conversely, overexpression of CD36 increased survivin expression in CRC cells. Additionally, shRNA knockdown of FASN induced CD36 expression in CRC cells. Immunofluorescence imaging of primary CRC cells treated with TVB-3664 showed an upregulation of membrane-bound CD36. CONCLUSION. Our studies indicate that CD36 upregulation is associated with an increase in cellular proliferation via upregulation of survivin in CRC cells. The correlation between CD36 expression and FASN suggest a connection between CD36 and de novo lipid synthesis. Furthermore, a decrease in FASN expression is associated with CD36 induction, suggesting a possible mechanism of resistance to FASN inhibition. Better understanding of the role of CD36 in CRC may provide new therapeutic approaches for treatment of CRC patients Citation Format: James Drury, Naser Jafari, B. Mark Evers Evers, Yekaterina Y. Zaytseva. Overexpression of CD36 promotes colorectal cancer cell proliferation via upregulation of survivin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4375.

Abstract 1986: Breast cancer-secreted exosomes stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumor progression

Abstract Background: Emerging evidence supports the pivotal roles of adipocytes in breast cancer progression. Beige/brown adipose tissue that activates thermogenesis is suggested to contribute to the hypermetabolic state. However, the mediators and mechanisms remain unclear. Methods: Survival probabilities for recurrence-free survival (RFS) of 106 breast cancer patients were estimated using the Kaplan-Meier method based on the immunohistochemistry results of several biomarkers. Biochemical studies were performed to characterize the novel interrelation between breast cancer cells and adipocytes. Results: In the survival analysis, high MCT4 expression in stromal adipose tissue and overexpression of CD36 or FATP1 in malignant tissue predict poor prognosis for breast cancer patients. We show that tumor-surrounding adipocytes exhibit an altered phenotype in terms of upregulated beige/brown characteristics and increased catabolism. This increase in catabolism is associated with an activated state characterized by the release of metabolites, including free fatty acids, pyruvate, lactate and ketone bodies. Likewise, tumor cells cocultivated with mature adipocytes exhibit metabolic adaptation and an aggressive phenotype in vitro and in vivo. Mechanistically, we show that tumour cells induce beige/brown differentiation and remodel metabolism in resident adipocytes by secreting exosomes that carry high levels of miRNA-144 and miRNA-126. Cancer cell-secreted miRNA-144 promotes beige/brown adipocyte characteristics by downregulating the MAP3K8/ERK1/2/PPARγ axis. We also found that exosomal miRNA-126 remodels metabolism by disrupting IRS/Glut-4 signalling, activating the AMPK/autophagy pathway and stabilizing HIF1α expression in imminent adipocytes. In vivo inhibition of miRNA-144 or miRNA-126 decreases adipocyte-induced tumour growth. Conclusions: These results demonstrate that cancer-derived exosomal miRNA-144 and miRNA-126 can reprogram the systemic energy metabolism to facilitate tumor progression by inducing beige/brown differentiation and enhancing catabolism in recipient adipocytes. Citation Format: Juanjuan Li, Qi Wu, Zhiyu Li, Si Sun, Shan Zhu, Lijun Wang, Juan Wu, Yimin Zhang, Jingping Yuan, Shengrong Sun, Changhua Wang. Breast cancer-secreted exosomes stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1986.

Increased uptake of oxLDL does not exert lipotoxic effects in insulin-secreting cells.

Modified lipoproteins can negatively affect beta cell function and survival. However, the mechanisms behind interactions of modified lipoproteins with beta cells - and in particular, relationships to increased uptake - are only partly clarified. By over-expressing the scavenger receptor CD36 (Tet-on), we increased the uptake of fluorescent low-density modified lipoprotein (oxLDL) into insulin-secreting INS-1 cells. The magnitude of uptake followed the degree of CD36 over-expression. CD36 over-expression increased concomitant efflux of 3H-cholesterol in proportion to the cellular contents of 3H-cholesterol. Exposure to concentrations of oxLDL from 20 to 100 µg/mL dose-dependently increased toxicity (evaluated by MTT) as well as apoptosis. However, the increased uptake of oxLDL due to CD36 over-expression did not exert additive effects on oxLDL toxicity - neither on viability, nor on glucose-induced insulin release and cellular content. Reciprocally, blocking CD36 receptors by Sulfo-N-Succinimidyl Oleate decreased the uptake of oxLDL but did not diminish the toxicity. Pancreatic islets of CD36-/- mice displayed reduced uptake of 3H-cholesterol-labeled oxLDL vs wild type but similar toxicity to oxLDL. OxLDL was found to increase the expression of CD36 in islets and INS-1 cells. In summary, given the experimental conditions, our results indicate that (1) increased uptake of oxLDL is not responsible for toxicity of oxLDL, (2) increased efflux of the cholesterol moiety of oxLDL counterbalances, at least in part, increased uptake and (3) oxLDL participates in the regulation of CD36 in pancreatic islets and in INS-1 cells.

Insulin Resistance-Related Proteins Are Overexpressed in Patients and Rats Treated With Olanzapine and Are Reverted by Pueraria in the Rat Model.

Olanzapine, a commonly used second-generation antipsychotic, causes severe metabolic adverse effects, such as elevated blood glucose and insulin resistance (IR). Previous studies have proposed that overexpression of CD36, GGPPS, PTP-1B, GRK2, and adipose triglyceride lipase may contribute to the development of metabolic syndrome, and Pueraria could eliminate the metabolic adverse effects. The study aimed to investigate the association between olanzapine-associated IR and IR-related proteins (IRRPs) and determine the role of Pueraria in protection against the metabolic adverse effects of olanzapine. The expression levels of IRRPs were examined in schizophrenia patients and rat models with long-term olanzapine treatment. The efficacy of Pueraria on anti-IR by reducing the expression of IRRPs was comprehensively evaluated. Our study demonstrated that in schizophrenia patients chronically treated with olanzapine, the expression levels of IRRPs in patients with a high IR index significantly increased, and these phenomena were further confirmed in a rat model. The expression levels of IRRPs were reduced significantly in Pueraria-treated IR rat models. The body weight, blood glucose, and IR index were restored to levels similar to those of normal controls. The IRRPs are closely related to IR induced by olanzapine, and Pueraria could interfere with olanzapine-associated IR and revert overexpressed IRRPs. These findings suggest that IRRPs are key players in olanzapine-associated IR and that Pueraria has potential as a clinical drug to prevent the metabolic adverse effects of olanzapine, further improving compliance of schizophrenia patients.

High Membranous Expression of Fatty Acid Transport Protein 4 Is Associated with Tumorigenesis and Tumor Progression in Clear Cell Renal Cell Carcinoma.

The increased requirement of fatty acids forces cancer cells to enhance uptake of fatty acids from the extracellular milieu, in addition to de novo lipogenesis. Coexpression of cluster of differentiation 36 (CD36) with fatty acid transport protein 4 (FATP4) or long-chain acyl CoA synthetase 1 (ACSL1) synergistically activated fatty acid uptake in experimental models. In this study, we investigated the immunohistochemical expression of CD36, FATP4, and ACSL1 in 180 cases of clear cell renal cell carcinoma (RCC) in comparison with 80 specimens of the normal kidney. We also examined the clinical implication of these three fatty acid transporters in RCC, which was validated by an open-access The Cancer Genome Atlas data analysis. Both CD36 and FATP4 revealed higher membranous expressions in RCC tumor cells than in normal cells. In contrast, ACSL1 expression was remarkably reduced in RCC tumor cells compared to normal cells. CD36, FATP4, and ACSL1 showed high expressions in 74 (41.1%), 85 (47.2%), and 72 (40.0%) out of 180 RCC cases, respectively. Clinically, high FATP4 in tumor cells was associated with female gender (p = 0.05), high TNM stage (p = 0.039), tumor necrosis (p = 0.009), and tumor recurrence (p = 0.037), while high ACSL1 was only related to female gender (p = 0.023). CD36 expression revealed no correlation with the clinicopathologic parameters of RCC. Increased FATP4 expression displayed an association with short recurrence-free survival (p = 0.003). In conclusion, the high FATP4 expression was clinically associated with poor prognostic factors of RCC. Overexpression of membranous FATP4 and CD36 combined with reduced cytoplasmic expression of ACSL1 might be a tumor-specific feature of RCC, contributing to the tumorigenesis and tumor progression.

CD36 mediates palmitate acid-induced metastasis of gastric cancer via AKT/GSK-3\u03b2/\u03b2-catenin pathway

BackgroundGastric cancer (GC) has a clear predilection for metastasis toward the omentum which is primarily composed of adipose tissue, indicating that fatty acids may contribute to this phenomenon. However their function remains poorly understood in GC. In this study, we investigated the role of palmitate acid (PA) and its cellular receptor CD36 in the progression of GC.MethodsImmunohistochemical (IHC) staining was performed to detect CD36 expression in GC tissues and its clinical significance was determined statistically. CD36 over-expression and knock-down expression cell models were developed and tested in vitro. Wound-healing assays, migration assays, and invasion assays were performed and peritoneal implants into nude mice were done to assess the biological effects of PA and CD36. The underlying mechanisms were investigated using western blot, immunofluorescence (IF), quantitative real-time PCR (qRT-PCR) and antibody blocking assays.ResultsPA promoted the metastasis of GC by phosphorylation of AKT, which facilitated the nuclear localization of β-catenin through inactivation of GSK-3β via phosphorylation. This tumor-promoting effect of PA was mediated by CD36, a cell surface receptor of fatty acids (FAs). The higher the CD36 expression levels in GC tissues correlated with the poorer the prognosis of patients according to the TCGA database, the GEO database and our own clinical data.ConclusionsOur experiments established CD36 as a key mediator of FA-induced metastasis of GC via the AKT/GSK-3β/β-catenin signaling pathway. CD36 might, therefore, constitute a potential therapeutic target for clinical intervention in GC.

CD36- and obesity-associated granulosa cells dysfunction.

Emerging evidence indicates that obesity impairs granulosa cell (GC) function, but the underlying mechanisms remain unclear. Gene expression profiles in GC of non-polycystic ovary syndrome (PCOS) obese (NPO), PCOS obese (PO), PCOS normal weight (PN) and non-PCOS normal weight (NPN) patients were analysed by microarray analysis. Compared with the NPN group, there were 16, 545 and 416 differently expressed genes in the NPO, PO and PN groups respectively. CD36 was the only intersecting gene, with greater than two fold changes in expression between the NPO versus NPN and PO versus NPN comparisons, and was not present in the PN versus NPN comparison. In addition, levels of CD36 protein were higher in GC from obese than normal weight patients. Furthermore, CD36 overexpression in a GC line inhibited cell proliferation, as determined by the cell counting kit-8 (CCK8) test, promoted cell apoptosis, as determined by flow cytometry, and inhibited the secretion of oestradiol by depositing triglyceride in cells and increasing cellular lipid peroxide levels. These adverse effects were reduced by sulfo-N-succinimidyloleate, a specific inhibitor of CD36. Together, the findings of this study suggest that obesity with and without PCOS should be regarded as separate entities, and that CD36 overexpression in GC of obese patients is one of the mechanisms by which obesity impairs GC function.

MiR-1254 Functions as a Tumor Suppressor in Oral Squamous Cell Carcinoma by Targeting CD36.

Oral squamous cell carcinoma is one of the most common cancers around the world. The patients with oral squamous cell carcinoma are often diagnosed at late stages, leading to unfavorable prognosis. MicroRNAs might function as oncogenes or tumor suppressor genes in the tumorigenesis of cancer. This study aimed to explore the role of miR-1254 in oral squamous cell carcinoma. We examined the expression levels of miR-1254 in oral squamous cell carcinoma tissue samples and cell line.Proliferation and invasion assays were performed in oral squamous cell carcinoma cells with miR-1254 overexpression or underexpression. The potential regulatory mechanisms were also explored. We found that miR-1254 was significantly reduced in oral squamous cell carcinoma tissues and cell lines. In addition, downregulation of miR-1254 in oral squamous cell carcinoma tumor tissues was closely associated with cancer staging and lymph node metastasis. Enforced expression of miR-1254 significantly inhibited proliferation and invasion in oral cancer cells, and downregulation of miR-1254 promoted the oncogenic activities of oral cancer cells. CD36 was identified as a direct downstream target of miR-1254 by the luciferase reporter assay. Overexpression of CD36 partially restored the proliferation and invasion capacity inhibited by miR-1254. CD36 expression was inversely correlated with miR-1254 expression in the oral squamous cell carcinoma tissues. Taken together, our study provided the compelling evidence that miR-1254 might inhibit the progression of OSCC by partially downregulating CD36, and restoration of miR-1254 may represent an effective strategy for treating oral squamous cell carcinoma.

Abstract 1443: Overexpression of CD36 promotes tumorigenesis in colorectal cancer

Abstract Fatty acid translocase (CD36), a multifunctional glycoprotein, has an important role in fatty acid metabolism as a fatty acid receptor and transporter. The presence of CD36 positive metastasis-initiating cells correlates with a poorer prognosis in glioblastoma and oral carcinoma. Fatty acid synthase (FASN), a critical enzyme involved in de novo lipogenesis, is upregulated and associated with poorer prognosis in many cancers including colorectal cancer (CRC). The role of CD36 in primary and metastatic CRC as well as its relation to de novo fatty acid synthesis is not understood. The purpose of our study was: (i) to determine the role of CD36 in primary and metastatic CRC, and (ii) to delineate the association of CD36 expression with FASN as a possible mechanism of resistance to FASN inhibition. METHODS. Expression of CD36 and FASN was assessed in a CRC tumor microarray (matched normal colon and primary tumor; 56 cases) as well as matched normal colon, primary and metastatic tumors (liver [n=12] and lung metastasis [n=5]) by immunohistochemistry. CD36 expression was analyzed in control and FASN shRNA knockout CRC cells and tissues from APC/FASN/CRE mouse models by western blot. Cell proliferation was assessed in primary CRC cells established from patient derived xenografts (PDX) treated in combination with Sulfo-N-succinimidyl oleate (SSO), an irreversible inhibitor of CD36, and FASN inhibitor TVB-3664. CD36 expression levels in primary and metastatic PDX derived CRC cells were analyzed via western blot and immunofluorescence imaging. RESULTS. CD36 is overexpressed in primary tumors as compared to normal colon mucosa and its expression positively correlates with expression of FASN. Cell proliferation was significantly reduced when CD36 was inhibited by SSO and a further reduction in cell proliferation was observed when SSO treatment was combined with TVB-3664. Treatment with SSO induced apoptotic markers such as cleaved capspase-3 and decreased survivin. Western blot analysis of primary and metastatic CRC cells showed an upregulation of CD36 expression in the metastatic CRC cells. Additionally, FASN shRNA knockdown of FASN in CRC cells and Cre recombinase-mediated intestinal deletion of FASN in an APC/FASN/CRE mouse model led to an induction of CD36 expression. Immunofluorescence imaging of primary CRC treated with TVB-3664 showed an upregulation of membrane bound CD36. CONCLUSION. CD36 upregulation is associated with CRC progression and inhibition of CD36 decreases proliferation and survival of primary CRC cells. Correlation between expression of CD36 and FASN suggests an interconnection between CD36 and de novo lipid synthesis. Furthermore, a decrease in FASN expression is associated with an induction of CD36, suggesting a possible mechanism of resistance to FASN inhibition. Better understanding the role of CD36 may provide new therapeutic approaches for treatment of CRC patients. Citation Format: James M. Drury, Naser Jafari, B Mark Evers, Yekaterina Y. Zaytseva. Overexpression of CD36 promotes tumorigenesis in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1443.

Human CD36 overexpression in renal tubules accelerates the progression of renal diseases in a mouse model of folic acid-induced acute kidney injury.

BackgroundAcute kidney injury (AKI) is a risk factor for progression to chronic kidney disease, with even subclinical AKI episodes progressing to chronic kidney disease. Several risk factors such as preexisting kidney disease, hyperglycemia, and hypertension may aggravate renal disease after AKI. However, mechanisms underlying the progression of AKI are still unclear. This study identified the effect of human cluster of differentiation 36 (CD36) overexpression on the progression of folic acid-induced AKI.MethodsPax8–rtTA/tetracycline response element–human CD36 transgenic mice were used to elucidate the effect of human CD36 overexpression in the proximal tubules on folic acid-induced AKI.ResultsResults of histological analysis showed severely dilated tubules with casts and albuminuria in folic acid-treated transgenic mice overexpressing human CD36 compared with folic acid-treated wild-type mice. In addition, analysis of mRNA expression showed a significant increase in the collagen 3a1 gene in folic acid-treated transgenic mice overexpressing human CD 36 compared with folic acid-treated wild type mice.ConclusionHuman CD36-overexpressing transgenic mice showed severe pathological changes and albuminuria compared with wild-type mice. Moreover, mRNA expression of the collagen 3a1 gene increased in folic acid-treated transgenic mice. These results suggest that human CD36 overexpression is a risk factor of AKI and its progression to chronic kidney disease.

Enhancing fatty acid utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing optic atrophy 1 processing in the failing heart.

Heart failure (HF) is characterized by reduced fatty acid (FA) utilization associated with mitochondrial dysfunction. Recent evidence has shown that enhancing FA utilization may provide cardioprotection against HF. Our aim was to investigate the effects and the underlying mechanisms of cardiac FA utilization on cardiac function in response to pressure overload. Transverse aortic constriction (TAC) was used in C57 mice to establish pressure overload-induced HF. TAC mice fed on a high fat diet (HFD) exhibited increased cardiac FA utilization and improved cardiac function and survival compared with those on control diet. Such cardioprotection could also be provided by cardiac-specific overexpression of CD36. Notably, both HFD and CD36 overexpression attenuated mitochondrial fragmentation and improved mitochondrial function in the failing heart. Pressure overload decreased ATP-dependent metalloprotease (YME1L) expression and induced the proteolytic cleavage of the dynamin-like guanosine triphosphatase OPA1 as a result of suppressed FA utilization. Enhancing FA utilization upregulated YME1L expression and subsequently rebalanced OPA1 processing, resulting in restoration of mitochondrial morphology in the failing heart. In addition, cardiac-specific overexpression of YME1L exerted similar cardioprotective effects against HF to those provided by HFD or CD36 overexpression. These findings demonstrate that enhancing FA utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing OPA1 processing in pressure overload-induced HF, suggesting a unique metabolic intervention approach to improving cardiac functions in HF.

Prolactin improves hepatic steatosis via CD36 pathway

Prolactin (PRL) is a multifunctional polypeptide with effects on metabolism, however, little is known about its effect on hepatic steatosis and lipid metabolism. Herein, we aimed to assess the role of PRL in the development of non-alcoholic fatty liver disease (NAFLD). The serum PRL levels of 456 patients with NAFLD, 403 controls without NAFLD diagnosed by ultrasound, and 85 individuals with liver histology obtained during metabolic surgery (44 female and 30 male patients with NAFLD and 11 age-matched non-NAFLD female individuals) were evaluated. The expression of the gene encoding the prolactin receptor (PRLR) and signalling molecules involved in hepatic lipid metabolism were evaluated in human liver and HepG2 cells. The effects of overexpression of PRLR or fatty acid translocase (FAT)/CD36 or knockdown of PRLR on hepatic lipid metabolism were tested in free fatty acid (FFA)-treated HepG2 cells. Circulating PRL levels were lower in individuals with ultrasound-diagnosed NAFLD (men: 7.9 [range, 5.9-10.3] µg/L; women: 8.7 [range, 6.1-12.4] µg/L) than those with non-NAFLD (men: 9.1 [range, 6.8-13.0] µg/L, p = 0.002; women: 11.6 [range, 8.2-16.1] µg/L, p <0.001). PRL levels in patients with biopsy-proven severe hepatic steatosis were lower compared with those with mild-to-moderate hepatic steatosis in both men (8.3 [range, 5.4-9.5] µg/L vs. 9.7 [range, 7.1-12.3] µg/L, p = 0.031) and women (8.5 [range, 4.2-10.6] µg/L vs. 9.8 [range, 8.2-15.7] µg/L, p = 0.027). Furthermore, hepatic PRLR gene expression was significantly reduced in patients with NAFLD and negatively correlated with CD36 gene expression. In FFA-induced HepG2 cells, PRL treatment or PRLR overexpression significantly reduced the expression of CD36 and lipid content, effects that were abrogated after silencing of PRLR. Furthermore, overexpression of CD36 significantly reduced the PRL-mediated improvement in lipid content. Our results reveal a novel association between the central nervous system and the liver, whereby PRL/PRLR improved hepatic lipid accumulation via the CD36 pathway. Our clinical study suggests a negative association between prolactin (PRL)/prolactin receptor (PRLR) and the presence of non-alcoholic fatty liver disease (NAFLD). Using cell experiments, we found that PRL ameliorates hepatic steatosis via the hepatic PRLR and fatty acid translocase (FAT)/CD36, a key transporter of free fatty acid uptake in liver. Our findings suggest a novel approach to improving NAFLD using PRL and PRLR. Clinical trial number: NCT03296605.

Ubiquitinated CD36 sustains insulin-stimulated Akt activation by stabilizing insulin receptor substrate 1 in myotubes

Both the magnitude and duration of insulin signaling are important in executing its cellular functions. Insulin-induced degradation of insulin receptor substrate 1 (IRS1) represents a key negative feedback loop that restricts insulin signaling. Moreover, high concentrations of fatty acids (FAs) and glucose involved in the etiology of obesity-associated insulin resistance also contribute to the regulation of IRS1 degradation. The scavenger receptor CD36 binds many lipid ligands, and its contribution to insulin resistance has been extensively studied, but the exact regulation of insulin sensitivity by CD36 is highly controversial. Herein, we found that CD36 knockdown in C2C12 myotubes accelerated insulin-stimulated Akt activation, but the activated signaling was sustained for a much shorter period of time as compared with WT cells, leading to exacerbated insulin-induced insulin resistance. This was likely due to enhanced insulin-induced IRS1 degradation after CD36 knockdown. Overexpression of WT CD36, but not a ubiquitination-defective CD36 mutant, delayed IRS1 degradation. We also found that CD36 functioned through ubiquitination-dependent binding to IRS1 and inhibiting its interaction with cullin 7, a key component of the multisubunit cullin-RING E3 ubiquitin ligase complex. Moreover, dissociation of the Src family kinase Fyn from CD36 by free FAs or Fyn knockdown/inhibition accelerated insulin-induced IRS1 degradation, likely due to disrupted IRS1 interaction with CD36 and thus enhanced binding to cullin 7. In summary, we identified a CD36-dependent FA-sensing pathway that plays an important role in negative feedback regulation of insulin activation and may open up strategies for preventing or managing type 2 diabetes mellitus.

Association of peripheral blood mononuclear cells adenylate cyclase-associated protein 1 mRNA with chronic kidney disease

Aim: Several studies have demonstrated that a proinflammatory cytokine resistin is an important contributor to cardiovascular risk in patients with chronic kidney disease (CKD), as well as its ability to stimulate overexpression of CD36 in vitro. Adenylate cyclase-associated protein 1 (CAP1) is a recently identified receptor for human resistin that mediates proinflammatory effects of resistin. Since CAP1 has not been previously evaluated in CKD, the aim of this study was to determine peripheral blood mononuclear cells (PBMCs) CAP1, CD36, resistin mRNA and plasma resistin concertation in CKD patients.

CD36 overexpression: a possible etiopathogenic mechanism of atherosclerosis in patients with prediabetes and diabetes

RationaleCD36 is a scavenger receptor located on monocytes which is involved in foam cell transformation.AimTo evaluate CD36 expression under different glycemic states in both healthy subjects and in atherosclerotic patients.Subjects and methodsIn order to evaluate the possible effects of hyperglycemia on CD36 expression in healthy subjects, an in vitro experiment was carried out using monocyte in three different conditions: extreme hyperglycemia (HG), euglycemia (EG) and in the absence of glucose. On the other hand, three groups of atherosclerotic patients were evaluated according to their glycemic conditions: normoglycemic (NG), prediabetic (preDM) and diabetic (DM) patients. CD36 expression (mRNA, non-glycated and glycated protein) was analyzed in monocytes.ResultsCD36 mRNA expression in the in vitro experiment peaked at 4 and 24 h under HG conditions. No differences in mRNA levels were found in the EG and control group. The level of non-glycated proteins was higher in HG and EG conditions compared with control group. Glycated protein expression was inhibited by glucose in a sustained manner. In atherosclerotic patients, a significant association was observed when comparing glycated CD36 protein expression in DM with NG patients (p = 0.03). No significant differences were found in mRNA and non-glycated CD36 expression in these patients. Moreover, BMI, insulin, weight and treatment were shown to be related to CD36 expression (mRNA, non-glycated and glycated protein levels, depending of the case) in atherosclerotic patients.ConclusionsHyperglycemia is an important modulator of CD36 mRNA and non-glycated protein expression in vitro, increasing de novo synthesis in healthy subjects. In atherosclerotic patients, there are progressive increases in CD36 receptors, which may be due to a post-translational stimulus.

Fatty acid translocase promoted hepatitis B virus replication by upregulating the levels of hepatic cytosolic calcium

Hepatitis B virus (HBV) is designated a “metabolovirus” due to the intimate connection between the virus and host metabolism. The nutrition state of the host plays a relevant role in the severity of HBV infection. Metabolic syndrome (MS) is prone to increasing HBV DNA loads and accelerating the progression of liver disease in patients with chronic hepatitis B (CHB). Cluster of differentiation 36 (CD36), also named fatty acid translocase, is known to facilitate long-chain fatty acid uptake and contribute to the development of MS. We recently found that CD36 overexpression enhanced HBV replication. In this study, we further explored the mechanism by which CD36 overexpression promotes HBV replication. Our data showed that CD36 overexpression increased HBV replication, and CD36 knockdown inhibited HBV replication. RNA sequencing found some of the differentially expressed genes were involved in calcium ion homeostasis. CD36 overexpression elevated the cytosolic calcium level, and CD36 knockdown decreased the cytosolic calcium level. Calcium chelator BAPTA-AM could override the HBV replication increased by CD36 overexpression, and the calcium activator thapsigargin could improve the HBV replication reduced by CD36 knockdown. We further found that CD36 overexpression activated Src kinase, which plays an important role in the regulation of the store-operated Ca2+ channel. An inhibitor of Src kinase (SU6656) significantly reduced the CD36-induced HBV replication. We identified a novel link between CD36 and HBV replication, which is associated with cytosolic calcium and the Src kinase pathway. CD36 may represent a potential therapeutic target for the treatment of CHB patients with MS.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

CD36 Gene Expression Induced by Fish Oil in Abdominal Adipose Tissue of Rats with Metabolic Syndrome

CD36 Gene Expression Induced by Fish Oil in Abdominal Adipose Tissue of Rats with Metabolic Syndrome Introduction: CD36 is a ubiquitously expressed transmembrane glycoprotein primarily localized in tissues with high levels of fatty acid oxidation. According to its broad binding specificity and signal transduction capabilities, CD36 is thought to be involved in several physiological and pathological events related to metabolic syndrome, which underlies diabetes and cardiovascular diseases, major causes of morbidity and mortality in most of the world. Objective and Method: The aim of this study was to evaluate the effect of dietary fish oil (n-3 PUFAs) administration on adipose tissue CD36 mRNA expression levels in rats with metabolic syndrome induced by 30% sucrose administration in drinking water during 21 weeks. Results and Discussion: After dietary fish oil administration (6 weeks), lower blood pressure and serum concentrations of insulin, non-esterified fatty acids, triacylglycerols and HOMA-IR index were observed, in combination with increased expression levels of CD36 in adipose tissue which would result in enhanced fatty acids uptake, storage and oxidation and the consequent increase in insulin sensitivity. Conclusion: our results show that the overexpression of CD36 in adipocytes could be one of the mechanisms by which fish oil is beneficial to ameliorate metabolic syndrome, through the modulation of fatty acids metabolism.