In Vivo Monitoring of Fabp7 Expression in Transgenic Zebrafish.

In zebrafish, like in mammals, radial glial cells (RGCs) can act as neural progenitors during development and regeneration in adults. However, the heterogeneity of glia subpopulations entails the need for different specific markers of zebrafish glia. Currently, fluorescent protein expression mediated by a regulatory element from the glial fibrillary acidic protein (gfap) gene is used as a prominent glia reporter. We now expand this tool by demonstrating that a regulatory element from the mouse Fatty acid binding protein 7 (Fabp7) gene drives reliable expression in fabp7-expressing zebrafish glial cells. By using three different Fabp7 regulatory element-mediated fluorescent protein reporter strains, we reveal in double transgenic zebrafish that progenitor cells expressing fluorescent proteins driven by the Fabp7 regulatory element give rise to radial glia, oligodendrocyte progenitors, and some neuronal precursors. Furthermore, Bergmann glia represent the almost only glial population of the zebrafish cerebellum (besides a few oligodendrocytes), and the radial glia also remain in the mature cerebellum. Fabp7 regulatory element-mediated reporter protein expression in Bergmann glia progenitors suggests their origin from the ventral cerebellar proliferation zone, the ventricular zone, but not from the dorsally positioned upper rhombic lip. These new Fabp7 reporters will be valuable for functional studies during development and regeneration.

Fatty acid binding protein type 7 deficiency preserves auditory function in noise-exposed mice.

Fatty acid-binding protein 7 (FABP7) is vital for uptake and trafficking of fatty acids in the nervous system. To investigate the involvement of FABP7 in noise-induced hearing loss (NIHL) pathogenesis, we used Fabp7 knockout (KO) mice generated via CRISPR/Cas9 in the C57BL/6 background. Initial auditory brainstem response (ABR) measurements were conducted at 9 weeks, followed by noise exposure at 10 weeks. Subsequent ABRs were performed 24 h later, with final measurements at 12 weeks. Inner ears were harvested 24 h after noise exposure for RNA sequencing and metabolic analyses. We found no significant differences in initial ABR measurements, but Fabp7 KO mice showed significantly lower thresholds in the final ABR measurements. Hair cell survival was also enhanced in Fabp7 KO mice. RNA sequencing revealed that genes associated with the electron transport chain were upregulated or less impaired in Fabp7 KO mice. Metabolomic analysis revealed various alterations, including decreased glutamate and aspartate in Fabp7 KO mice. In conclusion, FABP7 deficiency mitigates cochlear damage following noise exposure. This protective effect was supported by the changes in gene expression of the electron transport chain, and in several metabolites, including excitotoxic neurotransmitters. Our study highlights the potential therapeutic significance of targeting FABP7 in NIHL.

Potential effects of brain lipid binding protein in the pathogenesis of amyotrophic lateral sclerosis.

Current studies suggest that the abnormal alteration of brain lipid binding protein (BLBP) might participate in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, the detailed understanding of ALS pathogenesis been yet to be elucidated. Therefore, this research intended to explore the potential effects of BLBP in ALS. The observation and analysis of BLBP-altered features in various anatomical areas and different spinal segments was conducted at the pre-onset, onset, and progression stages of Tg(SOD1*G93A)1Gur (TG) mice and the same periods of age-matched SOD1 wild-type (WT) mice by fluorescence immunohistochemistry and western blotting. BLBP-positive cells were comprehensively distributed in various spinal anatomical areas, especially in both the anterior and posterior horn, around the central canal and in anterior, lateral, and posterior funiculi. Overall, BLBP expression tended to increase from the pre-onset to the onset to the progression stages of the same periods of age-matched WT mice. Furthermore, in TG mice, BLBP expression in the entire spinal cord significantly increased from onset to the progression stage. BLBP was expressed in neurons, astrocytes, and radial glial cells, and at the early and late stages of neural precursor cells (NPCs) and was predominantly distributed outside the cell nucleus. The increase of BLBP-positive cells was closely related to neural cell reduction in TG mice. The distribution and increased expression of BLBP among the cervical, thoracic, and lumbar segments of the spinal cord might participate in the development of ALS and exert potential effects in the pathogenesis of ALS by regulating NPCs.

A combined computational-biophysical approach to understanding fatty acid binding to FABP7.

Members of the fatty acid binding protein (FABP) family function as intracellular transporters of long-chain fatty acids and other hydrophobic molecules to different cellular compartments. Brain FABP (FABP7) exhibits ligand-directed differences in cellular transport. For example, when FABP7 binds to docosahexaenoic acid (DHA), the complex relocates to the nucleus and influences transcriptional activity, whereas FABP7 bound with monosaturated fatty acids remains in the cytosol. Preferential binding of FABP7 to polyunsaturated fatty acids like DHA has been previously observed and is thought to play a role in differential localization. However, we find that at 37°C, FABP7 does not display strong selectivity, suggesting that the conformational ensemble of FABP7 and its perturbation upon binding may be important. We use molecular dynamics simulations, NMR, and a variety of biophysical techniques to better understand the conformational ensemble of FABP7, how it is perturbed by fatty acid binding, and how this may be related to ligand-directed transport. We find that FABP7 has high degree of conformational heterogeneity that is substantially reduced upon ligand binding. We also observe substantial heterogeneity in ligand binding poses, which is consistent with our finding that ligand binding is resistant to mutations in key polar residues in the binding pocket. Our NMR experiments show that DHA binding leads to chemical shift perturbations in residues near the nuclear localization signal, which may point toward a mechanism of differential transport.

Oleic acid-bound FABP7 drives glioma cell proliferation through regulation of nuclear lipid droplet formation.

Fatty acid-binding protein 7 (FABP7), one of the fatty acid (FA) chaperones involved in the modulation of intracellular FA metabolism, is highly expressed in glioblastoma, and its expression is associated with decreased patients' prognosis. Previously, we demonstrated that FABP7 requires its binding partner to exert its function and that a mutation in the FA-binding site of FABP7 affects tumour biology. Here, we explored the role of FA ligand binding for FABP7 function in tumour proliferation and examined the mechanism of FABP7 and ligand interaction in tumour biology. We discovered that among several FA treatment, oleic acid (OA) boosted cell proliferation of FABP7-expressing cells. In turn, OA increased FABP7 nuclear localization, and the accumulation of FABP7-OA complex in the nucleus induced the formation of nuclear lipid droplet (nLD), as well as an increase in colocalization of nLD with promyelocytic leukaemia (PML) nuclear bodies. Furthermore, OA increased mRNA levels of proliferation-related genes in FABP7-expressing cells through histone acetylation. Interestingly, these OA-boosted functions were abrogated in FABP7-knockout cells and mutant FABP7-overexpressing cells. Thus, our findings suggest that FABP7-OA intracellular interaction may modulate nLD formation and the epigenetic status thereby enhancing transcription of proliferation-regulating genes, ultimately driving tumour cell proliferation.

Nuclear FABP7 regulates cell proliferation of wild-type IDH1 glioma through caveolae formation.

Isocitrate dehydrogenase 1 (IDH1) is a key enzyme in cellular metabolism. IDH1 mutation (IDH1mut) is the most important genetic alteration in lower grade glioma, whereas glioblastoma (GB), the most common malignant brain tumor, often has wild-type IDH1 (IDH1wt). Although there is no effective treatment yet for neither IDH1wt nor IDHmut GB, it is important to note that the survival span of IDH1wt GB patients is significantly shorter than those with IDH1mut GB. Thus, understanding IDH1wt GB biology and developing effective molecular-targeted therapies is of paramount importance. Fatty acid-binding protein 7 (FABP7) is highly expressed in GB, and its expression level is negatively correlated with survival in malignant glioma patients; however, the underlying mechanisms of FABP7 involvement in tumor proliferation are still unknown. In this study, we demonstrate that FABP7 is highly expressed and localized in nuclei in IDH1wt glioma. Wild-type FABP7 (FABP7wt) overexpression in IDH1wt U87 cells increased cell proliferation rate, caveolin-1 expression, and caveolae/caveosome formation. In addition, FABP7wt overexpression increased the levels of H3K27ac on the caveolin-1 promoter through controlling the nuclear acetyl-CoA level via the interaction with ACLY. Consistent results were obtained using a xenograft model transplanted with U87 cells overexpressing FABP7. Interestingly, in U87 cells with mutant FABP7 overexpression, both in vitro and in vivo phenotypes shown by FABP7wt overexpression were disrupted. Furthermore, IDH1wt patient GB showed upregulated caveolin-1 expression, increased levels of histone acetylation, and increased levels of acetyl-CoA compared with IDH1mut patient GB. Taken together, these data suggest that nuclear FABP7 is involved in cell proliferation of GB through caveolae function/formation regulated via epigenetic regulation of caveolin-1, and this mechanism is critically important for IDH1wt tumor biology.

Silencing of circular RNA PUM1 inhibits clear cell renal cell carcinoma progression through the miR-340-5p/FABP7 axis.

Circular RNAs (circRNAs) monitor the development of clear cell renal cell carcinoma (ccRCC). However, the role of CircPUM1 in ccRCC malignancy is not studied. We estimated the mechanism of CircPUM1 in ccRCC progression in this study. CircPUM1 expression in ccRCC tissues and cells was detected. The expression of CircPUM1 was interfered in ccRCC cells, and its effects on the growth of ccRCC cells were studied. Nuclear/cytosol fractionation assay was performed for the location of CircPUM1, and the downstream miR, gene, and pathway involved in ccRCC progression were explored through gain- and loss-of-function experiments. CircPUM1 was highly expressed in ccRCC samples and cells. Inhibition of CircPUM1 prevented the growth ccRCC cells. CircPUM1 was localized in the cytoplasm and bound to miR-340-5p. Overexpression of miR-340-5p inhibited the growth of ccRCC cells. miR-340-5p targeted FABP7, and CircPUM1 induced FABP7 expression and the activation of MEK/ERK pathway through competitively binding to miR-340-5p. Overexpression of FABP7 attenuated the inhibitory effect of CircPUM1 silencing on the growth of ccRCC cells. Overall, CircPUM1 upregulates FABP7 expression by competitively binding to miR-340-5p, and then activates the MEK/ERK pathway, thus promoting ccRCC progression.

FABP7 Facilitates Uptake of Docosahexaenoic Acid in Glioblastoma Neural Stem-like Cells.

Glioblastoma (GBM) is an aggressive tumor with a dismal prognosis. Neural stem-like cells contribute to GBM's poor prognosis by driving drug resistance and maintaining cellular heterogeneity. GBM neural stem-like cells express high levels of brain fatty acid-binding protein (FABP7), which binds to polyunsaturated fatty acids (PUFAs) ω-6 arachidonic acid (AA) and ω-3 docosahexaenoic acid (DHA). Similar to brain, GBM tissue is enriched in AA and DHA. However, DHA levels are considerably lower in GBM tissue compared to adult brain. Therefore, it is possible that increasing DHA content in GBM, particularly in neural stem-like cells, might have therapeutic value. Here, we examine the fatty acid composition of patient-derived GBM neural stem-like cells grown as neurosphere cultures. We also investigate the effect of AA and DHA treatment on the fatty acid profiles of GBM neural stem-like cells with or without FABP7 knockdown. We show that DHA treatment increases DHA levels and the DHA:AA ratio in GBM neural stem-like cells, with FABP7 facilitating the DHA uptake. We also found that an increased uptake of DHA inhibits the migration of GBM neural stem-like cells. Our results suggest that increasing DHA content in the GBM microenvironment may reduce the migration/infiltration of FABP7-expressing neural stem-like cancer cells.

A prospective study revealing the role of an immune-related eRNA, WAKMAR2, in breast cancer.

Enhancer RNAs (eRNAs) are a subclass of non-coding RNAs that are generated during the transcription of enhancer regions and play an important role in tumourigenesis. In this study, we focused on the crucial eRNAs that participate in immune responses in invasive breast cancer (IBC). We first used The Cancer Genome Atlas and Human enhancer RNA Atlas to screen for tissue-specific eRNAs and their target genes. Through Pearson correlation analysis with immune genes, the eRNA WAKMAR2 was identified as a key candidate involved in IBC. Our further research suggested that WAKMAR2 is crucial in regulating the tumour microenvironment and may function by regulating immune-related genes, including IL27RA, RAC2, FABP7, IGLV1-51, IGHA1, and IGHD. Quantitative reverse transcription-polymerase chain reaction was used to detect the expression of WAKMAR2 in IBC and normal tissues, and the effect of WAKMAR2 on the regulation of downstream genes in MB-231 and MCF7 cells was studied in vitro. WAKMAR2 was found to be highly involved in tumour immunity and was downregulated in IBC tissues. Furthermore, the expression of WAKMAR2 and its target genes was observed at the pan-cancer level. This study provides evidence to suggest new potential targets for the treatment of breast cancer.

Improvement of hyperlipidemia by aerobic exercise in mice through a regulatory effect of miR-21a-5p on its target genes.

Hyperlipidemia is a risk factor for cardiovascular disease, and miR-21a-5p plays an important role in the occurrence and progression of hyperlipidemia. Here, we aimed to investigate the mechanism of aerobic exercise improved hyperlipidemia through enhancing miR-21a-5p expression. In this study, high-fat/high-cholesterol diet mice received 8 weeks of aerobic exercise intervention, then we collected plasma and liver samples, we found that there had a notable improvement in weight gain, blood lipid level, and liver steatosis in hyperlipidemia mice after 8 weeks of aerobic exercise intervention. Besides, aerobic exercise significantly up-regulated the expression of miR-21a-5p and provoked favorable changes in the expression of target genes. Knockdown of miR-21a-5p resulted in dysregulation of lipid metabolism and increased expression of FABP7, HMGCR, ACAT1, and OLR1. While aerobic exercise could alleviate miR-21a-5p knock-down induced lipid metabolism disorder. Taken together, these results demonstrated that aerobic exercise improved hyperlipidemia through miR-21a-5p-induced inhibition of target genes FABP7, HMGCR, ACAT1, and OLR1.

HIF1α-Regulated Expression of the Fatty Acid Binding Protein Family Is Important for Hypoxic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus.

The hypoxic microenvironment and metabolic reprogramming are two major contributors to the phenotype of oncogenic virus-infected cells. Infection by Kaposi's sarcoma-associated herpesvirus (KSHV) stabilizes hypoxia-inducible factor 1α (HIF1α) and reprograms cellular metabolism. We investigated the comparative transcriptional regulation of all major genes involved in fatty acid and amino acid metabolism in KSHV-positive and -negative cells grown under normoxic or hypoxic conditions. We show a distinct regulation of genes involved in both fatty acid and amino acid metabolism in KSHV-positive cells grown in either normoxic or hypoxic conditions, with a particular focus on genes involved in the acetyl coenzyme A (acetyl-CoA) pathway. The fatty acid binding protein (FABP) family of genes, specifically FABP1, FABP4, and FABP7, was also observed to be synergistically upregulated in hypoxia by KSHV. This pattern of FABP gene expression was also seen in naturally infected KSHV BC3 or BCBL1 cells when compared to KSHV-negative DG75 or BL41 cells. Two KSHV-encoded antigens, which positively regulate HIF1α, the viral G-protein coupled receptor (vGPCR), and the latency-associated nuclear antigen (LANA) were shown to drive upregulation of the FABP gene transcripts. Suppression of FABPs by RNA interference resulted in an adverse effect on hypoxia-dependent viral reactivation. Overall, this study provides new evidence, which supports a rationale for the inhibition of FABPs in KSHV-positive cells as potential strategies, for the development of therapeutic approaches targeting KSHV-associated malignancies.IMPORTANCE Hypoxia is a detrimental stress to eukaryotes and inhibits several cellular processes, such as DNA replication, transcription, translation, and metabolism. Interestingly, the genome of Kaposi's sarcoma-associated herpesvirus (KSHV) is known to undergo productive replication in hypoxia. We investigated the comparative transcriptional regulation of all major genes involved in fatty acid and amino acid metabolism in KSHV-positive and -negative cells grown under normoxic or hypoxic conditions. Several metabolic pathways were observed differentially regulated by KSHV in hypoxia, specifically, the fatty acid binding protein (FABP) family genes (FABP1, FABP4, and FABP7). KSHV-encoded antigens, vGPCR and LANA, were shown to drive upregulation of the FABP transcripts. Suppression of FABPs by RNA interference resulted in an adverse effect on hypoxia-dependent viral reactivation. Overall, this study provides new evidence, which supports a rationale for the inhibition of FABPs in KSHV-positive cells as potential strategies, for the development of therapeutic approaches targeting KSHV-associated malignancies.

Ligand Bound Fatty Acid Binding Protein 7 (FABP7) Drives Melanoma Cell Proliferation Via Modulation of Wnt/ß-Catenin Signaling.

PURPOSE: Fatty acid-binding protein 7 (FABP7) involved in intracellular lipid dynamics, is highly expressed in melanomas and associated with decreased patient survival. Several studies put FABP7 at the center of melanoma cell proliferation. However, the underlying mechanisms are not well deciphered. This study examines the effects of FABP7 on Wnt/ß-catenin signaling that enhances proliferation in melanoma cells. METHODS: Skmel23 cells with FABP7 silencing and Mel2 cells overexpressed with wild-type FABP7 (FABP7wt) and mutated FABP7 (FABP7mut) were used. Cell proliferation and migration were analyzed by proliferation and wound-healing assay, respectively. Transcriptional activation of the Wnt/ß-catenin signaling was measured by luciferase reporter assay. The effects of a specific FABP7 inhibitor, MF6, on proliferation, migration, and modulation of the Wnt/ß-catenin signaling were examined. RESULTS: FABP7 siRNA knockdown in Skmel23 decreased proliferation and migration, cyclin D1 expression, as well as Wnt/ß-catenin activity. Similarly, FABP7wt overexpression in Mel2 cells increased these effects, but FABP7mut abrogated these effects. Pharmacological inhibition of FABP7 function with MF6 suppressed FABP7-regulated proliferation of melanoma cells. CONCLUSION: These results suggest the importance of the interaction between FABP7 and its ligands in melanoma proliferation modulation, and the beneficial implications of therapeutic targeting of FABP7 for melanoma treatment.

Upregulation of FABP7 inhibits acute kidney injury-induced TCMK-1 cell apoptosis via activating the PPAR gamma signalling pathway.

Acute kidney injury (AKI) is a frequently seen critical disorder in the clinic. The current research aimed to examine the role of hydroxyacid oxidase 2 (FABP7) in AKI-induced cell apoptosis. A total of 289 overlapping genes were used to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and to construct a protein-protein interaction (PPI) network using the DAVID database and Cytoscape software. The 10 hub genes of the PPI network were screened out using the cytohubba plug-in of Cytoscape software. FABP7 represented both the differentially expressed gene (DEG) from the GSE44925 and GSE62732 datasets and the top hub gene of the PPI network. The results of the PAS assay showed that FABP7 knockout in vivo aggravated lipopolysaccharide (LPS)-induced AKI. Meanwhile, LPS inhibited cell viability and the expression of FABP7, PPARγ, PPARα, PTEN and p27kip1, and increased the TNF-α level, and cleaved caspase-3/-9 expression and the phosphorylation of PTEN in vitro. FABP7 overexpression reversed the effects of LPS on inhibiting cell viability and proliferation, promoting cell apoptosis, increasing the expression of FABP7, PPARγ, PTEN and p27kip1, and reducing cleaved caspase-3/-9 expression and the phosphorylation of PTEN, but had no influence on PPARα expression. The PPARγ signal pathway inhibitors blocked the protective effect of FABP7 overexpression in LPS-treated TCMK-1 cells, while the PPARγ signal pathway activator inhibited the harmful effect of FABP7 inhibition in LPS-treated TCMK-1 cells. In conclusion, FABP7 overexpression inhibited the AKI-induced cell apoptosis and promoted the proliferation through activating the PPARγ signal pathway in vivo and in vitro.

Fatty acid binding protein 7 mediates linoleic acid-induced cell death in triple negative breast cancer cells by modulating 13-HODE.

Different fatty acids have distinct effects on the survival of breast cancer cells, which could be mediated by fatty acid binding proteins (FABPs), a family of lipid chaperones. Due to the diverse structures of the members of FABP family, each FABP demonstrates distinct binding affinities to different fatty acids. Of note, FABP7 is predominantly expressed in triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer. Yet, the role of FABP7 in modulating the effects of fatty acids on TNBC survival was unclear. In contrast to the high expression of FABP7 in human TNBC tumours, FABP7 protein was undetectable in TNBC cell lines. Hence, a FABP7 overexpression model was used for this study, in which the transduced TNBC cell lines (MDA-MB-231 and Hs578T) were treated with various mono- and polyunsaturated fatty acids. Oleic acid (OA), docosahexaenoic acid (DHA) and arachidonic acid (AA) inhibited TNBC cell growth at high concentrations, with no differences resulted from FABP7 overexpression. Interestingly, overexpression of FABP7 augmented linoleic acid-induced cell death in MDA-MB-231 cells. The increased cell death may be explained by a decrease in 13-HODE, a pro-tumorigenic oxidation product of linoleic acid. The phenotype was, however, attenuated with a rescue treatment using 25 nM 13-HODE. The decrease in 13-HODE was potentially due to fatty acid partitioning modulated by FABP7, as demonstrated by a 3-fold increase in fatty acid oxidation. Our findings suggest that linoleic acid could be a potential therapeutic strategy for FABP7-overexpressing TNBC patients.

Circadian expression of Fabp7 mRNA is disrupted in Bmal1 KO mice.

The astrocyte brain-type fatty acid binding protein (Fabp7) gene expression cycles globally throughout mammalian brain, and is known to regulate sleep in multiple species, including humans. The mechanisms that control circadian Fabp7 gene expression are not completely understood and may include core circadian clock components. Here we examined the circadian expression of Fabp7 mRNA in the hypothalamus of core clock gene Bmal1 knock-out (KO) mice. We observed that the circadian rhythm of Fabp7 mRNA expression is blunted, while overall Fabp7 mRNA levels are significantly higher in Bmal1 KO compared to control (C57BL/6 J) mice. We did not observe any significant changes in levels of hypothalamic mRNA expression of Fabp3 or Fabp5, two other fatty acid binding proteins expressed in mammalian brain, between Bmal1 KO and control mice. These results suggest that Fabp7 gene expression is regulated by circadian processes and may represent a molecular link controlling the circadian timing of sleep with sleep behavior.

Study of FABP's interactome and detecting new molecular targets in clear cell renal cell carcinoma.

Fatty acids (FAs) play a crucial role in the development of clear cell renal cell carcinoma (ccRCC), FAs function requires the participation of fatty-acid-binding protein (FABP). Current studies have shown that different members of the FABP's family play different roles in the tumorigenesis of ccRCC. Therefore, the systematic analysis of FABPs will be of great significance. However, the diverse expression patterns and prognostic values of nine FABPs have yet to be elucidated. In this study, through multiple analysis and verification of multiple databases, such as ONCOMINE, The Human Protein Atlas, UALCAN, Gene Expression Profiling Interactive Analysis, and cBioPortal, we found that the expression of FABP1 was significantly downregulated and the expression of FABP5/6/7 was significantly upregulated in ccRCC compared with renal tissues, and the patients with high messenger RNA (mRNA) levels of the FABP5/6/7 or low mRNA levels of FABP1 were predicted to have a lower overall survival or disease-free survival. Further analysis by the protein-protein interaction (PPI), Gene Ontology pathway, and Kyoto Encyclopedia of Genes and Genomes pathway showed that FABPs were mainly involved in the peroxisome proliferator-activated receptor (PPAR) pathway. In coexpression analysis, we found that FABP1/5/6/7 was coexpressed with transforming growth factor-ß1 (TGF-ß1), PPARA, and LPL. This study implied that FABP1/5/6/7 could act as an important tumor biomarker of ccRCC; the role of FABPs may be related to PPAR or TGF-ß pathway.

FABP7 is a key metabolic regulator in HER2+ breast cancer brain metastasis.

Overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer patients is associated with increased incidence of breast cancer brain metastases (BCBM), but the mechanisms underlying this phenomenon remain unclear. Here, to identify brain-predominant genes critical for the establishment of BCBM, we conducted an in silico screening analysis and identified that increased levels of fatty acid-binding protein 7 (FABP7) correlate with a lower survival and higher incidence of brain metastases in breast cancer patients. We validated these findings using HER2+ BCBM cells compared with parental breast cancer cells. Importantly, through knockdown and overexpression assays, we characterized the role of FABP7 in the BCBM process in vitro and in vivo. Our results uncover a key role of FABP7 in metabolic reprogramming of HER2 + breast cancer cells, supporting a glycolytic phenotype and storage of lipid droplets that enable their adaptation and survival in the brain microenvironment. In addition, FABP7 is shown to be required for upregulation of key metastatic genes and pathways, such as integrins-Src and VEGFA, and for the growth of HER2+ breast cancer cells in the brain microenvironment in vivo. Together, our results support FABP7 as a potential target for the treatment of HER2+ BCBM.

The role of fatty acid binding protein 7 in spinal cord astrocytes in a mouse model of experimental autoimmune encephalomyelitis.

Fatty acid binding protein 7 (FABP7) is expressed in astrocytes of the developing and mature central nervous system, and modulates astrocyte function by controlling intracellular fatty acid homeostasis. Astrocytes in the spinal cord have an important role in the process of myelin degeneration and regeneration. In the present study, the authors examined the role of FABP7 in astrocytes in a mouse model of experimental autoimmune encephalomyelitis (EAE), which is an established model of multiple sclerosis (MS). FABP7 was expressed in the white matter astrocytes and increased after EAE onset; particularly strong expression was observed in demyelinating regions. In FABP7-knockout (KO) mice, the onset of EAE symptoms occurred earlier than in wild type (WT) mice, and mRNA expression levels of inflammatory cytokines (IL-17 and TNF-α) were higher in FABP7-KO lumbar spinal cord than in WT lumbar spinal cord at early stage of EAE. Interestingly, however, the clinical score was significantly reduced in FABP7-KO mice compared with WT mice in the late phase of EAE. Moreover, the area exhibiting expression of fibronectin, which is an extracellular matrix protein mainly produced by astrocytes and inhibits remyelination of oligodendrocytes, was significantly decreased in FABP7-KO compared with WT mice. Collectively, FABP7 in astrocyte may have a role to protect from the induction of inflammation leading to demyelination in CNS at early phase of EAE. Moreover, FABP7 may be involved in the regulation of fibronectin production through the modification of astrocyte activation at late phase of EAE.

Limited overlap in significant hits between genome-wide association studies on two airflow obstruction definitions in the same population.

BACKGROUND: Airflow obstruction is a hallmark of chronic obstructive pulmonary disease (COPD), and is defined as either the ratio between forced expiratory volume in one second and forced vital capacity (FEV1/FVC) < 70% or < lower limit of normal (LLN). This study aimed to assess the overlap between genome-wide association studies (GWAS) on airflow obstruction using these two definitions in the same population stratified by smoking. METHODS: GWASes were performed in the LifeLines Cohort Study for both airflow obstruction definitions in never-smokers (NS = 5071) and ever-smokers (ES = 4855). The FEV1/FVC < 70% models were adjusted for sex, age, and height; FEV1/FVC < LLN models were not adjusted. Ever-smokers models were additionally adjusted for pack-years and current-smoking. The overlap in significantly associated SNPs between the two definitions and never/ever-smokers was assessed using several p-value thresholds. To quantify the agreement, the Pearson correlation coefficient was calculated between the p-values and ORs. Replication was performed in the Vlagtwedde-Vlaardingen study (NS = 432, ES = 823). The overlapping SNPs with p < 10- 4 were validated in the Vlagtwedde-Vlaardingen and Rotterdam Study cohorts (NS = 1966, ES = 3134) and analysed for expression quantitative trait loci (eQTL) in lung tissue (n = 1087). RESULTS: In the LifeLines cohort, 96% and 93% of the never- and ever-smokers were classified concordantly based on the two definitions. 26 and 29% of the investigated SNPs were overlapping at p < 0.05 in never- and ever-smokers, respectively. At p < 10- 4 the overlap was 4% and 6% respectively, which could be change findings as shown by simulation studies. The effect estimates of the SNPs of the two definitions correlated strongly, but the p-values showed more variation and correlated only moderately. Similar observations were made in the Vlagtwedde-Vlaardingen study. Two overlapping SNPs in never-smokers (NFYC and FABP7) had the same direction of effect in the validation cohorts and the NFYC SNP was an eQTL for NFYC-AS1. NFYC is a transcription factor that binds to several known COPD genes, and FABP7 may be involved in abnormal pulmonary development. CONCLUSIONS: The definition of airflow obstruction and the population under study may be important determinants of which SNPs are associated with airflow obstruction. The genes FABP7 and NFYC(-AS1) could play a role in airflow obstruction in never-smokers specifically.

Role of FABP7 in tumor cell signaling.

Lipids are major molecules for the function of organisms and are involved in the pathophysiology of various diseases. Fatty acids (FAs) signaling and their metabolism are some of the most important pathways in tumor development, as lipids serve as energetic sources during carcinogenesis. Fatty acid binding proteins (FABPs) facilitate FAs transport to different cell organelles, modulating their metabolism along with mediating other physiological activities. FABP7, brain-typed FABP, is thought to be an important molecule for cell proliferation in healthy as well as diseased organisms. Several studies on human tumors and tumor-derived cell lines put FABP7 in the center of tumorigenesis, and its high expression level has been reported to correlate with poor prognosis in different tumor types. Several types of FABP7-expressing tumors have shown an up-regulation of cell signaling activity, but molecular mechanisms of FABP7 involvement in tumorigenesis still remain elusive. In this review, we focus on the expression and function of FABP7 in different tumors, and possible mechanisms of FABP7 in tumor proliferation and migration.