Showing papers on "FABP7 published in 2014"

The nuclear receptor REV-ERBα regulates Fabp7 and modulates adult hippocampal neurogenesis.

Abstract: The function of the nuclear receptor Rev-erbα (Nr1d1) in the brain is, apart from its role in the circadian clock mechanism, unknown. Therefore, we compared gene expression profiles in the brain between wild-type and Rev-erbα knock-out (KO) animals. We identified fatty acid binding protein 7 (Fabp7, Blbp) as a direct target of repression by REV-ERBα. Loss of Rev-erbα manifested in memory and mood related behavioral phenotypes and led to overexpression of Fabp7 in various brain areas including the subgranular zone (SGZ) of the hippocampus, where neuronal progenitor cells (NPCs) can initiate adult neurogenesis. We found increased proliferation of hippocampal neurons and loss of its diurnal pattern in Rev-erbα KO mice. In vitro, proliferation and migration of glioblastoma cells were affected by manipulating either Fabp7 expression or REV-ERBα activity. These results suggest an important role of Rev-erbα and Fabp7 in adult neurogenesis, which may open new avenues for treatment of gliomas as well as neurological diseases such as depression and Alzheimer.

Functional characterization of FABP3, 5 and 7 gene variants identified in schizophrenia and autism spectrum disorder and mouse behavioral studies

Abstract: Disturbances of lipid metabolism have been implicated in psychiatric illnesses. We previously reported an association between the gene for fatty acid binding protein 7 (FABP7) and schizophrenia. Furthermore, we identified and reported several rare non-synonymous polymorphisms of the brain-expressed genes FABP3, FABP5 and FABP7 from schizophrenia and autism spectrum disorder (ASD), diseases known to part share genetic architecture. Here, we conducted further studies to better understand the contribution these genes make to the pathogenesis of schizophrenia and ASD. In postmortem brains, we detected altered mRNA expression levels of FABP5 in schizophrenia, and of FABP7 in ASD and altered FABP5 in peripheral lymphocytes. Using a patient cohort, comprehensive mutation screening identified six missense and two frameshift variants from the three FABP genes. The two frameshift proteins, FABP3 E132fs and FABP7 N80fs, formed cellular aggregates and were unstable when expressed in cultured cells. The four missense mutants with predicted possible damaging outcomes showed no changes in intracellular localization. Examining ligand binding properties, FABP7 S86G and FABP7 V126L lost their preference for docosahexaenoic acid to linoleic acid. Finally, mice deficient in Fabp3, Fabp5 and Fabp7 were evaluated in a systematic behavioral test battery. The Fabp3 knockout (KO) mice showed decreased social memory and novelty seeking, and Fabp7 KO mice displayed hyperactive and anxiety-related phenotypes, while Fabp5 KO mice showed no apparent phenotypes. In conclusion, disturbances in brain-expressed FABPs could represent an underlying disease mechanism in a proportion of schizophrenia and ASD sufferers.

HDAC1 and HDAC2 Control the Specification of Neural Crest Cells into Peripheral Glia

Abstract: Schwann cells, the myelinating glia of the peripheral nervous system (PNS), originate from multipotent neural crest cells that also give rise to other cells, including neurons, melanocytes, chondrocytes, and smooth muscle cells. The transcription factor Sox10 is required for peripheral glia specification. However, all neural crest cells express Sox10 and the mechanisms directing neural crest cells into a specific lineage are poorly understood. We show here that histone deacetylases 1 and 2 (HDAC1/2) are essential for the specification of neural crest cells into Schwann cell precursors and satellite glia, which express the early determinants of their lineage myelin protein zero (P0) and/or fatty acid binding protein 7 (Fabp7). In neural crest cells, HDAC1/2 induced expression of the transcription factor Pax3 by binding and activating the Pax3 promoter. In turn, Pax3 was required to maintain high Sox10 levels and to trigger expression of Fabp7. In addition, HDAC1/2 were bound to the P0 promoter and activated P0 transcription. Consistently, in vivo genetic deletion of HDAC1/2 in mouse neural crest cells led to strongly decreased Sox10 expression, no detectable Pax3, virtually no satellite glia, and no Schwann cell precursors in dorsal root ganglia and peripheral nerves. Similarly, in vivo ablation of Pax3 in the mouse neural crest resulted in strongly reduced expression of Sox10 and Fabp7. Therefore, by controlling the expression of Pax3 and the concerted action of Pax3 and Sox10 on their target genes, HDAC1/2 direct the specification of neural crest cells into peripheral glia.

Gene expression of fatty acid transport and binding proteins in the blood-brain barrier and the cerebral cortex of the rat: differences across development and with different DHA brain status.

Abstract: Specific mechanisms for maintaining docosahexaenoic acid (DHA) concentration in brain cells but also transporting DHA from the blood across the blood-brain barrier (BBB) are not agreed upon. Our main objective was therefore to evaluate the level of gene expression of fatty acid transport and fatty acid binding proteins in the cerebral cortex and at the BBB level during the perinatal period of active brain DHA accretion, at weaning, and until the adult age. We measured by real time RT-PCR the mRNA expression of different isoforms of fatty acid transport proteins (FATPs), long-chain acyl-CoA synthetases (ACSLs), fatty acid binding proteins (FABPs) and the fatty acid transporter (FAT)/CD36 in cerebral cortex and isolated microvessels at embryonic day 18 (E18) and postnatal days 14, 21 and 60 (P14, P21 and P60, respectively) in rats receiving different n-3 PUFA dietary supplies (control, totally deficient or DHA-supplemented). In control rats, all the genes were expressed at the BBB level (P14 to P60), the mRNA levels of FABP5 and ACSL3 having the highest values. Age-dependent differences included a systematic decrease in the mRNA expressions between P14-P21 and P60 (2 to 3-fold), with FABP7 mRNA abundance being the most affected (10-fold). In the cerebral cortex, mRNA levels varied differently since FATP4, ACSL3 and ACSL6 and the three FABPs genes were highly expressed. There were no significant differences in the expression of the 10 genes studied in n-3 deficient or DHA-supplemented rats despite significant differences in their brain DHA content, suggesting that brain DHA uptake from the blood does not necessarily require specific transporters within cerebral endothelial cells and could, under these experimental conditions, be a simple passive diffusion process.

An investigation in to the role of fatty acid binding protein-7, insulin like growth factor binding protein-2 and phosphatase and tensin homolog in triple negative breast cancer, in vitro and in vivo

Abstract: Introduction Triple negative breast cancers are defined by their lack of expression of HER, oestrogen receptors and progesterone receptors. They account for around 10-24% of cases. To define a cancer by the biomarkers it does not express is unsatisfactory. Triple negative breast cancer has been linked to aspects of metabolism and metabolic disorders such as diabetes. There are several biomarkers that are of interest and overlap in both their roles in breast cancer and in aspects of metabolism. Fatty acid binding protein 7 (FABP7) is one of 9 FABPs that is involved in the transport, solubilisation and regulation of metabolism of various fatty acids. Expression profiling and immunohistochemistry (IHC) studies have identified FABP7 to be over-expressed in a subtype of breast cancer that can be considered almost synonymous with triple negative breast cancer; basal-like breast cancer, so called because it expresses cytokeratins that are characteristic of basal epithelial cells. The role of FABP7 in breast cancer is not fully understood and studies have given conflicting results in regards to the relation to prognosis. Evidence suggests that FABP7 can be regulated by methylation acetylation and exposure to fatty acids. Insulin like growth factor binding protein-2 (IGFBP-2) is a member of the IGF-axis that is responsible for altering cell growth and metabolism. IGFBP-2 has been found to be over-expressed in many cancers including those of the prostate and breast. Phosphotensin homolog (PTEN) is a tumour suppressor gene that is responsible for dephosphorylating PIP3 to inhibit the Akt pathway and thus inhibit cell growth and promote apoptosis. IGFBP-2 has IGF independent actions; it can down-regulate PTEN through binding of an integrin receptor and therefore have mitogenic and anti-apoptotic effects. Aims To study the expression of the metabolic biomarkers FABP7, IGFBP-2 and PTEN in clinical cases of Malaysian TN breast cancer. To use appropriate cell lines in order to more fully understand whether epigenetic mechanisms and FAs regulate FABP7 expression. To over-express FABP7 in a breast cancer cell lines and to further understand the role of FABP7 in breast cancer. Methods IHC was used to assess FABP7, PTEN and IGFBP-2 expression in a cohort of triple negative breast cancer cases. FAs, a demethylation agent-AZA and a histone deacetylase inhibitor-TSA were used to investigate what regulated FABP7 in cell lines. Over-expression experiments were used to understand the effect of FABP7 in breast cancer cell lines. Results FABP7 expression in patient samples was associated with lower grade, basal-like phenotype, FAS expression and although not significant, improved patient survival. Treatment of BT-20 and MDA-MB-231 cell lines with AZA and TSA resulted in increases in FABP7 mRNA expression. Fatty acid treatment led to changes in FABP7 mRNA expression. Combinations of AZA and fatty acids gave large increases in FABP7 mRNA expression. Over-expression of FABP7 in BT-20 cells resulted in increased cell viability and although not significant changes in expression of survivin, caspase 9 and their splice variants. IGFBP-2 expression was associated with poor patient survival though this was not significant. PTEN loss was a frequent event in the cohort of triple negative breast cancer cases; 48.3% of cases had PTEN loss. PTEN loss was associated with poor patient survival though this was not significant. PTEN loss was associated with expression of IGFBP-2. Discussion & Conclusions FABP7 is likely to play a role in patient survival as demonstrated in the patient samples. FABP7 over-expressing BT-20 cells tended to have increased survivin FL and ΔEX3 expression. Both increased mitochondrial activity and survivin expression have been found to be associated with improved prognosis in breast cancer and this may explain some mechanisms by which FABP7 results in better prognosis in the TN breast cancer cases in this study. Since FABP7 mRNA expression was not increased to fold changes comparable to oestrogen receptor re-expression after AZA and TSA treatment, it is unlikely that the FABP7 gene is methylated or regulated by acetylation. It is possible that there are genes upstream of FABP7 such as transcription factors that are regulated my methylation and acetylation and therefore impact on FABP7 expression after treatment with AZA and TSA. This is the first study that demonstrates the significant relationship between IGFBP-2 expression and PTEN loss in patient samples. PTEN loss is a frequent event in TN breast cancer. IGFBP-2 and PTEN loss may be useful markers of prognosis in TN breast cancer.

FABP7 (fatty acid binding protein 7, brain)

Abstract: Review on FABP7, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

Fatty Acid Uptake and Lipid Storage Induced by HIF-1α Contribute to Cell Growth and Survival after Hypoxia-Reoxygenation

Abstract: An in vivo model of antiangiogenic therapy allowed us to identify genes upregulated by bevacizumab treatment, including Fatty Acid Binding Protein 3 (FABP3) and FABP7, both of which are involved in fatty acid uptake. In vitro, both were induced by hypoxia in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. There was a significant lipid droplet (LD) accumulation in hypoxia that was time and O2 concentration dependent. Knockdown of endogenous expression of FABP3, FABP7, or Adipophilin (an essential LD structural component) significantly impaired LD formation under hypoxia. We showed that LD accumulation is due to FABP3/7-dependent fatty acid uptake while de novo fatty acid synthesis is repressed in hypoxia. We also showed that ATP production occurs via β-oxidation or glycogen degradation in a cell-type-dependent manner in hypoxia-reoxygenation. Finally, inhibition of lipid storage reduced protection against reactive oxygen species toxicity, decreased the survival of cells subjected to hypoxia-reoxygenation in vitro, and strongly impaired tumorigenesis in vivo.