Loss of fatty acid binding protein 3 ameliorates lipopolysaccharide-induced inflammation and endothelial dysfunction.

Circulating fatty acid-binding protein 3 (FABP3) is an effective biomarker of myocardial injury and peripheral artery disease (PAD). The endothelium, which forms the inner most layer of every blood vessel, is exposed to higher levels of FABP3 in PAD or following myocardial injury, but the pathophysiological role of endothelial FABP3, the effect of FABP3 exposure on endothelial cells, and related mechanisms are unknown. Here, we aimed to evaluate the pathophysiological role of endothelial FABP3 and related mechanisms in vitro. Our molecular and functional in vitro analyses show that (1) FABP3 is basally expressed in endothelial cells; (2) inflammatory stress in the form of lipopolysaccharide (LPS) upregulated endothelial FABP3 expression; (3) loss of endogenous FABP3 protected endothelial cells against LPS-induced endothelial dysfunction; however, exogenous FABP3 exposure exacerbated LPS-induced inflammation; (4) loss of endogenous FABP3 protected against LPS-induced endothelial dysfunction by promoting cell survival and anti-inflammatory and pro-angiogenic signaling pathways. Together, these findings suggest that gain-of endothelial FABP3 exacerbates, whereas loss-of endothelial FABP3 inhibits LPS-induced endothelial dysfunction by promoting cell survival and anti-inflammatory and pro-angiogenic signaling. We propose that an increased circulating FABP3 in myocardial injury or PAD patients may be detrimental to endothelial function, and therefore, therapies aimed at inhibiting FABP3 may improve endothelial function in diseased states.

Characterization of the fatty acid binding protein 3 (FABP3) promoter and its transcriptional regulation by cAMP response element binding protein 1 (CREB1) in goat mammary epithelial cells.

Fatty acid binding protein 3 (FABP3) is involved in signal transduction pathways, and in the uptake and utilization of long-chain fatty acids. However, the transcriptional regulation of FABP3 in goat is unclear. In this study, the FABP3 5' flanking region was amplified from goat (Capra hircus) genomic DNA. Luciferase reporter vectors containing promoter fragments of five different lengths were constructed and transfected into dairy goat mammary epithelial cells. The region of the promoter located between -1801 and -166 bp upstream of the transcription start site (TSS) exhibited the highest luciferase activity, and contained two cAMP response elements (CREs) located at -1632 bp and -189 bp. Interference with CREB1 significantly downregulated FABP3 promoter activity. In addition, FABP3 promoter activity was significantly reduced after mutation of the CRE1 (-1632 bp) and CRE2 (-189 bp) sites. Further analysis indicated that the CRE2 site was essential for the transcriptional activity induced by CREB1. These results demonstrated that CREB1 is involved in the transcriptional regulation of FABP3 expression in the goat mammary gland via a direct mechanism, thus revealing a novel signaling pathway involved in fatty acid metabolism in goat.

FABP3 overexpression promotes vascular fibrosis in Takayasu's arteritis by enhancing fatty acid oxidation in aorta adventitial fibroblasts.

OBJECTIVE: To identify the role of fatty acid binding protein 3 (FABP3) in vascular fibrosis in Takayasu's arteritis (TAK) and to explore the underlying molecular mechanism. METHODS: The expression of FABP3 and extracellular matrix proteins (ECMs) were detected in aorta tissues from TAK patients (n = 12) and healthy controls (n = 8) by immunohistochemistry. The concentration of serum proteins was determined by ELISA. CCK8 and Ki67 staining were used to measure aorta adventitial fibroblast (AAF) proliferation. Widely targeted lipidomic profiling was used to screen for associated metabolic pathways. Changes in ECMs and fatty acid oxidation (FAO)-related enzymes were determined by RT-qPCR and Western blot. The interactions between FABP3 and these enzymes were explored with a co-immunoprecipitation (Co-IP) assay. RESULTS: The expression of FABP3 was increased in the thickened adventitia of TAK patients and was positively correlated with the serum expression of ECMs. FABP3 knockdown inhibited AAF proliferation and ECM production, whereas FABP3 overexpression enhanced these processes. Further analysis revealed that FABP3 upregulation promoted carnitine palmitoyltransferase 1A and carnitine/acylcarnitine carrier protein (CACT) expression, two key enzymes in FAO, as well as adenosine triphosphate (ATP) levels. FABP3 and CACT were co-localized in the adventitia and bound to each other in AAFs. Etomoxir reversed the enhanced FAO, ATP production, AAF proliferation and ECM production mediated by FABP3 upregulation. Treatment with 60 g/day curcumin granules for 3 months reduced the level of serum FABP3. Curcumin also inhibited vascular fibrosis by reducing FABP3-enhanced FAO in AAFs. CONCLUSION: Elevated FABP3 expression accelerated vascular fibrosis in TAK, which was likely mediated by promoting FAO in AAFs.

Sterculia tragacantha Lindl Aqueous Leaf Extract Ameliorate Cardiomyopathy in Streptozotocin-induced Diabetic Rats via Urotensin II and FABP3 Expressions.

Sterculia tragacantha (ST) Lindl leaf is commonly used locally in the management of diabetes mellitus (DM) and its complications. This study was aimed at assessing the valuable effects of ST leaf on streptozotocin-diabetic cardiomyopathy (DCM). Streptozotocin was administered intraperitoneally to the experimental animals to induce DM, and hence, placed on different doses of ST for 14 days. Thereafter, on the 15th day of the experiment, the animals were euthanized, and a number of cardiomyopathy indices were investigated. The diabetic rats exhibited a momentous increase in hyperlipidemia, lipid peroxidation as well as a significant (p < 0.05) decline in antioxidant enzyme activities. The serum creatine kinase MB (CK-MB), C-reactive protein (CRP), cardiac troponin I, tumour necrosis factor-alpha (TNF-α) and urotensin II expression revealed a significant (p < 0.05) upsurge in diabetic rats. Also, the expression of GLUT4 and fatty acid-binding protein 3 (FABP3) were significantly (p < 0.05) reduced in diabetic rats. However, at the conclusion of the experimental trial ST significantly (p < 0.05) attenuated hyperlipidemia, oxidative stress biomarkers by augmenting the antioxidant enzyme activities and decrease in lipid peroxidation, ameliorated CK-MB, CRP, cardiac troponin I, TNF-α, and urotensin-II levels, and improved GLUT4 and FABP3 expressions. Similarly, the administration of ST prevented histological alterations in the heart of diabetic animals. Therefore, the obtained results suggest that ST could mitigate DCM in streptozotocin-induced diabetic rats.

Profiling the expression of fatty acid-binding proteins and fatty acid transporters in mouse microglia and assessing their role in docosahexaenoic acid-d5 uptake.

While the processes governing docosahexaenoic acid (DHA) trafficking across the blood-brain barrier have been elucidated, factors governing DHA uptake into microglia, an essential step for this fatty acid to exert its anti-inflammatory effects, are unknown. This study assessed the mRNA and protein expression of fatty acid-binding proteins (FABPs) and fatty acid transport proteins (FATPs) in mouse BV-2 cells and their mRNA expression in primary mouse microglia. The microglial uptake of DHA-d5, a surrogate of DHA, was assessed by LC-MS/MS following interventions including temperature reduction, silencing of various FABP isoforms, competition with DHA, and metabolic inhibition. It was found that DHA-d5 uptake at 4°C was 39.6% lower than at 37°C, suggesting that microglial uptake of DHA-d5 likely involves passive and/or active uptake mechanisms. Of all FABP and FATP isoforms probed, only FABP3, FABP4, FABP5, FATP1, and FATP4 were expressed at both the mRNA and protein level. Silencing of FABP3, FABP4, and FABP5 resulted in no change in cellular DHA-d5 uptake, nor did concomitant DHA administration or the presence of 0.1% sodium azide/50 mM 2-deoxy-D-glucose. This study is the first to identify the presence of FABPs and FATPs in mouse microglia, albeit these proteins are not involved in the microglial uptake of DHA-d5.

An α-synuclein decoy peptide prevents cytotoxic α-synuclein aggregation caused by fatty acid binding protein 3.

α-synuclein (αSyn) is a protein known to form intracellular aggregates during the manifestation of Parkinson's disease. Previously, it was shown that αSyn aggregation was strongly suppressed in the midbrain region of mice that did not possess the gene encoding the lipid transport protein fatty acid binding protein 3 (FABP3). An interaction between these two proteins was detected in vitro, suggesting that FABP3 may play a role in the aggregation and deposition of αSyn in neurons. To characterize the molecular mechanisms that underlie the interactions between FABP3 and αSyn that modulate the cellular accumulation of the latter, in this report, we used in vitro fluorescence assays combined with fluorescence microscopy, transmission electron microscopy, and quartz crystal microbalance assays to characterize in detail the process and consequences of FABP3-αSyn interaction. We demonstrated that binding of FABP3 to αSyn results in changes in the aggregation mechanism of the latter; specifically, a suppression of fibrillar forms of αSyn and also the production of aggregates with an enhanced cytotoxicity toward mice neuro2A cells. Because this interaction involved the C-terminal sequence region of αSyn, we tested a peptide derived from this region of αSyn (αSynP130-140) as a decoy to prevent the FABP3-αSyn interaction. We observed that the peptide competitively inhibited binding of αSyn to FABP3 in vitro and in cultured cells. We propose that administration of αSynP130-140 might be used to prevent the accumulation of toxic FABP3-αSyn oligomers in cells, thereby preventing the progression of Parkinson's disease.

Peroxisome proliferator-activated receptor gamma regulates genes involved in milk fat synthesis in mammary epithelial cells of water buffalo.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a critical transcription factor regulating lipid and glucose metabolism. However, the regulatory effect of PPARγ on milk fat synthesis in buffalo mammary gland is not clear. In order to explore the role of buffalo PPARG gene in milk fat synthesis, lentivirus-mediated interference was used to knock it down and then the recombinant fusion expression vector was transfected into buffalo mammary epithelial cell (BMEC) to overexpress it. PPARG gene knockdown significantly decreased the expression of CD36, FABP3, FABP4, ACSS2, ELOVL6, DGAT2, BTN1A1, AGPAT6, LPIN1, ABCG2, PPARGC1A, INSIG1, FASN, and SREBF2 genes and significantly upregulated the expression of INSIG2 gene but had no significant effect on the expression of ACSL1, GPAM, and SREBF1 genes. PPARG overexpression significantly increased the relative mRNA abundance of CD36, FABP3, FABP4, ACSS2, ELOVL6, DGAT2, BTN1A1, AGPAT6, LPIN1, PPARGC1A, INSIG1, and SREBF2 genes and significantly downregulated the expression of INSIG2 gene but had no significant effect on the expression of ACSL1, GPAM, ABCG2, FASN, and SREBF1 genes. In addition, knockdown/overexpression of PPARG gene significantly decreased/increased triacylglycerol (TAG) content in BMECs. This study revealed that buffalo PPARG gene is a key gene regulating buffalo milk fat synthesis.

Maturation system affects lipid accumulation in bovine oocytes.

This study evaluated the effects of three maturation systems, namely invitro (MatV) and invivo (MatS) systems, as well as intrafollicular transfer of immature oocytes (IFIOT; MatT), on the accumulation of lipid droplets in bovine oocytes. Lipids were evaluated using confocal microscopy and transmission electron microscopy. The expression of genes related to lipid metabolism, namely acyl-CoA synthetase short chain family member 2 (ACSS2), ELOVL fatty acid elongase 1 (ELOVL1) and fatty acid binding protein 3 (FABP3), was quantified by quantitative polymerase chain reaction. The mean (±s.d.) area occupied by lipids in immature oocytes (13±2%) was similar to those matured invivo (MatS, 16±2%; MatT, 12±2%). However, there was a significant increase in lipids in oocytes in the MatV group (24±2%) compared with all other groups (P<0.001). In the ultrastructural evaluations, MatV oocytes also showed the highest lipid content. The expression of ELOVL1 and FABP3 was similar in the MatS and IFIOT groups. However, transcript levels of ACSS2 were lower in IFIOT than MatV oocytes. These results indicate, for the first time, that oocytes matured by IFIOT are similar to those matured invivo with regard to lipid accumulation, which indicates better quality than those matured invitro.

Possible involvement of fatty acid binding proteins in psychiatric disorders.

Polyunsaturated fatty acids (PUFAs) are essential for brain development and function. Increasing evidence has shown that an imbalance of PUFAs is associated with various human psychiatric disorders, including autism and schizophrenia. However, the mechanisms underlying the effects of PUFAs on brain functions at cellular and molecular levels remain unclear. Since PUFAs are insoluble in water, specific transporters are required to deliver PUFAs to appropriate intracellular compartments. Fatty acid-binding proteins (FABPs), the cellular chaperones of PUFAs, are involved in PUFA intracellular trafficking, signal transduction, and gene transcription. Therefore, we focused on the relationship between FABP-regulated PUFA homeostasis in the brain and neuronal plasticity. The authors previously reported that FABP3, which preferentially binds to n-6 PUFAs, is strongly expressed in the gamma-aminobutyric acid (GABAergic) inhibitory interneurons of the adult mouse anterior cingulate cortex (ACC), which is a component of the limbic cortex and is important for the coordination of cognitive and emotional behaviors. Interestingly, Fabp3 KO mice show increased GABA synthesis and abnormal excitatory/inhibitory balance in the ACC. In addition, studies have indicated that FABP7, which preferentially binds to n-3 PUFAs, controls lipid raft function in astrocytes, and astrocytic Fabp7 deficiency results in an altered response of astrocytes to external stimuli. Furthermore, Fabp7 KO mice exhibit aberrant dendritic morphology, and decreased spine density and excitatory synaptic transmission in pyramidal neurons. This review summarizes relationship between PUFAs or FABPs and human psychiatric disorders and discusses recent progress in elucidating the function of FABPs, especially FABP3 and 7, in the brain.

Exosomes isolated from the miR-215-modified bone marrow mesenchymal stem cells protect H2O2-induced rat myoblasts via the miR-215/FABP3 pathway.

This study aimed to investigate the potential effects of miR-215, with exosomes as carriers, against skeletal muscle injury. Exosomes were isolated from rat bone marrow mesenchymal stem cells (rBMSCs) or rBMSCs overexpressing miR-215. Subsequently, rat myoblasts (L6) were treated with different exosomes and mimics, then exposed to H2O2. Cell viability and apoptosis were determined using the Cell Counting Kit-8 and Annexin V-FITC cell apoptosis assay kits, respectively. Reverse-transcriptase quantitative PCR (RT-qPCR) was used to examine the expression of related genes. Transmission electron microscopy, Nanosight, and western blotting showed that the exosomes were successfully isolated. PKH67 staining revealed that both exosomes and miR-215-modified exosomes were taken up by L6 cells. FABP3 was found to be the target gene of miR-215 via a dual luciferase reporter gene assay. In the L6 cells treated with H2O2, cell viability was significantly inhibited, whereas apoptosis significantly increased (P < 0.05). Exosomes significantly enhanced the viability of H2O2-induced cells and inhibited their apoptosis (P < 0.05). In addition, RT-qPCR showed that in the H2O2-induced L6 cells, FABP3, CDKN1A, and TP53 were significantly upregulated, while CCNB1 was significantly downregulated (P < 0.05). However, their expression levels were significantly reversed after treatment with miR-215-modified exosomes (P < 0.05). These findings indicate that the miR-215-modified exosomes may exert protective effects against skeletal muscle injury through the miR-215/FABP3 pathway and regulate the expression of CDKN1A, CCNB1, and TP53.

Impaired Acquisition of Nicotine-Induced Conditioned Place Preference in Fatty Acid-Binding Protein 3 Null Mice.

Nicotine causes psychological dependence through its interactions with nicotinic acetylcholine receptors in the brain. We previously demonstrated that fatty acid-binding protein 3 (FABP3) colocalizes with dopamine D2 receptors (D2Rs) in the dorsal striatum, and FABP3 deficiency leads to impaired D2R function. Moreover, D2R null mice do not exhibit increased nicotine-induced conditioned place preference (CPP) following chronic nicotine administration. To investigate the role of FABP3 in nicotine-induced CPP, FABP3 knockout (FABP3-/-) mice were evaluated using a CPP apparatus following consecutive nicotine administration (0.5 mg/kg) for 14 days. Importantly, nicotine-induced CPP was suppressed in the conditioning, withdrawal, and relapse phases in FABP3-/- mice. To resolve the mechanisms underlying impaired nicotine-induced CPP in these mice, we assessed c-Fos expression and Ca2+/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) signaling in both dopamine D1 receptor (D1R)- and D2R-positive neurons in the nucleus accumbens (NAc). Notably, 64% of dopamine receptor-positive neurons in the mouse NAc expressed both D1R and D2R. Impaired nicotine-induced CPP was correlated with lack of responsiveness of both CaMKII and ERK phosphorylation. The number of D2R-positive neurons was increased in FABP3-/- mice, while the number of D1R-positive neurons and the responsiveness of c-Fos expression to nicotine were decreased. The aberrant c-Fos expression was closely correlated with CaMKII but not ERK phosphorylation levels in the NAc of FABP3-/- mice. Taken together, these results indicate that impaired D2R signaling due to lack of FABP3 may affect D1R and c-Fos signaling and underlie nicotine-induced CPP behaviors.

Fatty acid-binding protein 3 regulates differentiation of IgM-producing plasma cells.

Plasma cells (PCs), which aim to protect host health, produce various subsets of immunoglobulin (Ig) in response to extracellular pathogens. Blimp-1 (encoded by Prdm1)-a protein that is highly expressed by PCs-is important for PC functions, including the generation of Igs. Fatty acid-binding protein 3 (FABP3) is a carrier protein of polyunsaturated fatty acids (PUFAs) and participates in multiple cellular functions. Although the functions of FABP3 in neurons and cardiac myocytes are well-noted, their roles in immune cells remain to be fully elucidated. In this study, we demonstrate that FABP3 is expressed in activated B cells and that FABP3 promotes PC development and IgM secretion. Moreover, we provide the first evidence that FABP3 is necessary for Blimp-1 expression, by regulating the histone modification of its promoter region. Taken together, our findings reveal that FABP3 acts as a positive regulator of B-cell activation by controlling histone acetylation of the Blimp-1 gene, thereby playing a role in host defense against pathogens.

Network pharmacology of bioactives from Sorghum bicolor with targets related to diabetes mellitus.

BACKGROUND: Sorghum bicolor (SB) is rich in protective phytoconstituents with health benefits and regarded as a promising source of natural anti-diabetic substance. However, its comprehensive bioactive compound(s) and mechanism(s) against type-2 diabetes mellitus (T2DM) have not been exposed. Hence, we implemented network pharmacology to identify its key compounds and mechanism(s) against T2DM. METHODS: Compounds in SB were explored through GC-MS and screened by Lipinski's rule. Genes associated with the selected compounds or T2DM were extracted from public databases, and the overlapping genes between SB-compound related genes and T2DM target genes were identified using Venn diagram. Then, the networking between selected compounds and overlapping genes was constructed, visualized, and analyzed by RStudio. Finally, affinity between compounds and genes was evaluated via molecular docking. RESULTS: GC-MS analysis of SB detected a total of 20 compounds which were accepted by the Lipinski's rule. A total number of 16 compounds-related genes and T2DM-related genes (4,763) were identified, and 81 overlapping genes between them were selected. Gene set enrichment analysis exhibited that the mechanisms of SB against T2DM were associated with 12 signaling pathways, and the key mechanism might be to control blood glucose level by activating PPAR signaling pathway. Furthermore, the highest affinities were noted between four main compounds and six genes (FABP3-Propyleneglyco monoleate, FABP4-25-Oxo-27-norcholesterol, NR1H3-Campesterol, PPARA-ß-sitosterol, PPARD-ß-sitosterol, and PPARG-ß-sitosterol). CONCLUSION: Our study overall suggests that the four key compounds detected in SB might ameliorate T2DM severity by activating the PPAR signaling pathway.

Transcriptomic analysis of micropapillary high grade T1 urothelial bladder cancer.

No consensus currently exist on the optimal treatment of patients with high-risk nonmuscle invasive (HGT1) micropapillary variant of bladder cancer (MPBC). Transcripsome analysis may allow stratification of MPBC-HGT1 enabling prediction of recurrence and guide therapeutic management for individual patients. Whole transcriptome RNA-Sequencing of tumors from 23 patients with MPBC-HGT1 and 64 conventional urothelial carcinomas (cUC) (reference set) was performed. Differentially expressed genes between MPBC-HGT1 and cUC-HGT1 were explored. Cox proportional hazard models and Kapplan-Meier methods were used to assess the relation between time to progression (TTP) and individual gene expression adjusting for clinical covariates. Over 3000 genes were differentially expressed in MPBC-HGT1 as compared with cUC-HGT1 and a 26-gene signature is characteristic of MPBC within HGT1. A set of three genes; CD36, FAPB3 and RAETE1; were significantly associated with TTP. High expression of FABP3 and CD36 were associated with shorter TTP (p = 0.045 and p = 0.08) as was low expression of RAET1E (p = 0.01). Our study suggest that a 26-gene signature can define MPBC-HGT1 within conventional urothelial carcinomas. A prognostic risk index of three genes (FABP3, CD36 and RAET1E) was found to be associated with shorter TTP and may help classify a group of patients with MPBC-HGT1 with high-risk of early progression. These observations might have implications in terms of radical cystectomy recommendation in MPBC patients.

FABP3-mediated membrane lipid saturation alters fluidity and induces ER stress in skeletal muscle with aging.

Sarcopenia is characterized by decreased skeletal muscle mass and function with age. Aged muscles have altered lipid compositions; however, the role and regulation of lipids are unknown. Here we report that FABP3 is upregulated in aged skeletal muscles, disrupting homeostasis via lipid remodeling. Lipidomic analyses reveal that FABP3 overexpression in young muscles alters the membrane lipid composition to that of aged muscle by decreasing polyunsaturated phospholipid acyl chains, while increasing sphingomyelin and lysophosphatidylcholine. FABP3-dependent membrane lipid remodeling causes ER stress via the PERK-eIF2α pathway and inhibits protein synthesis, limiting muscle recovery after immobilization. FABP3 knockdown induces a young-like lipid composition in aged muscles, reduces ER stress, and improves protein synthesis and muscle recovery. Further, FABP3 reduces membrane fluidity and knockdown increases fluidity in vitro, potentially causing ER stress. Therefore, FABP3 drives membrane lipid composition-mediated ER stress to regulate muscle homeostasis during aging and is a valuable target for sarcopenia.

A Five-Gene Signature Based on Stromal/Immune Scores in the Tumor Microenvironment and Its Clinical Implications for Liver Cancer.

Increasing evidence highlights the clinical significance of stromal cells and immune cells in the liver cancer microenvironment. However, reliable prognostic models have not been well established. This study aimed to develop a gene signature for liver cancer based on stromal and immune scores. Using the estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) algorithm, stromal and immune scores were estimated based on the transcriptome profile of The Cancer Genome Atlas (TCGA) liver cancer cohort. Stromal-/immune-related differentially expressed genes were identified, followed by functional enrichment analysis. The Cox regression model was used to select prognostic genes and construct a gene signature. Its predictive potential was evaluated by receiver operating characteristic (ROC). The correlation between the risk score and immune cell infiltration was analyzed using Tumor Immune Estimation Resource (TIMER). Three hundred sixty-four upregulated and 10 downregulated stromal-/immune-related genes were identified, were mainly enriched in immune-related processes and pathways. Through univariate and multivariate cox survival analysis, a five-gene risk score was constructed, composed of FABP3, HTRA3, OLFML2B, PDZD4 and SLAMF6. Patients with high score indicated a poorer prognosis than those with low risk score. The areas under the ROC curves of overall survival (OS), progression-free interval, 3-, 5-year, OS status were 0.68, 0.57, 0.72, 0.74 and 0.728, indicating its well performance on predicting patients' prognoses. Furthermore, the risk score and the five genes were significantly correlated with immune cell infiltration in the tumor microenvironment. In this study, we proposed a prognostic five-gene signature based on stromal/immune scores in the liver cancer microenvironment.

A novel long noncoding RNA, ENSGALG00000021686, regulates the intracellular transport of fatty acids by targeting the FABP3 gene in chicken.

Fatty acids (FAs) are essential for the vital movement of humans and animals. Their metabolism is, in part, regulated by FABP3. In our previous study, a novel lncRNA (ENSGALG00000021686, L21686) was identified, and FABP3 was predicted as its target gene. Here, using chicken myocytes, lymphocytes, and different tissues, L21686 target on the FABP3 gene, FABP3 mRNA expression, and their effect on FA metabolism are explored. The results show that the highest expression of L21686 is in muscle tissue, a significant energy-consuming tissue. L21686 expression is consistent with FABP3 mRNA expression. We also show that under the different treatments, the levels of FABP3 mRNA and protein in myocytes and lymphocytes change in tandem with L21686 expression. Moreover, the dual-luciferase reporter assay provided direct evidence that L21686 targets the FABP3 gene. Finally, it was found that the content of free FAs increases along with the up-regulation of L21686 and the FABP3 gene. Malonyl CoA content does not change under the different treatments, suggesting that L21686 regulates the intake of extracellular FAs in chicken. Further, the changes in lipoprotein lipase (LPL), sterol-regulatory element binding protein 1 (SREBP-1), fatty acid synthase (FASN), and acetyl-CoA carboxylase (ACC) mRNA levels support this view. In summary, our data show that the new lncRNA (L21686) regulates the intake of extracellular FAs in chicken cells in vitro by targeting the expression of the FABP3 gene. Our findings will help to establish the groundwork and provide a new clue for deciphering the regulation of FAs metabolism in chicken.

High fat diet altered cardiac metabolic gene profile in Psammomys obesus gerbils.

BACKGROUND: In metabolic disorders, myocardial fatty infiltration is critically associated with lipotoxic cardiomyopathy. METHODS: Twenty Psammomys obesus gerbils were randomly assigned to normal plant or high fat diet. Sixteen weeks later, myocardium was sampled for pathobiological evaluation. RESULTS: A sixteen-week high fat diet resulted in myocardial structure disorganization, with collagen deposits, lipid accumulation, cardiomyocyte apoptosis and inflammatory cell infiltration. Myocardial expressions of glucose transporter GLUT1 and pyruvate dehydrogenase (PDH) inhibitor, PDH kinase (PDK)4 increased, while insulin-regulated GLUT4 expression remained unchanged. Myocardial expressions of molecules regulating fatty acid transport, CD36 and fatty acid binding protein (FABP)3, were increased, while expression of rate-controlling fatty acid ß-oxidation, carnitine palmitoyl transferase (CPT)1B decreased. Myocardial expression of AMP-activated protein kinase (AMPK), decreased, while expression of peroxisome proliferator activated receptors (PPAR)-α and -γ did not change. CONCLUSION: In high fat diet fed Psammomys obesus, an original experimental model of nutritionally induced metabolic syndrome mixing genetic predisposition and environment interactions, a short period of high fat feeding was sufficient to induce myocardial structural alterations, associated with altered myocardial metabolic gene expression in favor of lipid accumulation.

Altered Expression of Three EGFR Posttranslational Regulators MDGI, MIG6, and EIG121 in Invasive Breast Carcinomas.

Epidermal growth factor receptor (EGFR) signalling is a highly regulated process with a tight balance between receptor activation and inactivation in invasive breast carcinomas (IBCs) particularly in triple-negative carcinomas (TNC). Clinical trials using anti-EGFR therapies are actually performed although no activating alterations (mutations, amplifications, or rearrangements) of EGFR have been clearly recognized in order to identify new targeted modalities for IBCs. We explored mammary-derived growth inhibitor (MDGI), estrogen-induced gene-121 (EIG121), and mitogen-induced gene-6 (MIG6), three posttranslational EGFR trafficking molecules implicated in EGFR spatiotemporal regulatory pathway. We quantified MDGI, EIG121, and MIG6 at mRNA levels by using real-time quantitative RT-PCR in a series of 440 IBCs and at protein levels by using immunohistochemistry in a series of 88 IBCs. Results obtained by RT-PCR showed that in IBCs, MDGI, MIG6, and EIG121 mRNA were mainly underexpressed (25.7%, 45.0%, and 16.1%, respectively) particularly in the TNC subtype for EIG121 (60.3%). We also observed mRNA overexpression of MDGI and EIG121, respectively, in 12.7% and 22.3% of IBCs. These altered mRNA expressions were confirmed at the protein level. Some links were found between expression patterns of these three genes and several classical pathological and clinical parameters. Only EIG121 was found to have a prognostic significance (p = 0.0038). Altered expression of these three major EGFR posttranslational negative regulators could create an aberrant EGFR-mediated oncogenic signalling pathway in IBCs. MDGI, MIG6, and EIG121 expression status also may be potential useful biomarkers (sensitivity or resistance) in targeted EGFR therapy.

Correlation between increased atrial expression of genes related to fatty acid metabolism and autophagy in patients with chronic atrial fibrillation.

Atrial metabolic disturbance contributes to the onset and development of atrial fibrillation (AF). Autophagy plays a role in maintaining the cellular energy balance. We examined whether atrial gene expressions related to fatty acid metabolism and autophagy are altered in chronic AF and whether they are related to each other. Right atrial tissue was obtained during heart surgery from 51 patients with sinus rhythm (SR, n = 38) or chronic AF (n = 13). Preoperative fasting serum free-fatty-acid levels were significantly higher in the AF patients. The atrial gene expression of fatty acid binding protein 3 (FABP3), which is involved in the cells' fatty acid uptake and intracellular fatty acid transport, was significantly increased in AF patients compared to SR patients; in the SR patients it was positively correlated with the right atrial diameter and intra-atrial electromechanical delay (EMD), parameters of structural and electrical atrial remodeling that were evaluated by an echocardiography. In contrast, the two groups' atrial contents of diacylglycerol (DAG), a toxic fatty acid metabolite, were comparable. Importantly, the atrial gene expression of microtubule-associated protein light chain 3 (LC3) was significantly increased in AF patients, and autophagy-related genes including LC3 were positively correlated with the atrial expression of FABP3. In conclusion, in chronic AF patients, the atrial expression of FABP3 was upregulated in association with autophagy-related genes without altered atrial DAG content. Our findings may support the hypothesis that dysregulated cardiac fatty acid metabolism contributes to the progression of AF and induction of autophagy has a cardioprotective effect against cardiac lipotoxicity in chronic AF.