Upregulation Of Fatty Acid Binding Protein Research Articles

Abstract 159: Endothelial Fatty Acid-binding Proteins Contribute To The Pathogenesis Of Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Objectives: To determine whether upregulation of fatty-acid binding protein 4 and 5 (FABP4/5) is critical in pathogenesis of PAH. Methods: FABP4/5 expression was examined in PA endothelial cells (PAECs) and lung tissues from patients with PAH. Plasma proteome analysis was performed in human PAH samples. Echocardiography, hemodynamics, histology, and immunostaining were performed to evaluate the lung and heart PH phenotypes in Egln1 Tie2Cre (CKO) mice and Egln1 Tie2Cre /Fabp4-5 -/- (TKO) mice. Results: Both FABP4 and FABP5 were highly induced in ECs of CKO mice and PAECs from IPAH patients. Plasma levels of FABP4/5 were upregulated in IPAH patients and directly correlated with severity of hemodynamics and biochemical parameters. Genetic deletion of Fabp4-5 in CKO mice caused a reduction of right ventricular systolic pressure (RVSP) and RV hypertrophy, attenuated pulmonary vascular remodeling and prevented the right heart failure. Fabp4/5 deletion also normalized EC glycolysis, reduced ROS and HIF-2α expression, and decreased aberrant EC proliferation in CKO lungs. Conclusions: PH causes aberrant expression of FABP4/5 in pulmonary ECs which leads to enhanced EC glycolysis and hyperproliferation, contributing to the accumulation of arterial ECs and vascular remodeling and exacerbating the disease.

PPARα and PPARγ Signaling Is Enhanced in the Brain of the Naked Mole-Rat, a Mammal that Shows Intrinsic Neuroprotection from Oxygen Deprivation.

Naked mole-rats (NMRs) are a long-lived animal that do not develop age-related diseases including neurodegeneration and cancer. Additionally, NMRs have a profound ability to consume reactive oxygen species (ROS) and survive long periods of oxygen deprivation. Here, we evaluated the unique proteome across selected brain regions of NMRs at different ages. Compared to mice, we observed numerous differentially expressed proteins related to altered mitochondrial function in all brain regions, suggesting that the mitochondria in NMRs may have adapted to compensate for energy demands associated with living in a harsh, underground environment. Keeping in mind that ROS can induce polyunsaturated fatty acid peroxidation under periods of neuronal stress, we investigated docosahexaenoic acid (DHA) and arachidonic acid (AA) peroxidation under oxygen-deprived conditions and observed that NMRs undergo DHA and AA peroxidation to a far less extent compared to mice. Further, our proteomic analysis also suggested enhanced peroxisome proliferator-activated receptor (PPAR)-retinoid X receptor (RXR) activation in NMRs via the PPARα-RXR and PPARγ-RXR complexes. Correspondingly, we present several lines of evidence supporting PPAR activation, including increased eicosapetenoic and omega-3 docosapentaenoic acid, as well as an upregulation of fatty acid-binding protein 3 and 4, known transporters of omega-3 fatty acids and PPAR activators. These results suggest enhanced PPARα and PPARγ signaling as a potential, innate neuroprotective mechanism in NMRs.

FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism

Patients with cervical cancer (CCa) with lymph node metastasis (LNM) have an extremely poor prognosis. Elucidation of the molecular mechanisms underlying LNM may provide clinical therapeutic strategies for CCa. Upregulation of fatty acid-binding protein 5 (FABP5) expression in CCa tumours was demonstrated to positively correlate with LNM. However, the precise role and mechanisms of FABP5 in the LNM of CCa remain unknown.Methods: The diagnostic value of FABP5 as a predictor of LNM in CCa was evaluated in CCa tumour samples. The functional role of FABP5 and its upstream and downstream regulatory factors were investigated by gain-of-function and loss-of-function assays in vitro and in vivo. A mouse model of LNM was used to determine the effect of FABP5 on LNM and the therapeutic value of FABP5 targeting.Results: We demonstrated that FABP5 was markedly upregulated in CCa with LNM and correlated with poor prognosis. FABP5 protein was an independent predictor of LNM in a multivariate logistic analysis. Furthermore, FABP5 promoted epithelial-mesenchymal transition, lymphangiogenesis, and LNM by reprogramming fatty acid (FA) metabolism. Mechanistically, FABP5 promoted lipolysis and FA synthesis, which led to an increase in intracellular fatty acids (FAs) that activated NF-κB signalling, thus inducing LNM. Importantly, administration of orlistat, which attenuates FA metabolism reprogramming, inhibited FABP5-induced LNM in CCa. The pro-metastatic effect of FABP5 was reduced by miR-144-3p. Moreover, miR-144-3p was significantly downregulated and FABP5 was upregulated in CCa in a hypoxic microenvironment.Conclusion: Our findings highlight a FA metabolism-dependent mechanism of FABP5-induced LNM. Moreover, the expression and biological function of FABP5 can be regulated by miR-144-3p in hypoxia. Our study identifies FABP5 as a potential diagnostic biomarker and therapeutic target for LNM in CCa.

A vicious loop of fatty acid-binding protein 4 and DNA methyltransferase 1 promotes acute myeloid leukemia and acts as a therapeutic target.

Aberrant DNA methylation mediated by deregulation of DNA methyltransferases (DNMT) is a key hallmark of acute myeloid leukemia (AML), yet efforts to target DNMT deregulation for drug development have lagged. We previously demonstrated that upregulation of fatty acid-binding protein 4 (FABP4) promotes AML aggressiveness through enhanced DNMT1-dependent DNA methylation. Here we demonstrate that FABP4 upregulation in AML cells occurs through vascular endothelial growth factor (VEGF) signaling, thus elucidating a crucial FABP4-DNMT1 regulatory feedback loop in AML biology. We show that FABP4 dysfunction by its selective inhibitor BMS309403 leads to downregulation of DNMT1, decrease of global DNA methylation and re-expression of p15INK4B tumor suppressor gene by promoter DNA hypomethylation in vitro, ex vivo and in vivo. Functionally, BMS309403 suppresses cell colony formation, induces cell differentiation, and, importantly, impairs leukemic disease progression in mouse models of leukemia. Our findings highlight AML-promoting properties of the FABP4-DNMT1 vicious loop, and identify an attractive class of therapeutic agents with a high potential for clinical use in AML patients. The results will also assist in establishing the FABP4-DNMT1 loop as a target for therapeutic discovery to enhance the index of current epigenetic therapies.

Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth.

Intra-abdominal tumors, such as ovarian cancer, have a clear predilection for metastasis to the omentum, an organ primarily composed of adipocytes. Currently, it is unclear why tumor cells preferentially home to and proliferate in the omentum, yet omental metastases typically represent the largest tumor in the abdominal cavities of women with ovarian cancer. We show here that primary human omental adipocytes promote homing, migration and invasion of ovarian cancer cells, and that adipokines including interleukin-8 (IL-8) mediate these activities. Adipocyte-ovarian cancer cell coculture led to the direct transfer of lipids from adipocytes to ovarian cancer cells and promoted in vitro and in vivo tumor growth. Furthermore, coculture induced lipolysis in adipocytes and β-oxidation in cancer cells, suggesting adipocytes act as an energy source for the cancer cells. A protein array identified upregulation of fatty acid-binding protein 4 (FABP4, also known as aP2) in omental metastases as compared to primary ovarian tumors, and FABP4 expression was detected in ovarian cancer cells at the adipocyte-tumor cell interface. FABP4 deficiency substantially impaired metastatic tumor growth in mice, indicating that FABP4 has a key role in ovarian cancer metastasis. These data indicate adipocytes provide fatty acids for rapid tumor growth, identifying lipid metabolism and transport as new targets for the treatment of cancers where adipocytes are a major component of the microenvironment.

Fatty Acid-binding Protein 5 and PPARβ/δ Are Critical Mediators of Epidermal Growth Factor Receptor-induced Carcinoma Cell Growth

Epidermal growth factors and their receptors (EGFRs) promote breast cancer cell proliferation and can drive tumorigenesis. However, the molecular mechanisms that mediate these effects are incompletely understood. We previously showed that mammary tumor development in the mouse model of breast cancer MMTV-neu, a model characterized by amplification of the EGFR ErbB2 in mammary tissue, correlates with a marked up-regulation of fatty acid-binding protein 5 (FABP5). FABP5 functions to deliver ligands to and enhance the transcriptional activity of the nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta), a receptor whose target genes include genes involved in cell growth and survival. We show here that in MCF-7 mammary carcinoma cells, EGFR signaling directly up-regulates the expression of FABP5. The data demonstrate that treatment of these cells with the EGFR ligand heregulin-beta1 signals through the ERK and the phophatidylinositol-3-kinase cascades, resulting in activation of the transcription factor NF-kappaB. In turn, NF-kappaB induces the expression of FABP5 through two cognate response elements in the promoter of this gene. The observations further demonstrate that FABP5 and PPARbeta/delta are critical mediators of the ability of EGFR to enhance cell proliferation, indicating that this transcriptional pathway plays a key role in EGFR-induced tumorigenesis. Additional observations indicate that the expression of FABP5 is down-regulated by the Krüppel-like factor KLF2, suggesting a tumor suppressor activity for this factor.

Proteomic changes in the hypothalamus and retroperitoneal fat from male F344 rats subjected to repeated light–dark shifts

Chronic circadian desynchronization induced by repeated 12 h light-dark cycle shifts conducted twice weekly resulted in elevated food intake, body weight gain, and retroperitoneal fat mass in male F344 rats. Using a proteomic approach, we found that repeated light-dark shifts caused changes in expression levels of five hypothalamic (four upregulated) and 22 retroperitoneal fat (13 upregulated) 2-DE protein spots. Proteins involved in carbohydrate metabolism and in the citric acid cycle were upregulated, indicating a positive energy balance status. In addition, the hypothalamic gamma-amino butyric acid (GABA) aminotransferase was upregulated, thus suggesting a connection between the brain GABAeric system and the modulation of food intake. Furthermore, the upregulation of fatty acid-binding protein 4 and the downregulation of 78 kDa glucose-regulated protein in the fat implicated the development of insulin resistance. We observed the upregulation of two antioxidant enzymes that might serve as protection against insulin dysfunction associated with oxidative stress. Finally, the downregulation of hypothalamic voltage-dependent anion-selective channel protein 1 and fat ATP synthase suggested a reduction in synthesis of mitochondrial ATP. These findings are in partial agreement with those of studies of obesity induced by genotype and a high-fat diet.