Epidermal Fatty Acid-binding Protein Research Articles

Concomitant decrease of E- and A-FABP expression predicts worse survival in urothelial bladder cancer patients

Non-muscle invasive bladder cancers (NMIBC) pTa-pT1 are depicted by a high risk of recurrence and/or progression with an unpredictable clinical evolution. Our aim was to identify, from the original resection specimen, tumors that will progress to better manage patients. We previously showed that A-FABP (Adipocyte- Fatty Acid Binding Protein) loss predicted NMIBC progression. Here we determined by immunohistochemistry the prognostic value of E-FABP (Epidermal-Fatty Acid Binding Protein) expression in 210 tumors (80 pTa, 75 pT1, 55 pT2-T4). Thus, E-FABP low expression was correlated with a high grade/stage, the presence of metastatic lymph nodes, and visceral metastases (p < 0.001). Unlike A-FABP in NMIBC, E-FABP low expression was not associated with RFS or PFS in Kaplan–Meier analysis. But patients of the overall cohort with a high E-FABP expression had a longer mOS (53.8 months vs. 29.3 months, p = 0.029). The immunohistochemical analysis on the same NMIBC tissue sections revealed that when A-FABP is absent, a high E-FABP expression is detected. E-FABP could compensate A-FABP loss. Interestingly, patients, whose original tumor presents both low E-FABP and negative A-FABP, had the worse survival, those maintaining the expression of both markers had better survival. To conclude, the combined evaluation of A- and E-FABP expression allowed to stratify patients with urothelial carcinoma for optimizing treatment and follow-up.

Keratinocyte FABP5-VCP complex mediates recruitment of neutrophils in psoriasis

One of the hallmarks of intractable psoriasis is neutrophil infiltration in skin lesions. However, detailed molecular mechanisms of neutrophil chemotaxis and activation remain unclear. Here, we demonstrate a significant upregulation of epidermal fatty acid binding protein (E-FABP, FABP5) in the skin of human psoriasis and psoriatic mouse models. Genetic deletion of FABP5 in mice by global knockout and keratinocyte conditional (Krt6a-Cre) knockout, but not myeloid cell conditional (LysM-Cre) knockout, attenuates psoriatic symptoms. Immunophenotypic analysis shows that FABP5 deficiency specifically reduces skin recruitment of Ly6G+ neutrophils. Mechanistically, activated keratinocytes produce chemokines and cytokines that trigger neutrophil chemotaxis and activation in an FABP5-dependent manner. Proteomic analysis further identifies that FABP5 interacts with valosin-containing protein (VCP), a key player in NF-κB signaling activation. Silencing of FABP5, VCP, or both inhibits NF-κB/neutrophil chemotaxis signaling. Collectively, these data demonstrate dysregulated FABP5 as a molecular mechanism promoting NF-κB signaling and neutrophil infiltration in psoriasis pathogenesis.

Keratinocyte FABP5-VCP complex mediates recruitment of neutrophils in psoriasis

Abstract Psoriasis is a common chronic inflammatory skin disease. One of the hallmarks of psoriasis is the abundance of neutrophil infiltration in the skin lesions. However, the detailed molecular mechanisms of neutrophil chemotaxis and activation remains unclear. Here we demonstrated an upregulation of epidermal fatty acid binding protein (E-FABP, also known as FABP5) in skin tissue from both human psoriasis and imiquimod (IMQ)-induced psoriatic mouse model. Genetic deletion of FABP5 in global knockout mice and keratinocyte conditional (Krt6a-Cre) knockout mice, but not in myeloid cell conditional (Lysm-Cre) knockout mice, attenuated the skin erythema, thickness, and desquamation. Immunophenotypic analysis showed that FABP5 deficiency reduced the recruitment of Ly6G+ neutrophils in the dermis and ear of IMQ-treated mice. Mechanistically, activated keratinocytes in IMQ-treated mice produced chemokines and cytokines (e.g., CXCL8, IL-36γ) that triggered neutrophil chemotaxis and activation in a FABP5-dependent manner. Proteomic and IP analyses further identified that FABP5 interacted with a valosin-containing protein (VCP), a key player in NFκB signaling pathway in human keratinocytes. Silencing of FABP5 inhibited VCP-mediated IκBα phosphorylation and NFκB signaling activation. Collectively, these data suggest that FABP5 in keratinocytes interacts with VCP to activate NFκb signaling, thus playing an essential role in the neutrophil infiltration in psoriatic skin lesions. R01AI137324, #LINK#R01CA180986#ENDLINK#

Consumption of fish oil high-fat diet induces murine hair loss via epidermal fatty acid binding protein in skin macrophages

Fats are essential in healthy diets, but how dietary fats affect immune cell function and overall health is not well understood. Mimicking human high-fat diets (HFDs), which are rich in different fatty acid (FA) components, we fed mice various HFDs from different fat sources, including fish oil and cocoa butter. Mice consuming the fish oil HFD exhibit a hair-loss phenotype. Further studies show that omega-3 (n-3) FAs in fish oil promote atypical infiltration of CD207- (langerin-) myeloid macrophages in skin dermis, which induce hair loss through elevated TNF-α signaling. Mechanistically, epidermal fatty acid binding protein (E-FABP) is demonstrated to play an essential role in inducing TNF-α-mediated hair loss by activating the n-3 FA/ROS/IL-36 signaling pathway in dermal resident macrophages. Absence of E-FABP abrogates fish oil HFD-induced murine hair loss. Altogether, these findings support a role for E-FABP as a lipid sensor mediating n-3 FA-regulated macrophage function and skin health.

Resveratrol Inhibits Proliferation and Induces Autophagy by Blocking SREBP1 Expression in Oral Cancer Cells

Resveratrol is a polyphenolic antioxidant found in grapes, red wine, and peanuts and has been reported to have anti-neoplastic effects on various cancer types. However, the exact mechanism of its anti-cancer effects in oral cancer is not fully understood and remains controversial. Resveratrol exhibits strong hypolipidemic effects; therefore, we examined its effect on lipid metabolism in oral cancer. Resveratrol significantly reduced cell viability and induced autophagic cell death in oral cancer cells but not in normal cells. This selective effect was accompanied by significantly reduced lipogenesis, which is caused by downregulation of the transcription factor sterol regulatory element-binding protein 1 (SREBP1) gene, followed by downregulation of the epidermal fatty acid-binding protein (E-FABP). It was strongly suggested that resveratrol-induced autophagy resulted from the inhibition of SREBP1-mediated cell survival signaling. Luciferase reporter assay further indicated that resveratrol has a potent and specific inhibitory effect on SREBP1-dependent transactivation. Importantly, resveratrol markedly suppressed the growth of oral cancer cells in an animal xenograft model, without exhibiting apparent cytotoxicity. In conclusion, resveratrol induces autophagy in oral cancer cells by suppressing lipid metabolism through the regulation of SREBP1 expression, which highlights a novel mechanism of the anti-cancer effect of resveratrol.

Topical VX-509 attenuates psoriatic inflammation through the STAT3/FABP5 pathway in keratinocytes

BackgroundPsoriasis is a chronic inflammatory disease, with lesions mainly manifesting as scaly erythematous plaques. The mild or moderate of psoriasis is the main type of patients in hospital, and topical application remains the preferred treatment option for psoriasis therapy, therefore, the development of novel topical agents has an essential role in psoriasis therapy. ObjectiveTo identify potential drugs for psoriasis topical treatment. MethodsWe performed drug screening by Imiquimod (IMQ)-induced psoriatic like inflammation in mouse model, followed mouse epidermis by RNA-seq to find the key molecules affecting the drug. The qRT-PCR, WB were performed to test mRNA and protein expression, and Chip assay had been conducted to examine Stat3 bound to promoter of FABP5. ResultsIn this study, we identified VX-509, which topical application significantly attenuated IMQ-induced psoriatic like inflammation in mouse model. And then, we verified Epidermal Fatty acid binding protein (E-FABP/FABP5) was significantly decreased in VX-509 treated mouse epidermis by RNA-seq. FABP5 is a key molecule in lipid metabolism, administration of FABP5 inhibitor or knock down of FABP5 expression remarkably abrogated psoriatic inflammation as well as lipid metabolism. Mechanistically, our finding showed that VX-509 blocked IL-22 induced signaling pathway, particular in activation of Stat3. Furthermore, we identified Stat3 is a transcriptional factor associated with FABP5 promoters and VX-509 treatment remarkably attenuated IL-22-induced FABP5 expression through Stat3 in KCs. ConclusionsThis study demonstrated administration of VX-509 is a potential promising topical drug for treatment of psoriasis, FABP5 is a critical targeted molecule in psoriasis therapy.

Salivary and Lacrimal Gland Alterations of the Epidermal Fatty Acid-Binding Protein (E-FABP) in Non-Obese Diabetic Mice.

The purpose of this study was to investigate the changes in E-FABP in the salivary and lacrimal glands of the Sjögren syndrome (SS) model non-obese diabetic mice (NOD). Cotton thread and ocular vital staining tests were performed on 10-week NOD male mice (n = 24) and age- and sex-matched wild-type (WT) mice (n = 25). Tear and saliva samples were collected at sacrifice for E-FABP ELISA assays. Salivary and lacrimal gland specimens underwent immunohistochemistry stainings for E-FABP. Real-time RT-PCR was also performed for the quantification of mRNA expression levels in the salivary and lacrimal glands. Corneal vital staining scores in the NOD mice were significantly higher compared with those for the wild-type mice (p = 0.0001). The mean tear E-FABP level showed a significantly lower concentration in the NOD mice (p = 0.001). The mean saliva E-FABP level also showed a significantly lower concentration in the NOD mice (p = 0.04). Immunohistochemistry revealed intense E-FABP staining in the LG acinar epithelium and less intense staining in the acinar epitheliae of the SGs in the NOD mice compared to the WT mice. Real-time RT-PCR for the mRNA expression of E-FABP showed a significantly decreased expression in the SG and a significant increase in the LG of the NOD mice compared to the WT mice. In conclusion, the E-FABP showed marked alterations in the tear film, saliva, lacrimal, and salivary glands of the NOD mouse, which may help explain the ocular surface changes in relation to the dry eye disease in this SS model mouse and keratoconjunctivitis sicca in SS patients.

Epidermal Fatty Acid‒Binding Protein Mediates Depilatory-Induced Acute Skin Inflammation

Depilatory creams are widely used to remove unwanted body hair, but people with sensitive skin are subject to depilatory-induced skin burn/inflammation. It remains unknown what makes their skin more sensitive than others. In this study, we show that epidermal fatty acid‒binding protein (E-FABP) expressed in the skin plays a critical role in promoting depilatory-induced acute skin inflammation in mouse models. Although a depilatory cream removed hair by breaking down keratin disulfide bonds, it activated cytosolic phospholipase A2, leading to activation of the arachidonic acid/E-FABP/peroxisome proliferator-activated receptor β signaling pathway in keratinocytes. Specifically, peroxisome proliferator-activated receptor β activation induced downstream targets (e.g., cyclooxygenase 2) and chemokine (e.g., CXCL1) production, which systemically mobilized neutrophils and recruited them to localize in the skin for acute inflammatory responses. Importantly, E-FABP deletion by CRISPR-Cas9 reduced cytosolic phospholipase A2/peroxisome proliferator-activated receptor β activation in keratinocytes, and genetic deletion of E-FABP protected mice from depilatory cream-induced neutrophil recruitment and skin inflammation. Our findings suggest E-FABP as a molecular sensor for sensitive skin by triggering depilatory-induced, lipid-mediated skin inflammatory responses.

Dietary Fats High in Linoleic Acids Impair Antitumor T-cell Responses by Inducing E-FABP-Mediated Mitochondrial Dysfunction.

The most recent American Dietary Guidelines (2020-2025) recommend shifting dietary fats from solid saturated fats to unsaturated oils. Dietary oils contain different compositions of unsaturated fatty acids (UFA). Oleic acid (OA) and linoleic acid (LA) are the most common UFA in dietary oils. How individual UFA in oils regulate immune cell function and cancer risk remains unclear. Here we demonstrated that high-fat diets (HFD) rich either in OA or LA induced a similar degree of murine obesity, but the LA-rich HFD specifically promoted mammary tumor growth. LA impaired antitumor T-cell responses by promoting naïve T-cell apoptosis and inhibiting TNFα production. While exogenous OA and LA were taken up by T cells with similar efficacy, only LA induced significant mitochondrial reactive oxygen species production and lipid peroxidation. Importantly, naïve T cells predominantly expressed epidermal fatty acid binding protein (E-FABP), which is central in facilitating LA mitochondrial transport and cardiolipin incorporation. Genetic depletion of E-FABP rescued LA-impaired T-cell responses and suppressed LA-rich HFD-associated mammary tumor growth. Collectively, these data suggest that dietary oils high in LA promote mammary tumors by inducing E-FABP-mediated T-cell dysfunction. SIGNIFICANCE: These findings suggest that modulation of dietary oil composition and inhibition of E-FABP activity may represent novel strategies to enhance T-cell function in the prevention and treatment of obesity-associated cancers.

Abstract PS8-27: Consumption of a high-fat diet rich in linoleic acid promotes mammary tumor growth

Abstract Consumption of high-fat diets rich in linoleic acid promotes mammary tumor growth Rong Jin1, Jiaqing Hao1, Edward Sauter2, Bing Li1 1Department of Microbiology and Immunology, University of Louisville, Louisville, KY2Hartford Healthcare Cancer Institute, Hartford, CT *To whom correspondence should be addressed: Bing Li, Department of Microbiology and Immunology, University of Louisville, 505 South Hancock Street, Louisville, KY, 40202. Telephone: 502-852-2678. Email: b.li@louisville.edu. AbstractBackground: The most recent Dietary Guidelines in 2015-2020 for Americans from the U.S. Department of Health and Human Services (DHH) and U.S. Department of Agriculture (USDA) recommends a healthy eating pattern with more oils but less saturated fats. Oils predominantly consist of unsaturated fats with either monounsaturated or polyunsaturated fatty acids (FAs). As high fat diets (HFDs) contribute to obesity, which increases the risk of breast cancer, in this report we evaluate whether the consumption of HFDs rich in different unsaturated fatty acids induces similar degrees of obesity and further determines the impact of different oils on mammary tumor growth using our unique murine mouse models. Hypothesis: Consumption of different oils impacts obesity-associated mammary tumor development. Methods: Weaned C57BL/6 wild type (WT) mice and epidermal fatty acid binding protein (E-FABP)-deficient (genetically depleted E-FABP) female mice were randomly grouped and fed either a safflower oil HFD (45% fat, rich in 18:2 polyunsaturated FAs) or an olive oil HFD (45% fat, rich in 18:1 monounsaturated FAs), or a control low fat diet (LFD). After 5 months on the diets, E0771 mammary tumor cells (0.5 × 106/mouse) were injected into the mammary fat pad and tumor volume was measured at 3-day intervals for tumor growth. Immune cell phenotype and functions were evaluated before and after tumor injection. The student’s t-test and/or ANOVA were used to compare immune cell function, obesity and tumor sizes in WT and E-FABP-/- mice, respectively. Results: Compared to the LFD diet, consumption of either safflower oil HFD or olive oil HFD was able to induce a similar degree of mouse obesity in WT mice. E-FABP deficiency has no obvious impact on HFD-induced mouse weight increase. Interestingly, while safflower oil-induced obesity significantly increased mammary tumor growth, olive oil-induced obesity did not promote mammary tumor growth when compared to LFD-fed lean mice. Immunophenotypic and functional analyses showed that mice on the safflower oil diet exhibited lower numbers of CD8+ T cells with reduced production of TNFa than mice on the olive oil diet or LFD. Moreover, safflower oil-associated tumor growth was compromised in mice genetically lacking of E-FABP expression. Mechanistically, E-FABP expression in T cells, especially in CD8+ T cells, mediated 18:2 linoleic acid-induced ROS production and T cell death, thus leading to impaired anti-tumor immunity in safflower oil-fed obese mice. Impact: Although oils are healthy dietary components as recommended by DHH and USDA, different oils exhibit diverse immunoregulatory effects in vivo. Overconsumption of oils with 18:2 FAs may cause obesity-associated breast cancer development. Citation Format: Rong Jin, Jiaqing Jiaqing, Di Yin, Yanmei Yi, Hua Yuan, Satuer Edward, Bing Li. Consumption of a high-fat diet rich in linoleic acid promotes mammary tumor growth [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-27.

Mycosis fungoides and Sézary syndrome tumor cells express epidermal fatty acid-binding protein, whose expression decreases with loss of epidermotropism.

Fatty acid binding protein (FABP) is a family of transport proteins for fatty acid (FA). Epidermal FABP (E-FABP) is highly expressed by resident memory T cells (TRM ) in the skin. It supports the uptake of exogenous FA for long-term survival of skin TRM . Mycosis fungoides (MF) is regarded as malignancy of skin TRM . In this study, we investigated E-FABP expression in psoriasis vulgaris (PV), atopic dermatitis (AD), MF, and Sézary syndrome (SS). E-FABP mRNA levels in PV were much higher than those in healthy controls. E-FABP mRNA levels in AD and MF/SS lesional skin were also significantly higher than those of normal skin. By immunohistochemical staining, E-FABP was positive in MF/SS lesional skin. Interestingly, E-FABP was stained positive in epidermotropic lymphoid cells in patch, plaque, and erythrodermic lesions of MF/SS, suggesting that a part of tumor cells expressed E-FABP. In tumorous lesions, however, most dermal tumor cells were negative for E-FABP. Immunohistochemical staining using patch/plaque lesions and tumorous lesions from the same patients also revealed that E-FABP expression decreased in tumorous lesions. Our study has suggested that MF/SS tumor cells express E-FABP, whose expression decreases with loss of epidermotropism.

Epidermal Fatty Acid-Binding Protein 5 (FABP5) Involvement in Alpha-Synuclein-Induced Mitochondrial Injury under Oxidative Stress.

The accumulation of α-synuclein (αSyn) has been implicated as a causal factor in the pathogenesis of Parkinson’s disease (PD). There is growing evidence that supports mitochondrial dysfunction as a potential primary cause of dopaminergic neuronal death in PD. Here, we focused on reciprocal interactions between αSyn aggregation and mitochondrial injury induced by oxidative stress. We further investigated whether epidermal fatty acid-binding protein 5 (FABP5) is related to αSyn oligomerization/aggregation and subsequent disturbances in mitochondrial function in neuronal cells. In the presence of rotenone, a mitochondrial respiratory chain complex I inhibitor, co-overexpression of FABP5 with αSyn significantly decreased the viability of Neuro-2A cells compared to that of αSyn alone. Under these conditions, FABP5 co-localized with αSyn in the mitochondria, thereby reducing mitochondrial membrane potential. Furthermore, we confirmed that pharmacological inhibition of FABP5 by its ligand prevented αSyn accumulation in mitochondria, which led to cell death rescue. These results suggested that FABP5 is crucial for mitochondrial dysfunction related to αSyn oligomerization/aggregation in the mitochondria induced by oxidative stress in neurons.

Effect of methotrexate treatment on the expression of epidermal-fatty acid-binding protein (E-FABP) and apolipoproteins in patients with psoriasis.

IntroductionEpidermal-fatty acid-binding protein (E-FABP) is a marker of transiently amplifying cells which are formed from stem cells in epidermis. Their role is an uptake of fatty acids and metabolism. Psoriatic keratinocytes overexpress E-FABPs, which leads to acanthosis and may explain the lipid’s disturbances in psoriasis.AimAssessment of FABP and apolipoprotein expression in patients treated with methotrexate (MTX).Material and methodsFABP expression in the lesional and perilesional psoriatic skin from 11 male patients compared to 5 healthy skin samples were evaluated by immunohistochemistry. FABP, apolipoprotein A1 (ApoA1) and B (ApoB) serum levels were assessed by ELISA. These parameters were evaluated before and after treatment with subcutaneous MTX (15 mg/wk for 12 weeks).ResultsExpression of E-FABP was lower in the control group than in the lesional and perilesional psoriatic skin, before and after treatment. After treatment the expression decreased in the lesional and perilesional skin. Serum E-FABP was higher in the control group (482.855 ±240.550 pg/ml) compared to patients, but not statistically significantly. After MTX treatment, a statistically significant reduction was observed in psoriatic patients. ApoA1 levels did not differ in the control and patients groups, both before and after treatment. In contrast, ApoB levels did not differ statistically between the control group (1447.126 ±311.11 ng/ml) and patients before treatment, while they were the lowest after treatment (1081.67 ±117.83 ng/ml vs. 808.306 ±103.72 ng/ml; p < 0.01).ConclusionsOur study confirms the beneficial effect of MTX, not only as an anti-proliferative effect, but also reducing the cardiovascular risk by decreasing atherogenic ApoB.

219 Epidermal fatty acid-binding protein is expressed by epidermis and dermal infiltrating cells in psoriasis, atopic dermatitis, and cutaneous T-cell lymphoma

219 Epidermal fatty acid-binding protein is expressed by epidermis and dermal infiltrating cells in psoriasis, atopic dermatitis, and cutaneous T-cell lymphoma

The Potential Effect of Fatty Acids from Pliek U on Epidermal Fatty Acid Binding Protein: Chromatography and Bioinformatic Studies

The fatty acid analysis in Pliek U and its bioinformatic studies had been carried out and reported. Herein, fatty acids were analyzed by gas chromatography-mass spectrometry (GC-MS), meanwhile their potential effect, based on its interaction on epidermal fatty acid binding protein (E-FABP), was studied by bioinformatics approach with reverse docking technique using palmitic acid as a control compound. For the stated purpose, two Pliek U extracts were prepared, namely ethanolic Pliek U extract (EPUE), and ethanolic of residue hexane of Pliek U extract (ERHPUE). The GC-MS results showed that lauric, myristic, palmitic, and oleic acids were predominant, followed by stearic, capric, linoleic, and caprylic acids. Reverse docking results showed that linoleic acid had the lowest binding affinity (-5.9 kcal/mol) and was strongly bound to E-FABP on the same side of amino acid GLN A98, ARG A81, TYR A22, and LYS A61. These findings indicated that linoleic acid has a potential utility as a drug candidate for atopic dermatitis treatment.

Epidermal Fatty Acid-Binding Protein: A Novel Marker in the Diagnosis of Dry Eye Disease in Sjögren Syndrome.

Purpose: Sjögren syndrome (SS) is a chronic inflammatory autoimmune disease of the lacrimal and salivary glands. This study compared the concentrations of epidermal fatty-acid binding protein (E-FABP) in the saliva, serum, and tears of SS patients with dry eye and dry mouth, with those of healthy adults to investigate the usefulness of E-FABP as a diagnostic marker for SS. Design: Prospective, observational case series. Participants: The subjects were 11 new patients with untreated Sjogren syndrome and 12 healthy control individuals. Methods: The diagnosis of SS was in accordance with the Ministry of Health, Labour and Welfare (Japan) Diagnostic Criteria (1999). Saliva, serum, and tear specimens were collected during internal medicine, dental, and ophthalmological examinations. The ophthalmological tests included the Dry Eye-related Quality of life Score (DEQS), tear break-up time (BUT), vital staining with fluorescein (FS) and lissamine green (LG), and the Schirmer test-1. The E-FABP concentration in the tears, saliva, and serum was measured by enzyme-linked immunosorbent assay (ELISA). Main outcome measure: The E-FABP concentrations were compared between patients and controls. Results: There were significant differences between the patient and healthy control groups in all ophthalmological test results. There were no significant differences between the groups in the E-FABP concentrations in the saliva (p = 0.1513) or the serum (p = 0.4799), but the E-FABP concentration in the tears significantly differed between groups. The E-FABP concentration in tears tended to be significantly lower in patients with SS (mean, 323.5 ± 325.6 pg/mL) than healthy control subjects (mean, 4076 pg/mL; p = 0.0136). The E-FABP concentration in tears significantly correlated with the results of dry eye parameters. Conclusion: The E-FABP concentration in tears appears to be related to ocular surface epithelial damage and tear stability and may be a promising novel biomarker in the diagnosis of SS.

Altered epidermal fatty acid-binding protein expression in hepatocellular carcinoma predicts unfavorable outcomes.

ObjectiveHepatocellular carcinoma (HCC) is a rapidly proliferating malignancy that requires large amounts of fatty acids to synthesize cellular membranes and provide energy. Epidermal fatty acid-binding protein (EFABP) is uniquely expressed in epidermal cells, but its role and expression in HCC are not clear.Subjects and methodsA total of 804 HCC specimens were collected to construct a tissue microarray (TMA) and for immunohistochemistry (IHC) analysis. The relationship between EFABP expression and clinical features of patients with HCC was analyzed.ResultsThe EFABP IHC score for HCC tissue was 0.76±0.69, being significantly higher than that for matched nontumorous tissue (0.48±0.55; P<0.001). Using the median IHC score (ie, 0.8) in the tumorous tissue, a high level of EFABP expression was found in 57.3% (461/804) of the cases. Patients with HCC displaying high EFABP expression had poorer tumor differentiation (P=0.029), more vascular invasion (P=0.006), and a higher proportion of late TNM stage disease (P=0.042). Kaplan–Meier analysis revealed that the patients with high EFABP expression had significantly worse outcomes in terms of overall survival (P=0.003), worse disease-free survival (P=0.021), and a higher probability of recurrence (P=0.014). Multivariate analysis indicated that EFABP expression was an independent prognostic variable for overall survival (P=0.021) and disease-free survival (P=0.044). For HCC recurrence, only vascular invasion (P=0.020) and EFABP expression (P=0.026) were independent risk factors.ConclusionOur data revealed that EFABP expression was increased in HCC samples. High EFABP expression was correlated with shorter survival times in patients with HCC and served as an independent factor for worse outcomes. Our study therefore provides a promising bio-marker for the prognostic prediction of HCC and a potential therapeutic target for the disease.

A novel fatty acid-binding protein 5-estrogen-related receptor α signaling pathway promotes cell growth and energy metabolism in prostate cancer cells.

Epidermal or cutaneous fatty acid-binding protein is an intracellular lipid-binding protein, also known as FABP5, and its expression level is closely related to cancer cell proliferation and metastatic activities in various types of carcinoma. However, the molecular mechanisms of FABP5 in cancer cell proliferation and its other functions have remained unclear. In the present study, we have clearly revealed that FABP5 activated expression of metabolic genes (ATP5B, LCHAD, ACO2, FH and MFN2) via a novel signaling pathway in an ERRα (estrogen-related receptor α)-dependent manner in prostate cancer cell lines. To clarify the novel function of FABP5, we examined the activation mechanisms of the ERRα target genes via FABP5. A direct protein-protein interaction between FABP5 and ERRα was demonstrated by immunoprecipitation and GST pull-down assays. We have clearly revealed that FABP5 interacted directly with transcriptional complex containing ERRα and its co-activator PGC-1β to increase expression of the ERRα target genes. In addition, we have shown that FABP5 knockdown induced high energy stress leading to induction of apoptosis and cell cycle arrest via AMPK-FOXO3A signaling pathway in prostate cancer cells, suggesting that FABP5 plays an important role in cellular energy status directing metabolic adaptation to support cellular proliferation and survival.

Fatty acid-binding protein 5 (FABP5) promotes lipolysis of lipid droplets, de novo fatty acid (FA) synthesis and activation of nuclear factor-kappa B (NF-κB) signaling in cancer cells

Fatty acid-binding proteins (FABPs) are involved in binding and storing hydrophobic ligands such as long-chain fatty acids, as well as transporting them to the appropriate compartments in the cell. Epidermal fatty acid-binding protein (FABP5) is an intracellular lipid-binding protein that is abundantly expressed in adipocytes and macrophages. Previous studies have revealed that the FABP5 expression level is closely related to malignancy in various types of cancer. However, its precise functions in the metabolisms of cancer cells remain unclear. Here, we revealed that FABP5 knockdown significantly induced downregulation of the genes expression, such as hormone-sensitive lipase (HSL), monoacylglycerol lipase (MAGL), elongation of long-chain fatty acid member 6 (Elovl6), and acyl-CoA synthetase long-chain family member 1 (ACSL1), which are involved in altered lipid metabolism, lipolysis, and de novo FA synthesis in highly aggressive prostate and breast cancer cells. Moreover, we demonstrated that FABP5 induced inflammation and cytokine production through the nuclear factor-kappa B signaling pathway activated by reactive oxygen species and protein kinase C in PC-3 and MDA-MB-231 cells. Thus, FABP5 might regulate lipid quality and/or quantity to promote aggressiveness such as cell growth, invasiveness, survival, and inflammation in prostate and breast cancer cells. In the present study, we have revealed for the first time that high expression of FABP5 plays a critical role in alterations of lipid metabolism, leading to cancer development and metastasis in highly aggressive prostate and breast cancer cells.

Saturated Fatty Acids Induce Ceramide-associated Macrophage Cell Death

Macrophages highly express epidermal fatty acid-binding protein and adipose fatty acid-binding protein. They actively uptake saturated and unsaturated fatty acids, which might play a critical role in regulating their immune functions. Numerous studies have shown that various fatty acids, saturated or unsaturated, may possess different impacts on cell growth and function. However, the approaches used for fatty acid preparation vary, which may lead to non-physiological results. Serum albumin, a natural carrier for fatty acids in mammalian peripheral blood, is recommended for forming a conjugate complex with the sodium salt of fatty acids to study fatty acid function in mammalian cells, thus minimizing the toxicity of fatty acid soap. Thus, a simple, relatively quick heating and sonicating method is developed and presented here for BSA-fatty acid conjugate formation. We describe a protocol using saturated fatty acids, especially stearic acids to induce severe cell death in mouse bone-marrow derived macrophages. We further demonstrate that saturated fatty acid-induced cell death is positively associated with accumulated cellular ceramide levels. This method can be extended for studies of the impact of fatty acid on other mammalian cells.