Fatty Acid Binding Protein 5 Research Articles

Abstract 372: Obesity matters: Prostate cancers that overexpress fatty acid binding protein 5 are more common in men who are overweight or obese

Abstract BACKGROUND: One of the hallmarks of the malignant phenotype is an increase in the cell's demand for fatty acids (FA). Many cancers, including prostate cancer, show increased expression of fatty acid synthase (FASN), a multi-component enzyme that catalyzes the de novo synthesis of the fatty acid palmitate. However recent observations suggest that alternate mechanisms for FA acquisition are also important, including the utilization of exogenous palmitate when it's available. Recently, through a biopsy-based molecular analysis of high risk prostate cancer, we identified a tumor subtype with very high (>10 fold) "outlier" overexpression of fatty acid binding protein 5 (FABP5). FABP5 is involved in lipid transport and signaling, and it facilitates the utilization of palmitate and other FAs from outside of the cell. De novo palmitate synthesis by the FASN pathway is energetically expensive compared to utilization of exogenous fatty acids. STUDY DESIGN: We proposed that prostate cancers that can efficiently utilize exogenous palmitate are at a selective advantage when dietary FAs are abundant. In this study, to test that hypothesis, we compared FABP5 and FASN expression levels in prostate cancers obtained from diagnostic biopsies from normal weight, overweight and obese study subjects. A total of 201 consecutive eligible prostate biopsy patients were prospectively enrolled; 151 (75%) of these patients were cancer positive. Prostate cancer FABP5 and FASN mRNA expression were measured by qrtPCR and FABP5/FASN and FASN/FABP5 expression ratios were determined for each cancer positive core. BMI and self-identified race were obtained from hospital records. RESULTS: The expression of FABP5 and the FABP5/FASN expression ratio were significantly higher in overweight and obese individuals compared to normal weight individuals (mean FABP5/FASN overexpression ratio of 20.2 in overweight/obese subjects vs 4.0 in normal weight subjects; p < 0.05). The highest levels of prostate cancer FABP5 outlier overexpression (FABP5/FASN > 100) were observed in African American subjects with BMI > 30, and high levels of FABP5 outlier overexpression were more strongly associated with overall Gleason sum in African American than in European American subjects. CONCLUSIONS: In our study population, prostate cancer subtypes with high levels of FABP5 overexpression were more common in biopsy patients who were overweight or obese compared to normal weight patients. The highest levels of FABP5 overexpression in were observed in prostate cancers from obese African American subjects. Such FABP5 dominant prostate cancers may utilize exogenous fatty acids more efficiently and be more sensitive to dietary interventions than the more widely studied FASN dominant prostate cancers. Funding: DOD Prostate Cancer Research Program Awards W8XWH-10-1-0543 (Grizzle, PI) and W81XWH-10-1-0544 (Gaston, PI) Citation Format: Sandra M. Gaston, Soroush Rais-Bahrami, James Kearns, Dennis Otali, Denise Oelschlager, Mark S. DeGuenther, Jeffrey W. Nix, Peter N. Kolettis, James E. Bryant, Robert A. Oster, William E. Grizzle. Obesity matters: Prostate cancers that overexpress fatty acid binding protein 5 are more common in men who are overweight or obese [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 372.

Dietary docosahexaenoic acid supplementation enhances expression of fatty acid‐binding protein 5 at the blood–brain barrier and brain docosahexaenoic acid levels

The cytoplasmic trafficking of docosahexaenoic acid (DHA), a cognitively beneficial fatty acid, across the blood-brain barrier (BBB) is governed by fatty acid-binding protein 5 (FABP5). Lower levels of brain DHA have been observed in Alzheimer's disease (AD), which is associated with diminished BBB expression of FABP5. Therefore, up-regulating FABP5 expression at the BBB may be a novel approach for enhancing BBB transport of DHA in AD. DHA supplementation has been shown to be beneficial in various mouse models of AD, and therefore, the aim of this study was to determine whether DHA has the potential to up-regulate the BBB expression of FABP5, thereby enhancing its own uptake into the brain. Treating human brain microvascular brain endothelial (hCMEC/D3) cells with the maximum tolerable concentration of DHA (12.5μM) for 72h resulted in a 1.4-fold increase in FABP5 protein expression. Associated with this was increased expression of fatty acid transport proteins 1 and 4. To study the impact of dietary DHA supplementation, 6- to 8-week-old C57BL/6 mice were fed with a control diet or a DHA-enriched diet for 21days. Brain microvascular FABP5 protein expression was up-regulated 1.7-fold in mice fed the DHA-enriched diet, and this was associated with increased brain DHA levels (1.3-fold). Despite an increase in brain DHA levels, reduced BBB transport of 14 C-DHA was observed over a 1min perfusion, possibly as a result of competitive binding to FABP5 between dietary DHA and 14 C-DHA. This study has demonstrated that DHA can increase BBB expression of FABP5, as well as fatty acid transporters, overall increasing brain DHA levels.

Abstract 5902: RNA sequencing analysis of taxane-resistant prostate cancer cells reveals potential candidate genes for therapeutic targeting

Abstract There is no cure for metastatic prostate cancer (PCa), the most commonly diagnosed cancer and third leading cause of cancer mortality among U.S. men. Patients with advanced PCa often develop resistance to conventional therapies resulting in metastatic castration-resistant PCa (mCRPC). Docetaxel (DTX) chemotherapy is the standard-of-care for mCRPC, followed by secondary chemotherapy with cabazitaxel (CBZ), yet chemoresistance and death inevitably occurs. While pharmacological agents targeting single survival pathways have shown promise at the bench side, clinical trials have failed. This is mostly due to the presence of redundant pathways utilized by PCa tumor cells to maintain chemoresistance. Therefore, we are interested in further defining molecular pathways associated with DTX-resistance in order to identify novel therapeutic targets to overcome this resistance. We hypothesized that RNA sequencing (RNAseq) analysis comparing the transcriptomes of chemosensitive and chemoresistant mCRPC cells will reveal potential targets for combinatorial therapies. RNAseq analysis of DTX-sensitive and -resistant PC3 and DU145 cells revealed a number of differentially regulated genes that were either unique to each cell line or common to both. We found that dipeptidyl peptidase 4 (DPP4), fatty acid binding protein 5 (FABP5), nestin (NES), and tetraspanin 8 (TSPAN8) were among the top most robustly and significantly upregulated genes in both DTX-resistant PC3 and DU145 cell lines. In-house qPCR studies validated the RNAseq results for these genes, and Western blotting analysis showed increased expression of these proteins in DTX-resistant cells, which correlated with increased mRNA expression. Interestingly, NES, TSPAN8, DPP4 are genes associated with development of the cancer stem-cell (CSC) phenotype. Other genes associated with CSCs were also upregulated in the DTX-resistant cells, suggesting that in vitro selection of mCRPC cells for DTX resistance may enrich for CSCs. This novel finding is consistent with recent studies implicating CSCs in PCa chemoresistance. Further analysis and validation of our RNAseq data will increase our understanding of DTX-resistance mechanisms in PCa cells, including the yet undefined functional role of CSC-related genes. These studies also reveal potential therapeutic targets to circumvent DTX resistance in PCa. Citation Format: Christina K. Cajigas-Du Ross, Leanne Woods-Burnham, Joshua Ramirez, Xin Chen, Charles Wang, Carlos A. Casiano. RNA sequencing analysis of taxane-resistant prostate cancer cells reveals potential candidate genes for therapeutic targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5902.

Fatty acid binding protein 5 promotes tumor angiogenesis and activates the IL6/STAT3/VEGFA pathway in hepatocellular carcinoma

BackgroundTumor angiogenesis is an essential process for facilitating tumor growth and metastasis. Fatty acid binding protein 5(FABP5)is highly expressed in hepatocellular carcinoma (HCC). Thus, we investigated the role of FABP5 in tumor angiogenesis during HCC development. MethodsIn this study, the protein and mRNA levels of FABP5 in matched HCC and adjacent noncancerous liver tissues from 43 patients were determined using immunohistochemistry and real-time quantitative PCR, respectively. Two HCC cell lines (Huh7 and SMMC-7721) and human umbilical vein endothelial cells (HUVECS) were used to investigate the pro-angiogenic effect of FABP5 by tube formation, CCK8 and Transwell migration assays. The expression levels of interleukin 6 (IL6) and vascular endothelial growth factor A (VEGFA) secreted from HCC cells were detected by enzyme-linked immunosorbent assay (ELISA). ResultsIn 43 HCC patients, the expression of FABP5 mRNA was positively correlated with intratumoral VEGFA mRNA expression. FABP5 mRNA expression was also associated with adverse HCC characteristics. In vitro, cell viability, cell migration and tube formation in HUVECs were enhanced with increasing expression of FABP5 in HCC cells. Downregulation of FABP5 expression inhibited the IL6/STAT3/VEGFA pathway in HCC cells and inhibited tumor angiogenesis. ConclusionFABP5 was shown to promote angiogenesis and activate the IL6/STAT3/VEGFA pathway in HCC. FABP5 may be a potential antiangiogenic target in the treatment of HCC.

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.

Peptidome Analysis Reveals Novel Serum Biomarkers for Children with Autism Spectrum Disorder in China.

Autism spectrum disorder (ASD) is a neurological and developmental disorder that begins early in childhood and lasts throughout one's life. Early diagnosis is essential for ASD since early treatment can enable children with ASD to make significant gains in language and social skills, but remains challenging since there are currently no specific biomarkers of ASD. This study is aimed to identify serum biomarkers for ASD. Serum of Han Chinese children with ASD (n=68) and age-matched healthy controls (n=80) is analyzed using magnetic bead-based separation combined with mass spectrum. Eight potential ASD serum biomarker peaks (m/z: 3886.69, 7775.12, 2381.71, 6638.63, 3319.17, 894.34, 4968.59, and 5910.53) with higher expression in ASD group are further identified as peptide regions of plasma serine protease inhibitor precursor (SERPINA5), platelet factor 4 (PF4), fatty acid binding protein 1(FABP1), apolipoprotein C-I precursor (APOC1), alpha-fetoprotein precursor (AFP), carboxypeptidase B2 (CPB2), trace amine-associated receptor 6 (TAAR6), and isoform1 of fibrinogen alpha chain precursor (FGA). The expression of identified proteins is validated by enzyme-linked immunosorbent assay (ELISA). These findings reveal the exceptional disease etiology of ASD from a serum proteomic perspective, and the identified proteins might be potential biomarkers for ASD diagnosis.

Skeletal muscle and liver gene expression profiles in finishing steers supplemented with Amaize.

Our main objective was to evaluate the effects of feeding α-amylase (Amaize, Alltech Inc., Nicholasville, KY, USA) for 140days on skeletal muscle and liver gene transcription in beef steers. Steers fed Amaize had lower average daily gain (p=.03) and gain:feed ratio (p=.05). No differences (p>.10) in serum metabolites or carcass traits were detected between the two groups but Amaize steers tended (p<.15) to have increased 12th rib fat depth. Microarray analysis of skeletal muscle revealed 21 differentially expressed genes (DEG), where 14 were up-regulated and seven were down-regulated in Amaize-fed steers. The bioinformatics analysis indicated that metabolic pathways involved in fat formation and deposition, stress response, and muscle function were activated, while myogenesis was inhibited in Amaize-fed steers. The quantitative PCR results for liver revealed a decrease (p<.01) in expression of fatty acid binding protein 1 (FABP1) and 3-hydroxybutyrate dehydrogenase 1 (BDH1) with Amaize. Because these genes are key for intracellular fatty acid transport, oxidation and ketone body production, data suggest a reduction in hepatic lipid catabolism. Future work to investigate potential positive effects of Amaize on cellular stress response, muscle function, and liver function in beef cattle appears warranted.

MP29-15 MAKE IT FROM SCRATCH OR HAVE IT DELIVERED? SATISFYING THE FATTY ACID DEMAND OF PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I1 Apr 2018MP29-15 MAKE IT FROM SCRATCH OR HAVE IT DELIVERED? SATISFYING THE FATTY ACID DEMAND OF PROSTATE CANCER Sandra Gaston, Soroush Rais-Bahrami, Jeffrey Nix, Peter Kolettis, James Bryant, James Kearns, Oelschlager Denise, Dennis Otali, and William Grizzle Sandra GastonSandra Gaston More articles by this author , Soroush Rais-BahramiSoroush Rais-Bahrami More articles by this author , Jeffrey NixJeffrey Nix More articles by this author , Peter KolettisPeter Kolettis More articles by this author , James BryantJames Bryant More articles by this author , James KearnsJames Kearns More articles by this author , Oelschlager DeniseOelschlager Denise More articles by this author , Dennis OtaliDennis Otali More articles by this author , and William GrizzleWilliam Grizzle More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.935AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES One of the hallmarks of the malignant phenotype is an increase in the cell's demand for fatty acids (FA). Many cancers, including prostate cancer (PrCa), show increased expression of fatty acid synthase (FASN), a multi-component enzyme that catalyzes the de novo synthesis of the FA palmitate. However recent observations suggest that alternate mechanisms for FA acquisition are also important, including the utilization of exogenous palmitate when it's available. Recently, through a biopsy-based molecular analysis of high risk PrCa, we identified a tumor subtype with very high (>10 fold) "outlier" overexpression of fatty acid binding protein 5 (FABP5). FABP5 is involved in lipid transport and signaling, and it facilitates the utilization of palmitate and other FAs from outside of the cell. De novo palmitate synthesis by the FASN pathway is energetically expensive compared to utilization of exogenous FAs. We propose that PrCas that can efficiently utilizes exogenous palmitate are at a selective advantage when dietary FAs are abundant. In this study, to test that hypothesis, we compared FABP5 and FASN expression levels in PrCas obtained from diagnostic biopsies from normal weight, overweight and obese study subjects. METHODS A total of 201 consecutive eligible prostate biopsy patients were prospectively enrolled; 151 (75%) of these patients were cancer positive. PrCa FABP5 and FASN mRNA expression were measured by qrtPCR and FABP5/FASN and FASN/FABP5 expression ratios were determined for each cancer positive core. BMI and self-identified race were obtained from hospital records. RESULTS The expression of FABP5 and the FABP5/FASN expression ratio were significantly higher in overweight and obese individuals compared to normal weight individuals (mean FABP5/FASN overexpression ratio of 20.2 in overweight/obese subjects vs 4.0 in normal weight subjects; p < 0.05). The highest levels of PrCa FABP5 outlier overexpression (FABP5/FASN > 100) were observed in African American subjects with BMI > 30. CONCLUSIONS Our results are consistent with a growing body of evidence suggesting that the well-recognized "addiction" of PrCa for FA can be satisfied by more than one mechanism. In our study population, PrCa subtypes with high levels of FABP5 overexpression were more common in biopsy patients who were overweight or obese. Such FABP5 dominant PrCa subtypes may be more sensitive to dietary interventions than the more widely studied FASN dominant PrCas. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e371 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Sandra Gaston More articles by this author Soroush Rais-Bahrami More articles by this author Jeffrey Nix More articles by this author Peter Kolettis More articles by this author James Bryant More articles by this author James Kearns More articles by this author Oelschlager Denise More articles by this author Dennis Otali More articles by this author William Grizzle More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Δ9-Tetrahydrocannabinol induces endocannabinoid accumulation in mouse hepatocytes: antagonism by Fabp1 gene ablation

Phytocannabinoids, such as Δ9-tetrahydrocannabinol (THC), bind and activate cannabinoid (CB) receptors, thereby "piggy-backing" on the same pathway's endogenous endocannabinoids (ECs). The recent discovery that liver fatty acid binding protein-1 (FABP1) is the major cytosolic "chaperone" protein with high affinity for both Δ9-THC and ECs suggests that Δ9-THC may alter hepatic EC levels. Therefore, the impact of Δ9-THC or EC treatment on the levels of endogenous ECs, such as N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), was examined in cultured primary mouse hepatocytes from WT and Fabp1 gene-ablated (LKO) mice. Δ9-THC alone or 2-AG alone significantly increased AEA and especially 2-AG levels in WT hepatocytes. LKO alone markedly increased AEA and 2-AG levels. However, LKO blocked/diminished the ability of Δ9-THC to further increase both AEA and 2-AG. In contrast, LKO potentiated the ability of exogenous 2-AG to increase the hepatocyte level of AEA and 2-AG. These and other data suggest that Δ9-THC increases hepatocyte EC levels, at least in part, by upregulating endogenous AEA and 2-AG levels. This may arise from Δ9-THC competing with AEA and 2-AG binding to FABP1, thereby decreasing targeting of bound AEA and 2-AG to the degradative enzymes, fatty acid amide hydrolase and monoacylglyceride lipase, to decrease hydrolysis within hepatocytes.

Resveratrol Suppresses the Growth and Enhances Retinoic Acid Sensitivity of Anaplastic Thyroid Cancer Cells.

Anaplastic thyroid cancer (ATC) is a highly lethal undifferentiated malignancy without reliable therapies. Retinoic acid (RA) has been employed to promote redifferentiation of thyroid cancers by increasing their I131 uptake and radio-sensitivity, but its effect(s) on ATCs has not yet been ascertained. Likewise, resveratrol induces cancer redifferentiation but, also in this case, its effects on ATCs remain unknown. These issues have been addresses in the current study using three human ATC cell lines (THJ-11T, THJ-16T, and THJ-21T) through multiple experimental approaches. The results reveal that RA exerts a small inhibitory effect on these cell lines. In comparison with normally cultured cells, the total cell number in resveratrol-treated THJ-16T and THJ-21T cultures significantly decreased (p < 0.05), and this effect was accompanied by reduced Cyclin D1 immuno-labeling, increased apoptotic fractions, and distinct caspase-3 activation. Resveratrol failed to inhibit growth but enhanced RA sensitivity of THJ-11T cells, suppressed peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ), and upregulated cellular retinoic acid-binding protein 2 (CRABP2) and retinoic acid receptor beta (RAR-β) expression. Increased thyroglobulin (Tg) and E-cadherin levels and appearance of membranous E-cadherin were evidenced in resveratrol-treated THJ-11T cells. Our results demonstrate for the first time: (1) the therapeutic value of resveratrol by itself or in combination with RA in the management of ATCs, (2) the capacity of resveratrol to overcome RA resistance in ATC cells by reprogramming CRABP2/RAR- and fatty acid-binding protein 5 (FABP5)/PPAR-β/δ-mediated RA signaling, and (3) the redifferentiating potential of resveratrol in ATC cells.

Fatty-acid–binding protein 5 controls retrograde endocannabinoid signaling at central glutamate synapses

Endocannabinoids (eCBs) are lipid-signaling molecules involved in the regulation of numerous behaviors and physiological functions. Released by postsynaptic neurons, eCBs mediate retrograde modulation of synaptic transmission and plasticity by activating presynaptic cannabinoid receptors. While the cellular mechanisms by which eCBs control synaptic function have been well characterized, the mechanisms controlling their retrograde synaptic transport remain unknown. Here, we demonstrate that fatty-acid-binding protein 5 (FABP5), a canonical intracellular carrier of eCBs, is indispensable for retrograde eCB transport in the dorsal raphe nucleus (DRn). Thus, pharmacological inhibition or genetic deletion of FABP5 abolishes both phasic and tonic eCB-mediated control of excitatory synaptic transmission in the DRn. The blockade of retrograde eCB signaling induced by FABP5 inhibition is not mediated by impaired cannabinoid receptor function or reduced eCB synthesis. These findings indicate that FABP5 is essential for retrograde eCB signaling and may serve as a synaptic carrier of eCBs at central synapses.

Mechanisms regulating brain docosahexaenoic acid uptake: what is the recent evidence?

To summarize recent advances pertaining to the mechanisms regulating brain docosahexaenoic acid (DHA) uptake. DHA is an omega-3 polyunsaturated fatty acid highly enriched in neuronal membranes and it is implicated in several important neurological processes. However, DHA synthesis is extremely limited within the brain. There are two main plasma pools that supply the brain with DHA: the nonesterified pool and the lysophosphatidylcholine (lysoPtdCho) pool. Quantitatively, plasma nonesterified-DHA (NE-DHA) is the main contributor to brain DHA. Fatty acid transport protein 1 (FATP1) in addition to fatty acid-binding protein 5 (FABP5) are key players that regulate brain uptake of NE-DHA. However, the plasma half-life of lysoPtdCho-DHA and its brain partition coefficient are higher than those of NE-DHA after intravenous administration. The mechanisms regulating brain DHA uptake are more complicated than once believed, but recent advances provide some clarity notably by suggesting that FATP1 and FABP5 are key contributors to cellular uptake of DHA at the blood-brain barrier. Elucidating how DHA enters the brain is important as we might be able to identify methods to better deliver DHA to the brain as a potential therapeutic.

Differential CRABP-II and FABP5 expression patterns and implications for medulloblastoma retinoic acid sensitivity.

Medulloblastoma (MB) cells exhibit different responses to retinoid acid (RA) for reasons that are poorly understood. RA signaling can be transduced by two approaches that are mediated by cellular retinoic acid-binding protein 2 (CRABP-II) as a tumor-suppressive pathway, and by fatty acid-binding protein 5 (FABP5) as a tumor-promoting pathway. The biological effects of RA on cancer cells are largely determined by the patterns of CRABP-II and FABP5 expression. This study aims to profile the statuses of CRABP-II and FABP5 expression in MB and to evaluate their correlation with RA sensitivities using RA-sensitive (Med-3) and RA-insensitive (UW228-2, UW228-3) MB cells. Our results show that CRABP-II is distinctly expressed and the level of FABP5 is extremely low in Med-3 cells, while the patterns of CRABP-II and FABP5 expression are reversed in UW228-2 and UW228-3 cells. RA up-regulates CRABP-II expression in Med-3 cells, whereas it up-regulates FABP5 expression in the other two cell lines. The FABP5-specific inhibitor BMS309403 increases the RA sensitivity of UW228-2 cells (p < 0.01). Tissue microarray-based immunohistochemical staining showed CRABP-II/FABP5 expression patterns in MB that were variable (CRABP-II−/FABP5−, CRABP-II−/FABP5+, CRABP-II+/FABP5− and CRABP-II+/FABP5+) and imbalanced (CRABP-II↑/FABP5↓ and CRABP-II↓/FABP5↑). MB cases exhibited patterns ofCRABP-II−/FABP5− (12.24%, 6/49), CRABP-II−/FABP5+ (30.61%, 15/49) or CRABP-II↓/FABP5↑ (12.24%, 6/49), implicating unresponsiveness or insensitivity to RA. In conclusion, the ratios of CRABP-II/FABP5 levels are closely related to the RA sensitivities of MB cells. The differential CRABP-II and FABP5 expression patterns are prospective parameters, and of potential value in personalized RA therapy for MB.

Transcriptomic and metabolomic responses induced in the livers of growing pigs by a short-term intravenous infusion of sodium butyrate

Previous studies showed that butyrate played benefit roles in the health and metabolism of animals. However, little information on the effects of butyrate on the metabolism of piglets at the extraintestinal level is available. The present study investigated transcriptomic and metabolomic responses in the livers of pigs to evaluate the effects of intravenous sodium butyrate (SB) on the body’s metabolism at the extraintestinal level. A total of 12 Duroc×Landrace×Large White growing barrows (60 days of age) fitted with jugular vein cannula were randomly allocated to either the SB group or the control (CO) group. Pigs in the SB group were intravenously infused with 10 ml SB (200 mmol/l) for 7 days, whereas pigs in the CO group were treated with the same amount of saline. The livers of pigs were collected for gene expression and metabolome analyses. The RNA sequencing (RNA-Seq) analysis showed that the mRNA expression of Acyl-CoA synthetase long-chain family member 1 (ACSL1), carnitine palmitoyltransferase 1A (CPT1A), acetyl-CoA acyltransferase 2 (ACAA2) and phosphoenolpyruvate carboxykinase 1 (PCK1) were downregulated (Q<0.05), whereas fatty acid binding protein 1 (FABP1) and cytochrome P450 family 7 subfamily A member 1 (CYP7A1) were upregulated (P<0.05) by SB treatment, indicating a decrease in fatty acid oxidation and gluconeogenesis and an increase in fatty acid transportation and cholesterol metabolism. Gas chromatography-mass spectrometry analysis showed that raffinose was enriched in the SB group compared with the CO group, indicating a decrease in metabolism of galactose. Moreover, SB treatment significantly decreased the concentration of blood cholesterol. The results suggest that a short-term intravenous infusion of SB could modulate hepatic lipid metabolism by decreasing fatty acid oxidation and increasing fatty acid transportation and cholesterol metabolism.

Siphonaxanthin, a Carotenoid From Green Algae, Inhibits Lipogenesis in Hepatocytes via the Suppression of Liver X Receptor α Activity.

Nonalcoholic fatty liver disease (NAFLD) has shown an increasing morbidity in recent years. Here, we demonstrated that siphonaxanthin (SPX), a rare marine carotenoid, exhibits a strong inhibitory effect on aggravated hepatic lipogenesis in vitro and would be a promising candidate in the prevention and alleviation of NAFLD in the future. In this study, we conducted a preliminary assessment of the effect of SPX on hepatic lipogenesis by using the HepG2 cell line, derived from human liver cancer, as a model of the liver. SPX significantly suppressed the excess accumulation of triacylglycerol induced by liver X receptor α (LXRα) agonist by downregulating a nuclear transcription factor named sterol regulatory element-binding protein-1c and a set of related genes. Moreover, fatty acid translocase (CD36) and fatty acid-binding protein-1, which regulates fatty acid uptake, also exhibited significant decrease in transcriptional levels. Furthermore, we found that SPX blocked LXRα activation and would be a promising candidate for antagonist of LXRα.

Human Liver Fatty Acid Binding Protein‐1 T94A Variant, Nonalcohol Fatty Liver Disease, and Hepatic Endocannabinoid System

Hepatic endocannabinoids (EC) and their major binding/"chaperone" protein (i.e., liver fatty acid binding protein-1 [FABP1]) are associated with development of nonalcoholic fatty liver (NAFLD) in animal models and humans. Since expression of the highly prevalent human FABP1 T94A variant induces serum lipid accumulation, it is important to determine its impact on hepatic lipid accumulation and the EC system. This issue was addressed in livers from human subjects expressing only wild-type (WT) FABP1 T94T (TT genotype) or T94A variant (TC or CC genotype). WT FABP1 males had lower total lipids (both neutral cholesteryl esters, triacylglycerols) and phospholipids than females. WT FABP1 males' lower lipids correlated with lower levels of the N-acylethanolamide DHEA and 2-monoacylglycerols (2-MAG) (2-OG, 2-PG). T94A expression in males increased the hepatic total lipids (triacylglycerol, cholesteryl ester), which is consistent with their higher level of CB1-potentiating 2-OG and lower antagonistic EPEA. In contrast, in females, T94A expression did not alter the total lipids, neutral lipids, or phospholipids, which is attributable to the higher cannabinoid receptor-1 (CB1) agonist arachidonoylethanolamide (AEA) and its CB1-potentiator OEA being largely offset by reduced potentiating 2-OG and increased antagonistic EPEA. Taken together, these findings indicate that T94A-induced alterations in the hepatic EC system contribute at least in part to the hepatic accumulation of lipids associated with NAFLD, especially in males.

Reduced blood-brain barrier expression of fatty acid-binding protein 5 is associated with increased vulnerability of APP/PS1 mice to cognitive deficits from low omega-3 fatty acid diets.

Lower levels of the cognitively beneficial docosahexaenoic acid (DHA) are often observed in Alzheimer's disease (AD) brains. Brain DHA levels are regulated by the blood-brain barrier (BBB) transport of plasma-derived DHA, a process facilitated by fatty acid-binding protein 5 (FABP5). This study reports a 42.1±12.6% decrease in the BBB transport of 14 C-DHA in 8-month-old AD transgenic mice (APPswe,PSEN1∆E9) relative to wild-type mice, associated with a 34.5±6.7% reduction in FABP5 expression in isolated brain capillaries of AD mice. Furthermore, short-term spatial and recognition memory deficits were observed in AD mice on a 6-month n-3 fatty acid-depleted diet, but not in AD mice on control diet. This intervention led to a dramatic reduction (41.5±11.9%) of brain DHA levels in AD mice. This study demonstrates FABP5 deficiency and impaired DHA transport at the BBB are associated with increased vulnerability to cognitive deficits in mice fed an n-3 fatty acid-depleted diet, in line with our previous studies demonstrating a crucial role of FABP5 in BBB transport of DHA and cognitive function.

Fatty Acid–Binding Protein 5 Mediates the Uptake of Fatty Acids, but not Drugs, Into Human Brain Endothelial Cells

The purpose of this study was to examine the involvement of fatty acid–binding protein 5 (FABP5), a lipid-binding protein expressed at the blood-brain barrier (BBB), in fatty acid and drug uptake into human brain endothelial cells. Following transfection with siRNA against hFABP5, human brain endothelial cell (hCMEC/D3) uptake of lipophilic ligands with varying affinity to FABP5 was assessed with intracellular concentrations quantified by liquid scintillation counting, HPLC, or LCMS/MS. The in situ BBB transport of [3H]-diazepam was also assessed in wild type and FABP5-deficient mice. hFABP5 siRNA reduced FABP5 expression in hCMEC/D3 cells by 39.9 ± 3.8% (mRNA) and 38.8 ± 6.6% (protein; mean ± SEM), leading to a reduction in uptake of [14C]-lauric acid, [3H]-oleic acid, and [14C]-stearic acid by 37.5 ± 8.8%, 41.7 ± 11.6%, and 50.7 ± 13.6%, respectively, over 1 min. No significant changes in [14C]-diazepam, pioglitazone, and troglitazone uptake were detected following FABP5 knockdown in hCMEC/D3 cells. Similarly, no difference in BBB transport of [3H]-diazepam was observed between wild type and FABP5-deficient mice. Therefore, although FABP5 facilitates brain endothelial cell uptake of fatty acids, it has limited effects on brain endothelial cell uptake and BBB transport of drugs with lower affinity for FABP5.

The Role of FABP5 in Radiation-Induced Human Skin Fibrosis.

Radiation-induced skin fibrosis is a detrimental and chronic disorder that occurs after radiation exposure. The molecular changes underlying the pathogenesis of radiation-induced fibrosis of human skin have not been extensively reported. Technical advances in proteomics have enabled exploration of the biomarkers and molecular pathogenesis of radiation-induced skin fibrosis, with the potential to broaden our understanding of this disease. In this study, we compared protein expression in radiation-induced fibrotic human skin and adjacent normal tissues using iTRAQ-based proteomics technology. We identified 186 preferentially expressed proteins (53 upregulated and 133 downregulated) between radiogenic fibrotic and normal skin tissues. The differentially expressed proteins included keratins (KRT5, KRT6A, KRT16 and KRT17), caspase-14, fatty acid-binding protein 5 (FABP5), SLC2A14 and resistin. Through bioinformatic analysis of the proximal promoters, common motifs and corresponding transcriptional factors were identified that associate with the dysregulated proteins, including PAX5, TBX1, CLOCK and AP2D. In particular, FABP5 (2.15-fold increase in fibrotic skin tissues), a transporter of hydrophobic fatty acids, was investigated in greater detail. Immunohistochemistry confirmed that the protein level of FABP5 was increased in fibrotic human skin tissues, especially in the epidermis. Overexpression of FABP5 resulted in nuclear translocation of SMAD2 and significant activation of the profibrotic TGF-β signaling pathway in human fibroblast WS1 cells. Moreover, exogenous FABP5 (FABP5-EGFP) could be incorporated by skin cells and intensify TGF-β signaling, indicating a communication between the microenvironment and skin fibrosis. Taken together, our findings illustrate the molecular changes during radiation-induced human skin fibrosis and the critical role of FABP5 in activating the TGF-β signaling pathway.

Gene expression profiling reveals candidate genes related to residual feed intake in duodenum of laying ducks.

Feed represents two-thirds of the total costs of poultry production, especially in developing countries. Improvement in feed efficiency would reduce the amount of feed required for production (growth or laying), the production cost, and the amount of nitrogenous waste. The most commonly used measures for feed efficiency are feed conversion ratio (FCR) and residual feed intake (RFI). As a more suitable indicator assessing feed efficiency, RFI is defined as the difference between observed and expected feed intake based on maintenance and growth or laying. However, the genetic and biological mechanisms regulating RFI are largely unknown. Identifying molecular mechanisms explaining divergence in RFI in laying ducks would lead to the development of early detection methods for the selection of more efficient breeding poultry. The objective of this study was to identify duodenum genes and pathways through transcriptional profiling in 2 extreme RFI phenotypes (HRFI and LRFI) of the duck population. Phenotypic aspects of feed efficiency showed that RFI was strongly positive with FCR and feed intake (FI). Transcriptomic analysis identified 35 differentially expressed genes between LRFI and HRFI ducks. These genes play an important role in metabolism, digestibility, secretion, and innate immunity including (), (), (), β (), and (). These results improve our knowledge of the biological basis underlying RFI, which would be useful for further investigations of key candidate genes for RFI and for the development of biomarkers.