Chromodomain Y-like (CDYL) inhibition ameliorates acute kidney injury in mice by regulating tubular pyroptosis.

Acute kidney injury (AKI) is a common disease, but lacking effective drug treatments. Chromodomain Y-like (CDYL) is a kind of chromodomain protein that has been implicated in transcription regulation of autosomal dominant polycystic kidney disease. Benzo[d]oxazol-2(3H)-one derivative (compound D03) is the first potent and selective small-molecule inhibitor of CDYL (KD = 0.5 µM). In this study, we investigated the expression of CDYL in three different models of cisplatin (Cis)-, lipopolysaccharide (LPS)- and ischemia/reperfusion injury (IRI)-induced AKI mice. By conducting RNA sequencing and difference analysis of kidney samples, we found that tubular CDYL was abnormally and highly expressed in injured kidneys of AKI patients and mice. Overexpression of CDYL in cisplatin-induced AKI mice aggravated tubular injury and pyroptosis via regulating fatty acid binding protein 4 (FABP4)-mediated reactive oxygen species production. Treatment of cisplatin-induced AKI mice with compound D03 (2.5 mg·kg-1·d-1, i.p.) effectively attenuated the kidney dysfunction, pathological damages and tubular pyroptosis without side effects on liver or kidney function and other tissue injuries. Collectively, this study has, for the first time, explored a novel aspect of CDYL for tubular epithelial cell pyroptosis in kidney injury, and confirmed that inhibition of CDYL might be a promising therapeutic strategy against AKI.

Fatty Acid-Binding Protein 4-Mediated Regulation Is Pivotally Involved in Retinal Pathophysiology: A Review.

Fatty acid-binding proteins (FABPs), a family of lipid chaperone molecules that are involved in intracellular lipid transportation to specific cellular compartments, stimulate lipid-associated responses such as biological signaling, membrane synthesis, transcriptional regulation, and lipid synthesis. Previous studies have shown that FABP4, a member of this family of proteins that are expressed in adipocytes and macrophages, plays pivotal roles in the pathogenesis of various cardiovascular and metabolic diseases, including diabetes mellitus (DM) and hypertension (HT). Since significant increases in the serum levels of FABP4 were detected in those patients, FABP4 has been identified as a crucial biomarker for these systemic diseases. In addition, in the field of ophthalmology, our group found that intraocular levels of FABP4 (ioFABP4) and free fatty acids (ioFFA) were substantially elevated in patients with retinal vascular diseases (RVDs) including proliferative diabetic retinopathy (PDR) and retinal vein occlusion (RVO), for which DM and HT are also recognized as significant risk factors. Recent studies have also revealed that ioFABP4 plays important roles in both retinal physiology and pathogenesis, and the results of these studies have suggested potential molecular targets for retinal diseases that might lead to future new therapeutic strategies.

Glial fibrillary acidic protein, neurofilament light, matrix metalloprotease 3 and fatty acid binding protein 4 as non-invasive brain tumor biomarkers.

BACKGROUND: Gliomas are aggressive malignant tumors, with poor prognosis. There is an unmet need for the discovery of new, non-invasive biomarkers for differential diagnosis, prognosis, and management of brain tumors. Our objective is to validate four plasma biomarkers - glial fibrillary acidic protein (GFAP), neurofilament light (NEFL), matrix metalloprotease 3 (MMP3) and fatty acid binding protein 4 (FABP4) - and compare them with established brain tumor molecular markers and survival. METHODS: Our cohort consisted of patients with benign and malignant brain tumors (GBM = 77, Astrocytomas = 26, Oligodendrogliomas = 23, Secondary tumors = 35, Meningiomas = 70, Schwannomas = 15, Pituitary adenomas = 15, Normal individuals = 30). For measurements, we used ultrasensitive electrochemiluminescence multiplexed immunoassays. RESULTS: High plasma GFAP concentration was associated with GBM, low GFAP and high FABP4 were associated with meningiomas, and low GFAP and low FABP4 were associated with astrocytomas and oligodendrogliomas. NEFL was associated with progression of disease. Several prognostic genetic alterations were significantly associated with all plasma biomarker levels. We found no independent associations between plasma GFAP, NEFL, FABP4 and MMP3, and overall survival. The candidate biomarkers could not reliably discriminate GBM from primary or secondary CNS lymphomas. CONCLUSIONS: GFAP, NEFL, FABP4 and MMP3 are useful for differential diagnosis and prognosis, and are associated with molecular changes in gliomas.

High Fatty Acid-Binding Protein 4 Expression Associated with Favorable Clinical Characteristics and Prognosis in Papillary Thyroid Carcinoma.

Fatty acid-binding protein 4 (FABP4), a fatty acid transporter that coordinates lipid metabolism, is reported to exert a tumorigenic role in certain cancers. We investigated the effects of FABP4 in the carcinogenesis of thyroid cancer. Bioinformatics data about FABP4 in thyroid cancer were collected from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Sixteen paired papillary thyroid cancer (PTC) tissues from Taipei Medical University (TMU) were gathered, and commercial thyroid cancer complementary (c)DNA and tissue arrays were purchased to measure FABP4 messenger (m)RNA and protein levels. By analyzing data from the GEO and TCGA, we showed that FABP4 mRNA was reduced in PTC and follicular thyroid carcinoma (FTC). In addition, a lower FABP4 mRNA level in PTC was associated with poor clinical parameters and outcomes in the TCGA database. Moreover, FABP4 transcripts and proteins were downregulated in PTC and FTC, and its mRNA expression was associated with PTC staging in clinical specimens. In the TCGA database and TMU cohort, FABP4 mRNA levels were associated with thyroglobulin (r = 0.511 and r = 0.656, respectively), thyroid peroxidase (r = 0.612 and r = 0.909, respectively), and sodium iodide symporter (r = 0.485 and r = 0.637, respectively) transcripts. In conclusion, FABP4 mRNA and protein levels were reduced in PTC and FTC, and may be used as a potential indicator for thyroid cancer evolution in clinical settings. Further, well-designed research to dissect the molecular mechanism of FABP4 in modulating thyroid carcinogenesis is needed.

Alcohol-Associated Liver Disease Outcomes: Critical Mechanisms of Liver Injury Progression.

Alcohol-associated liver disease (ALD) is a substantial cause of morbidity and mortality worldwide and represents a spectrum of liver injury beginning with hepatic steatosis (fatty liver) progressing to inflammation and culminating in cirrhosis. Multiple factors contribute to ALD progression and disease severity. Here, we overview several crucial mechanisms related to ALD end-stage outcome development, such as epigenetic changes, cell death, hemolysis, hepatic stellate cells activation, and hepatic fatty acid binding protein 4. Additionally, in this review, we also present two clinically relevant models using human precision-cut liver slices and hepatic organoids to examine ALD pathogenesis and progression.

A New Insight into Fatty Acid Binding Protein 4 Mechanisms and Therapeutic Implications in Obesity-Associated Diseases: A Mini Review.

Fatty acid binding proteins (FABPs), such as FABP4 (aP2, A-FABP), are essential for cellular lipid regulation, membrane-protein interactions, and the modulation of metabolic and inflammatory pathways. FABP4, primarily expressed in adipocytes, monocytes, and macrophages, is integrated into signaling networks that influence immune responses and insulin activity. It has been linked to obesity, inflammation, lipid metabolism, insulin resistance, diabetes, cardiovascular disease, and cancer. Inhibition of FABP4 is emerging as a promising strategy for treating obesity-related conditions, particularly insulin resistance and diabetes. Elevated FABP4 levels in individuals with a BMI above 30 underscore its association with obesity. Furthermore, FABP4 levels are higher not only in the tissues but also in the blood, promoting the onset and development of various cancers. Understanding its broader role reveals involvement in the mechanisms underlying metabolic syndrome, contributing to various metabolic and inflammatory responses. While blocking FABP4 offers an alternative therapeutic approach, a comprehensive understanding of potential side effects is crucial before clinical use. This review aims to provide concise insights into FABP4, elucidating its mechanisms and potential therapeutic applications in obesity and associated disorders, contributing to innovative interventions against metabolic syndrome and obesity.

Radiomics features based on dual-area CT predict the expression levels of fatty acid binding protein 4 and outcome in hepatocellular carcinoma.

RATIONALE AND OBJECTIVES: To evaluate the predictive value of tumor and peritumor radiomics in the fatty acid binding protein 4 (FABP4) expression levels and overall survival in patients with hepatocellular carcinoma. MATERIALS AND METHODS: The genomic data of HCC patients were obtained from The Cancer Genome Atlas. The Dual-area CT images of corresponding patients were downloaded from The Cancer Imaging Archive, for radiomics feature extraction, model construction and prognosis analysis. Simultaneously, using patients from Sichuan Provincial People's Hospital, the prognostic value of the radiomics model in HCC patients was validated. RESULTS: In the TCIA database, the area under the curve (AUC) values of the volumes of interest (VOI)whole model in the training set and internal validation set were 0.812 and 0.754, respectively, and the AUC value of VOIwhole+periphery in the training set and internal validation set were 0.866 and 0.779, respectively. In the VOIwhole and the VOIwhole+periphery model of the independent cohort, there were significant differences in OS between the high and low rad-score groups (P = 0.009, P = 0.021, respectively). Significant positive correlations can be observed between FABP4 expression and correlations with rad-score of VOIwhole model (r = 0.691) and VOIwhole+periphery model (r = 0.732) in the independent cohort. CONCLUSION: Radiomics models of tumor and peritumor Dual-area CT images could predict stably the expression levels of FABP4 and may be helping in personalized treatment strategies.

Alleviative effects of the parthenolide derivative ACT001 on insulin resistance induced by sodium propionate combined with a high-fat diet and its potential mechanisms.

The increasing side effects of traditional medications used to treat type II diabetes have made research into the development of safer and more effective natural medications necessary. ACT001, a derivative of parthenolide, has been shown to have good anti-inflammatory and antitumor effects; however, its role in diabetes is unclear. The short-chain fatty acid propionate is a common food preservative that has been found to cause disturbances in glucose metabolism in mice and humans. This study aimed to investigate whether sodium propionate could aggravate insulin resistance in obese mice and cause diabetes and to study the alleviative effects and potential mechanisms of action of ACT001 on insulin resistance in diabetic mice. Type II diabetic mice were adminietered sodium propionate combined with a high-fat diet (HFD + propionate) by gavage daily for four weeks. Biochemical analysis showed that ACT001 significantly affected blood glucose concentration in diabetic mice, mainly by downregulating the expression of phosphoenolpyruvate carboxykinase 2 and glucose-6-phosphatase. Meanwhile, the level of fatty acid-binding protein 4 in the liver was significantly decreased. ACT001 has a protective effect on the liver and adipose tissue of mice. In addition, the results of the running wheel experiment indicated that ACT001 alleviated the circadian rhythm disorder caused by insulin resistance to a certain extent. This study revealed the potential mechanism by which ACT001 alleviates insulin resistance and provides ideas for developing natural antidiabetic drugs.

High-expression of FABP4 in Tubules is a Risk Factor for Poor Prognosis in DKD Patients.

BACKGROUND: Lipid metabolism imbalance is involved in the mechanism of renal tubular injury in diabetic kidney disease (DKD). Fatty acid binding protein 4 (FABP4) has been reported to participate in cellular lipid toxicity. However, the expression of FABP4 in renal tissues of DKD and its correlation with clinical/ pathological parameters and prognosis have not been studied. METHODS: A retrospective cohort study was conducted in 108 hospitalized Type 2 diabetes (T2D) patients with renal injury, including 70 with DKD and 38 with NDKD (non-DKD). Clinical features, pathological findings, and follow-up parameters were collected. Serum and urine FABP4 were detected by ELISA. An immunohistochemistry stain was used to determine FABP4 in renal tubulointerstitium. A double immunofluorescence stain was employed to assess FABP4- and CD68-positive macrophages. Correlation analysis, logistic regression models, receiver operating characteristic (ROC), and Kaplan-Meier survival curve were performed for statistical analysis. RESULTS: DKD patients had increased expression of FABP4 and ectopic fat deposition in tubules. As shown by correlation analyses, FABP4 expression in renal tubules was positively correlated with UNAG (r=0.589, p=0.044) and ESRD (r=0.740, p=0.004). Multivariate regression analysis revealed that UNAG level was correlated with FABP4 expression level above median value (odds ratio:1.154, 95% confidence interval:1.009-1.321, p=0.037). High-expression of FABP4 in renal tubules of DKD was at an increased risk of ESRD. Increased FABP4 expression in inflammatory cells was also associated with ESRD in DKD. CONCLUSION: High-expression of FABP4 is involved in the pathogenesis of renal tubular lipid injury and is a risk factor for poor prognosis in DKD patients.

Integrated multi-omic analysis identifies fatty acid binding protein 4 as a biomarker and therapeutic target of ischemia-reperfusion injury in steatotic liver transplantation.

BACKGROUND AND AIMS: Due to a lack of donor grafts, steatotic livers are used more often for liver transplantation (LT). However, steatotic donor livers are more sensitive to ischemia-reperfusion (IR) injury and have a worse prognosis after LT. Efforts to optimize steatotic liver grafts by identifying injury targets and interventions have become a hot issue. METHODS: Mouse LT models were established, and 4D label-free proteome sequencing was performed for four groups: normal control (NC) SHAM, high-fat (HF) SHAM, NC LT, and HF LT to screen molecular targets for aggravating liver injury in steatotic LT. Expression detection of molecular targets was performed based on liver specimens from 110 donors to verify its impact on the overall survival of recipients. Pharmacological intervention using small-molecule inhibitors on an injury-related target was used to evaluate the therapeutic effect. Transcriptomics and metabolomics were performed to explore the regulatory network and further integrated bioinformatics analysis and multiplex immunofluorescence were adopted to assess the regulation of pathways and organelles. RESULTS: HF LT group represented worse liver function compared with NC LT group, including more apoptotic hepatocytes (P < 0.01) and higher serum transaminase (P < 0.05). Proteomic results revealed that the mitochondrial membrane, endocytosis, and oxidative phosphorylation pathways were upregulated in HF LT group. Fatty acid binding protein 4 (FABP4) was identified as a hypoxia-inducible protein (fold change > 2 and P < 0.05) that sensitized mice to IR injury in steatotic LT. The overall survival of recipients using liver grafts with high expression of FABP4 was significantly worse than low expression of FABP4 (68.5 vs. 87.3%, P < 0.05). Adoption of FABP4 inhibitor could protect the steatotic liver from IR injury during transplantation, including reducing hepatocyte apoptosis, reducing serum transaminase (P < 0.05), and alleviating oxidative stress damage (P < 0.01). According to integrated transcriptomics and metabolomics analysis, cAMP signaling pathway was enriched following FABP4 inhibitor use. The activation of cAMP signaling pathway was validated. Microscopy and immunofluorescence staining results suggested that FABP4 inhibitors could regulate mitochondrial membrane homeostasis in steatotic LT. CONCLUSIONS: FABP4 was identified as a hypoxia-inducible protein that sensitized steatotic liver grafts to IR injury. The FABP4 inhibitor, BMS-309403, could activate of cAMP signaling pathway thereby modulating mitochondrial membrane homeostasis, reducing oxidative stress injury in steatotic donors.

Fatty acid binding protein 4 (FABP4) induces chondrocyte degeneration via activation of the NF-κb signaling pathway.

The pathogenesis of osteoarthritis (OA) is still unclear. Fatty acid binding protein 4 (FABP4), a novel adipokine, has been found to play a role in OA. This study aimed to explore the role of NF-κB in FABP4-induced OA. In the in vivo study, four pairs of 12-week-old male FABP4 knockout (KO) and wild-type (WT) mice were included. The activation of NF-κB was assessed. In parallel, 24 6-week-old male C57/Bl6 mice were fed a high-fat diet (HFD) and randomly allocated to four groups: daily oral gavage with (1) PBS solution; (2) QNZ (NF-κB-specific inhibitor, 1 mg/kg/d); (3) BMS309403 (FABP4-specific inhibitor, 30 mg/kg/d); and (4) BMS309403 (30 mg/kg/d) + QNZ (1 mg/kg/d). The diet and treatment were sustained for 4 months. The knee joints were obtained to assess cartilage degradation, NF-κB activation, and subchondral bone sclerosis. In the in vitro study, a mouse chondrogenic cell line (ATDC5) was cultured. FABP4 was supplemented to stimulate chondrocytes, and the activation of NF-κB was investigated. In parallel, QNZ and NF-κB-specific siRNA were used to inhibit NF-κB. In vivo, the FABP4 WT mice had more significant NF-κB activation than the KO mice. Dual inhibition of FABP4 and NF-κB alleviated knee OA in mice. FABP4 has no significant effect on the activation of the JNK signaling pathway. In vitro, FABP4 directly activated NF-κB in chondrocytes. The use of QNZ and NF-κB-siRNA significantly alleviated the expression of catabolic markers of chondrocytes induced by FABP4. FABP4 induces chondrocyte degeneration by activating the NF-κB pathway.

Differential expressions of FASN, SCD, and FABP4 genes in the ribeye muscle of omega-3 oil-supplemented Tattykeel Australian White lambs.

BACKGROUND: The concept of the functional nutritional value of health-beneficial omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) is becoming a phenomenon among red meat consumers globally. This study examined the expressions of three lipogenic genes (fatty acid binding protein 4, FABP4, fatty acid synthase, FASN; and stearoyl-CoA desaturase, SCD) in the ribeye (Longissimus thoracis et lumborum) muscle of Tattykeel Australian White (TAW) lambs fed fortified omega-3 diets and correlations with fatty acids. To answer the research question, "are there differences in the expression of lipogenic genes between control, MSM whole grain and omega-3 supplemented lambs?", we tested the hypothesis that fortification of lamb diets with omega-3 will lead to a down-regulation of lipogenic genes. Seventy-five six-month old TAW lambs were randomly allocated to the (1) omega-3 oil-fortified grain pellets, (2) unfortified grain pellets (control) or (3) unfortified MSM whole grain pellets diet supplements to generate three treatments of 25 lambs each. The feeding trial lasted 47 days. RESULTS: From the Kruskal-Wallis test, the results showed a striking disparity in lipogenic gene expression between the three dietary treatments in which the FABP4 gene was significantly up-regulated by 3-folds in the muscles of lambs fed MSM Milling (MSM) whole grain diet compared to the omega-3 and control diets. A negative correlation was observed between FASN gene expression and intramuscular fat (IMF), eicosapentaenoic acid (EPA), total polyunsaturated fatty acids (PUFA), omega-6 polyunsaturated fatty acids (n-6 PUFA) and monounsaturated fatty acids (MUFA). The FABP4 gene expression was positively correlated (P < 0.05) with EPA and docosahexaenoic acid (DHA). CONCLUSION: Taken together, this study's results suggest that FABP4 and FASN genes perform an important role in the biosynthesis of fatty acids in the ribeye muscle of TAW lambs, and supplementary diet composition is an important factor influencing their expressions.

Investigating protein-membrane interactions using native reverse micelles constructed from naturally sourced lipids.

Advancing the study of membrane associated proteins and their interactions is dependent on accurate membrane models. While a variety of membrane models for high-resolution membrane protein study exist, most do not reflect the diversity of lipids found within biological membranes. In this work, we have developed native reverse micelles (nRMs) formulated with lipids from multiple eukaryotic sources, which encapsulate proteins and enable them to interact as they would with a biological membrane. Diverse formulations of nRMs using soy lecithin, porcine brain lipids, or bovine heart lipids combined with n-dodecylphosphocholine were developed and characterized by dynamic light scattering and 31 P-NMR. To optimize protein encapsulation, ubiquitin was used as a standard and protein NMR verified minimal changes to its structure. Peripheral membrane proteins, which bind reversibly to membranes, were encapsulated and include glutathione peroxidase 4 (GPx4), phosphatidylethanolamine-binding protein 1 (PEBP1), and fatty acid binding protein 4 (FABP4). All three proteins showed anticipated interactions with the membrane-like inner surface of the nRMs as assessed by protein NMR. The nRM formulations developed here allow for efficient, high-resolution study of membrane interacting proteins up to and beyond ~21 kDa, in a more biologically relevant context compared to other non-native membrane models. The approach outlined here may be applied to a wide range of lipid extracts, allowing study of a variety of membrane associated proteins in their specific biological context.

Fatty Acid-Binding Protein 4 is Essential for the Inflammatory and Metabolic Response of Microglia to Lipopolysaccharide.

Prolonged activation of microglia leads to excessive release of proinflammatory mediators, which are detrimental to brain health. Therefore, there are significant efforts to identify pathways mediating microglial activation. Recent studies have demonstrated that fatty acid-binding protein 4 (FABP4), a lipid binding protein, is a critical player in macrophage-mediated inflammation. Given that we have previously identified FABP4 in microglia, the aim of this study was to assess whether FABP4 activity contributed to inflammation, metabolism and immune function (i.e. immunometabolism) in immortalised mouse microglia (BV-2 cells) using the proinflammatory stimulus lipopolysaccharide (LPS) to induce general microglial activation. Microglial FABP4 expression was significantly increased following exposure to LPS, an outcome associated with a significant increase in microglial proliferation rate. LPS-stimulated BV-2 microglia demonstrated a significant increase in the production of reactive oxygen species (ROS) and tumour necrosis factor-alpha (TNF-α), phosphorylation of c-Jun N-terminal kinase (JNK), increased expression of Toll-like receptor 4 (TLR4), and reduced expression of uncoupling protein 2 (UCP2), all of which were reversed following FABP4 genetic silencing and chemical inhibition with BMS309403. The oxidation rate of 3H-oleic acid and microglial uptake of 3H-2-deoxy-D-glucose were modulated with LPS activation, processes which were restored with genetic and chemical inhibition of FABP4. This is the first study to report on the critical role of FABP4 in mediating the deleterious effects of LPS on microglial immunometabolism, suggesting that FABP4 may present as a novel therapeutic target to alleviate microglia-mediated neuroinflammation, a commonly reported factor in multiple neurodegenerative diseases.

Identification of Andrographolide as a novel FABP4 inhibitor for osteoarthritis treatment.

BACKGROUND AND PURPOSE: Fatty acid binding protein 4 (FABP4) has been identified as a contributor to cartilage degradation in osteoarthritis (OA) patients, and inhibiting FABP4 using small molecules has emerged as a promising approach for developing OA drugs. Our previous research showed that Andrographis paniculata, a medicinal plant, strongly inhibits FABP4 activity. This led us to hypothesize that Andrographis paniculata ingredients might have protective effects on OA cartilage through FABP4 inhibition. METHODS: We analyzed scRNA-seq data from joint tissue of OA patients (GSE152805; GSE145286) using Scanpy 1.9.1 and Single Cell Portal. We conducted docking analysis of FABP4 inhibitors using Autodock Vina v.1.0.2. We evaluated the anti-FABP4 activity using a fluorescence displacement assay and measured the fatty acid oxidation (FAO) activity using the FAOBlue assay. We used H2DCF-DA to measure reactive oxygen species (ROS) levels. We studied signaling pathways using bulk RNA sequencing and western blot analysis in human C28/I2 chondrocytes. We evaluated anti-OA activity in monosodium iodoacetate (MIA)-induced rats. RESULTS: We identified Andrographolide (AP) as a novel FABP4 inhibitor. Bulk RNA-sequencing analysis revealed that FABP4 upregulated FAO and ROS in chondrocytes, which was inhibited by AP. ROS generation activated the NF-κB pathway, leading to overexpression of a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4), which is a responsible factor for cartilage degradation in OA patients. AP inhibited FABP4, thereby reducing the overexpression of ADAMTS4 by inhibiting the NF-κB pathway. In MIA rats, AP treatment reduced the overexpression of ADAMTS4, repaired cartilage and subchondral bone, and promoted cartilage regeneration. CONCLUSION: Our results indicate that the inhibition of FABP4 activity by AP explains the anti-OA properties of Andrographis paniculata by protecting against cartilage degradation in OA patients. Additionally, our findings suggest that AP may be a promising therapeutic agent for OA treatment due to its ability to alleviate cartilage damage and bone erosion.

Fatty acid binding protein 4 has prognostic value in peripheral artery disease.

OBJECTIVE: Peripheral artery disease (PAD) remains undertreated, despite its association with major amputation and mortality. This is partly due to a lack of available disease biomarkers. The intracellular protein fatty acid binding protein 4 (FABP4) is implicated in diabetes, obesity, and metabolic syndrome. Given that these risk factors are strong contributors to vascular disease, we assessed the prognostic ability of FABP4 in predicting PAD-related adverse limb events. METHODS: This was a prospective case-control study with 3 years of follow-up. Baseline serum FABP4 concentrations were measured in patients with PAD (n = 569) and without PAD (n = 279). The primary outcome was major adverse limb event (MALE; defined as a composite of vascular intervention or major amputation). The secondary outcome was worsening PAD status (drop in ankle-brachial index ≥0.15). Kaplan-Meier and Cox proportional hazards analyses adjusted for baseline characteristics were conducted to assess the ability of FABP4 to predict MALE and worsening PAD status. RESULTS: Patients with PAD were older and more likely to have cardiovascular risk factors compared with those without PAD. Over the study period, MALE and worsening PAD status occurred in 162 (19%) and 92 (11%) patients, respectively. Higher FABP4 levels were significantly associated with 3-year MALE (unadjusted hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.04-1.27; adjusted HR, 1.18; 95% CI, 1.03-1.27; P = .022) and worsening PAD status (unadjusted HR, 1.18; 95% CI, 1.13-1.31; adjusted HR, 1.17; 95% CI, 1.12-1.28; P < .001). Three-year Kaplan-Meier survival analysis demonstrated that patients with high FABP4 levels had a decreased freedom from MALE (75% vs 88%; log rank = 22.6; P < .001), vascular intervention (77% vs 89%; log rank = 20.8; P < .001), and worsening PAD status (87% vs 91%; log rank = 6.16; P = .013). CONCLUSIONS: Individuals with higher serum concentrations of FABP4 are more likely to develop PAD-related adverse limb events. FABP4 has prognostic value in risk-stratifying patients for further vascular evaluation and management.

Cord blood fatty acid binding protein 4 and lipids in infants born small- or large-for-gestational-age.

Aim: Adverse (poor or excessive) fetal growth "programs" an elevated risk of type 2 diabetes. Fatty acid binding protein 4 (FABP4) has been implicated in regulating insulin sensitivity and lipid metabolism relevant to fetal growth. We sought to determine whether FABP4 is associated with poor or excessive fetal growth and fetal lipids. Methods: In a nested case-control study in the Shanghai Birth Cohort including 60 trios of small-for-gestational-age (SGA, an indicator of poor fetal growth), large-for-gestational-age (LGA, an indicator of excessive fetal growth) and optimal-for-gestational-age (OGA, control) infants, we measured cord blood concentrations of FABP4 and lipids [high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterols, triglycerides (TG)]. Results: Adjusting for maternal and neonatal characteristics, higher cord blood FABP4 concentrations were associated with a lower odds of SGA [OR = 0.29 (0.11-0.77) per log unit increment in FABP4, P = 0.01], but were not associated with LGA (P = 0.46). Cord blood FABP4 was positively correlated with both LDL (r = 0.29, P = 0.025) and HDL (r = 0.33, P = 0.01) in LGA infants only. Conclusion: FABP4 was inversely associated with the risk of SGA. The study is the first to demonstrate LGA-specific positive correlations of cord blood FABP4 with HDL and LDL cholesterols, suggesting a role of FABP4 in fetal lipid metabolism in subjects with excessive fetal growth.

Inflammatory Macrophage Interleukin-1ß Mediates High-Fat Diet-Induced Heart Failure With Preserved Ejection Fraction.

Diabetes mellitus (DM) is a main risk factor for diastolic dysfunction (DD) and heart failure with preserved ejection fraction. High-fat diet (HFD) mice presented with diabetes mellitus, DD, higher cardiac interleukin (IL)-1ß levels, and proinflammatory cardiac macrophage accumulation. DD was significantly ameliorated by suppressing IL-1ß signaling or depleting macrophages. Mice with macrophages unable to adopt a proinflammatory phenotype were low in cardiac IL-1ß levels and were resistant to HFD-induced DD. IL-1ß enhanced mitochondrial reactive oxygen species (mitoROS) in cardiomyocytes, and scavenging mitoROS improved HFD-induced DD. In conclusion, macrophage-mediated inflammation contributed to HFD-associated DD through IL-1ß and mitoROS production.

Exploiting Copaifera salikounda compounds as treatment against diabetes: An insight into their potential targets from a computational perspective.

Accumulating evidence has shown that medicinal plants have been exploited for treatment purposes since time immemorial. Thus, this study investigated the mitigating potentials of the ligands; n-hexadecanoic acid, 9-octadecenoic acid and octadecanoic acid from Copaifera salikounda seed pond extract reported to have antidiabetic potentials in our previous study using computational techniques. Fatty acid-binding protein 4 (FABP4) and peroxisome proliferator-activated receptor alpha (PPARα) were identified as potential receptors. Both molecular docking and Estimated ΔGbind revealed that each ligand exhibited high binding affinity to the respective proteins; this is quite sufficient to be termed favourable. A critical examination of the type and the nature of binding interactions and energy contributions have identified Arg106, Arg126 and Tyr128 in FABP4 and Gln277, Ser280, Tyr314, His440 and Tyr464 in PPARα as consistently being responsible for the binding interactions and stabilizations of each ligand to the individual proteins. The establishment of hydrogen bonding type of interaction and activity between the carboxylic acid moieties of these ligands and these crucial/unique residues goes further to buttress our assertion. A general study of the conformational state of these protein via RMSF and PCA plots goes further validate the observed structural trends wherein the presence of ligands induced seemly structural rigidity. In depth structural stability investigations went further to reveal that the 3D structures of these protein didn't deviate from it known native conformational stable state when bound with these ligands. Our findings indicate that the ligands have considerable inhibitory action against FABP4 and PPARα corroborating the reported antidiabetic potential of the extract.

FABP4 Controls Fat Mass Expandability (Adipocyte Size and Number) through Inhibition of CD36/SR-B2 Signalling.

Adipose tissue hypertrophy during obesity plays pleiotropic effects on health. Adipose tissue expandability depends on adipocyte size and number. In mature adipocytes, lipid accumulation as triglycerides into droplets is imbalanced by lipid uptake and lipolysis. In previous studies, we showed that adipogenesis induced by oleic acid is signed by size increase and reduction of FAT/CD36 (SR-B2) activity. The present study aims to decipher the mechanisms involved in fat mass regulation by fatty acid/FAT-CD36 signalling. Human adipose stem cells, 3T3-L1, and its 3T3-MBX subclone cell lines were used in 2D cell cultures or co-cultures to monitor in real-time experiments proliferation, differentiation, lipolysis, and/or lipid uptake and activation of FAT/CD36 signalling pathways regulated by oleic acid, during adipogenesis and/or regulation of adipocyte size. Both FABP4 uptake and its induction by fatty acid-mediated FAT/CD36-PPARG gene transcription induce accumulation of intracellular FABP4, which in turn reduces FAT/CD36, and consequently exerts a negative feedback loop on FAT/CD36 signalling in both adipocytes and their progenitors. Both adipocyte size and recruitment of new adipocytes are under the control of FABP4 stores. This study suggests that FABP4 controls fat mass homeostasis.