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Ectopic lipid accumulation induced lipotoxicity plays a crucial role in exacerbating the development of metabolic dysfunction-associated steatotic liver disease (MASLD), which affects over 30 % of the worldwide population and 85 % of the obese population. The growing demand for effective therapeutic agents highlights the need for high-efficacy lipotoxicity ameliorators and relevant therapeutic targets in the fight against MASLD. This study aimed to discover natural anti-lipotoxic and anti-MASLD candidates and elucidate the underlying mechanism and therapeutic targets. Utilizing palmitic acid (PA)-induced HepG-2 and primary mouse hepatocyte models, we identified linoleic acid (HN-002), a ligand of fatty acid binding protein 4 (FABP4), from the marine fungus Eutypella sp. F0219. HN-002 dose-dependently prevented lipid overload-induced hepatocyte damage and lipid accumulation, inhibited fatty acid esterification, and ameliorated oxidative stress. These beneficial effects were associated with improvements in mitochondrial adaptive oxidation. HN-002 treatment enhanced lipid transport into mitochondria and oxidation, inhibited mitochondrial depolarization, and reduced mitochondrial ROS (mtROS) level in PA-treated hepatocytes. Mechanistically, HN-002 treatment disrupted the interaction between KEAP1 and NRF2, leading to NRF2 deubiquitylation and nuclear translocation, which activated beneficial metabolic regulation. In vivo , HN-002 treatment (20 mg/kg/per 2 days, i. p.) for 25 days effectively reversed hepatic steatosis and liver injury in the fast/refeeding plus high-fat/high-cholesterol diet induced MASLD mice. These therapeutic effects were associated with enhanced mitochondrial adaptive oxidation and activation of NRF2 signaling in the liver. These data suggest that HN-002 would be an interesting candidate for MASLD by improving mitochondrial oxidation via the FABP4/KEAP1/NRF2 axis. The discovery offers new insights into developing novel anti- MASLD agents derived from marine sources. [Display omitted] • HN-002 is identified as a marine fungus-derived natural lipotoxicity ameliorator in hepatocytes. • HN-002 inhibits lipotoxicity and ameliorates MASLD in mice by activating NRF2 signaling with FABP4 as an upstream regulator. • Overexpression of FABP4 activates NRF2 signaling and inhibits lipotoxicity while inhibition of FABP4 weakens the anti-lipotoxic effects of HN-002. • FABP4 is an upstream regulator of KEAP1/NRF2 axis in hepatocytes. [ABSTRACT FROM AUTHOR]

In patients with sepsis, neutrophil apoptosis tends to be inversely proportional to the severity of sepsis, but its mechanism is not yet clear. This study aimed to explore the mechanism of fatty acid binding protein 4 (FABP4) regulating neutrophil apoptosis through combined analysis of gut microbiota and short-chain fatty acids (SCFAs) metabolism. First, neutrophils from bronchoalveolar lavage fluid (BALF) of patients with sepsis-induced acute respiratory distress syndrome (ARDS) were purified and isolated RNA was applied for sequencing. Then, the cecal ligation and puncture (CLP) method was applied to induce the mouse sepsis model. After intervention with differential SCFAs sodium acetate, neutrophil apoptosis and FABP4 expression were further analyzed. Then, FABP4 inhibitor BMS309403 was used to treat neutrophils. We found CLP group had increased lung injury score, lung tissue wet/dry ratio, lung vascular permeability, and inflammatory factors IL-1β, TNF-α, IL-6, IFN-γ, and CCL3 levels in both bronchoalveolar lavage fluid and lung tissue. Additionally, FABP4 was lower in neutrophils of ARDS patients and mice. Meanwhile, CLP-induced dysbiosis of gut microbiota and changes in SCFAs levels were observed. Further verification showed that acetic acids reduced neutrophil apoptosis and FABP4 expression via FFAR2. Besides, FABP4 affected neutrophil apoptosis through endoplasmic reticulum (ER) stress, and neutrophil depletion alleviated the promotion of ARDS development by BMS309403. Moreover, FABP4 in neutrophils regulated the injury of RLE-6TN through inflammatory factors. In conclusion, FABP4 affected by gut microbiota-derived SCFAs delayed neutrophil apoptosis through ER stress, leading to increased inflammatory factors mediating lung epithelial cell damage. [ABSTRACT FROM AUTHOR]

Background/Objectives: Moringa oleifera is a matrix plant with the high potential to cure several diseases with its medicinal and ethnopharmacological value and nutraceutical properties. In this study, we investigated the chemical and biological properties of this plant cultivated in our local region. Methods: Leaves, roots, seeds, stem bark, and twigs of oleifera were extracted and evaluated bioactivities targeting intracellular lipid accumulation and adipocyte differentiation in 3T3-L1 preadipocytes, and UHPLC-ESI-Orbitrap-MS/MS-Based molecular networking guided isolation and dereplication of metabolites from these extracts. Results: Five extracts of different organs of M. oleifera significantly stimulated intracellular lipid accumulation and adipocyte differentiation in 3T3-L1 preadipocytes in a concentration-dependent manner. These extracts markedly increased the expression of genes related to adipogenesis and lipogenesis. Notably, these extracts promoted peroxisome proliferator-activated receptor γ (PPARγ) activity and the expression of its target genes, including phosphoenolpyruvate carboxykinase, fatty acid-binding protein 4, and perilipin-2. These adipogenic and lipogenic effects of Moringa extracts through the regulation of PPARγ activity suggests their potential efficacy in preventing or treating type 2 diabetes. Furthermore, chemical investigation revealed high contents of phytonutrients as rich sources of secondary metabolites including glycosides, flavones, fatty acids, phenolics, and other compounds. In addition, in silico studies on major components of these extracts revealed the bioavailability of major components through their binding affinity to respective proteins targeting adipocyte differentiation. [ABSTRACT FROM AUTHOR]

Abstract Fatty acid-binding protein 4 (FABP4) plays an essential role in metabolism and inflammation. However, the role of FABP4 in alcoholic steatohepatitis (ASH) remains unclear. This study aimed to investigate the function and underlying mechanisms of FABP4 in the progression of ASH. We first obtained alcoholic hepatitis (AH) datasets from the National Center for Biotechnology Information–Gene Expression Omnibus database and conducted bioinformatics analysis to identify critical genes in the FABP family. We then established ASH models of the wild-type (WT) and Fabp4-deficient (Fabp4 −/−) mice to investigate the role of FABP4 in ASH. Additionally, we performed transcriptional profiling of mouse liver tissue and analyzed the results using integrative bioinformatics. The FABP4-associated signaling pathway was further verified. FABP4 was upregulated in two AH datasets and was thus identified as a critical biomarker for AH. FABP4 expression was higher in the liver tissues of patients with alcoholic liver disease and ASH mice than in the corresponding control samples. Furthermore, the Fabp4 −/− ASH mice showed reduced hepatic lipid deposition and inflammation compared with the WT ASH mice. Mechanistically, Fabp4 may be involved in regulating the p53 and sirtuin-1 signaling pathways, subsequently affecting lipid metabolism and macrophage polarization in the liver of ASH mice. Our results demonstrate that Fabp4 is involved in the progression of ASH and that Fabp4 deficiency may ameliorate ASH. Therefore, FABP4 may be a potential therapeutic target for ASH treatment.

Abstract Background Breast cancer is the most common cancer in women diagnosed in the U.S. and worldwide. Obesity increases breast cancer risk without clear underlying molecular mechanisms. Our studies demonstrate that circulating adipose fatty acid binding protein (A-FABP, or FABP4) links obesity-induced dysregulated lipid metabolism and breast cancer risk, thus potentially offering a new target for breast cancer treatment. Methods We immunized FABP4 knockout mice with recombinant human FABP4 and screened hybridoma clones with specific binding to FABP4. The potential effects of antibodies on breast cancer cells in vitro were evaluated using migration, invasion, and limiting dilution assays. Tumor progression in vivo was evaluated in various types of tumorigenesis models including C57BL/6 mice, Balb/c mice, and SCID mice. The phenotype and function of immune cells in tumor microenvironment were characterized with multi-color flow cytometry. Tumor stemness was detected by ALDH assays. To characterize antigen-antibody binding capacity, we determined the dissociation constant of selected anti-FABP4 antibodies via surface plasmon resonance. Further analyses in tumor tissue were performed using 10X Genomics Visium spatial single cell technology. Results Herein, we report the generation of humanized monoclonal antibodies blocking FABP4 activity for breast cancer treatment in mouse models. One clone, named 12G2, which significantly reduced circulating levels of FABP4 and inhibited mammary tumor growth, was selected for further characterization. After confirming the therapeutic efficacy of the chimeric 12G2 monoclonal antibody consisting of mouse variable regions and human IgG1 constant regions, 16 humanized 12G2 monoclonal antibody variants were generated by grafting its complementary determining regions to selected human germline sequences. Humanized V9 monoclonal antibody showed consistent results in inhibiting mammary tumor growth and metastasis by affecting tumor cell mitochondrial metabolism. Conclusions Our current evidence suggests that targeting FABP4 with humanized monoclonal antibodies may represent a novel strategy for the treatment of breast cancer and possibly other obesity- associated diseases.

Objectives: Excessive inflammation contributes to the pathogenesis of tendinopathy. Fatty acid binding protein 4 (FABP4) is a pro-inflammatory adipokine mediating various metabolic and inflammatory diseases. This study aimed to examine the expression of FABP4 and its association with the expressions of inflammatory cytokines in tendinopathy. The effects of a single injection of FABP4 on tendon pathology and inflammation were examined. The effect of FABP4 on the expressions of inflammatory cytokines and the effect of IL-1β on the expression of FABP4 in tendon-derived stem/progenitor cells (TDSCs) were also investigated. Methods: 1) Clinical patellar tendinopathy samples, healthy hamstring tendon samples, and healthy patellar tendon samples, 2) rotator cuff tendinopathy samples and healthy hamstring tendon samples; and 3) Achilles tendons of mice after saline or collagenase injection (CI) were stained for FABP4, IL-1β, IL-6, TNF-α and IL-10 by immunohistochemistry (IHC). For the rotator cuff tendinopathy samples, co-localization of FABP4 with IL-1β and TNF-α was done by immunofluorescent staining (IF). Mouse Achilles tendons injected with FABP4 or saline were collected for histology and IHC as well as microCT imaging post-injection. TDSCs were isolated from human and mouse tendons. The mRNA expressions of inflammatory cytokines in human and mouse TDSCs after the addition of FABP4 was quantified by qRT-PCR. The expression of FABP4 in TDSCs isolated from rotator cuff tendinopathy samples and healthy hamstring tendon samples was examined by IF. Mouse Achilles TDSCs were treated with IL-1β. The mRNA and protein expressions of FABP4 were examined by qRT-PCR and IF, respectively. Results: There was significant upregulation of FABP4 in the patellar tendinopathy samples and rotator cuff tendinopathy samples compared to their corresponding controls. FABP4 was mainly expressed in the pathological areas including blood vessels, hypercellular and calcified regions. The expressions of IL-1β and TNF-α increased in human rotator cuff tendinopathy samples and co-localized with the expression of FABP4. Collagenase induced tendinopathic-like histopathological changes and ectopic calcification in the mouse Achilles tendinopathy model. The expressions of inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-10) and FABP4 increased in hypercellular region, round cells chondrocyte-like cells and calcified regions in the mouse Achilles tendons post-collagenase injection. A single injection of FABP4 in mouse Achilles tendons induced histopathological changes resembling tendinopathy, with increased cell rounding, loss of collagen fiber alignment, and additionally presence of chondrocyte-like cells and calcification post-injection. The expressions of IL1-β, IL-6, TNF-α and IL-10 increased in mouse Achilles tendons post-FABP4 injection. FABP4 increased the expressions of IL10, IL6, and TNFa in human TDSCs as well as the expressions of Il1b, Il6, and Il10 in mouse TDSCs. Human tendinopathy TDSCs expressed higher level of FABP4 compared to healthy hamstring TDSCs. Besides, IL-1β increased the expression of FABP4 in mouse TDSCs. Conclusion: In conclusion, an upregulation of FABP4 is involved in excessive inflammation and pathogenesis of tendinopathy. TDSCs is a potential source of FABP4 during tendon inflammation. Translation potential of this article: FABP4 can be a potential treatment target of tendinopathy.

Fatty acid-binding protein 4 (FABP4) plays an essential role in metabolism and inflammation. However, the role of FABP4 in alcoholic steatohepatitis (ASH) remains unclear. This study aimed to investigate the function and underlying mechanisms of FABP4 in the progression of ASH. We first obtained alcoholic hepatitis (AH) datasets from the National Center for Biotechnology Information–Gene Expression Omnibus database and conducted bioinformatics analysis to identify critical genes in the FABP family. We then established ASH models of the wild-type (WT) and Fabp4-deficient (Fabp4−/−) mice to investigate the role of FABP4 in ASH. Additionally, we performed transcriptional profiling of mouse liver tissue and analyzed the results using integrative bioinformatics. The FABP4-associated signaling pathway was further verified. FABP4 was upregulated in two AH datasets and was thus identified as a critical biomarker for AH. FABP4 expression was higher in the liver tissues of patients with alcoholic liver disease and ASH mice than in the corresponding control samples. Furthermore, the Fabp4−/− ASH mice showed reduced hepatic lipid deposition and inflammation compared with the WT ASH mice. Mechanistically, Fabp4 may be involved in regulating the p53 and sirtuin-1 signaling pathways, subsequently affecting lipid metabolism and macrophage polarization in the liver of ASH mice. Our results demonstrate that Fabp4 is involved in the progression of ASH and that Fabp4 deficiency may ameliorate ASH. Therefore, FABP4 may be a potential therapeutic target for ASH treatment. [ABSTRACT FROM AUTHOR]

Adipocyte fatty acid-binding protein (A-FABP; FABP4) plays a significant role in the pathogenesis and progression of metabolically driven low-grade inflammation and organ damage. This study aimed to evaluate the performance of circulating FABP4 as a predictive and diagnostic biomarker for thalassemia-associated cardiometabolic events. This case-control study enrolled 50 adults with β-thalassemia and 30 age-, sex-, and body mass index-matched controls. Participants underwent a comprehensive evaluation, including complete blood count, liver and kidney function tests, serum blood glucose, lipid profile, and ferritin levels, pelviabdominal ultrasound, ECG, and echocardiography after taking a full medical history and conducting a clinical examination. Serum levels of FABP4 were measured using an Enzyme-Linked-Immunosorbent-Assay. The diagnostic performance of FABP4 was assessed using receiver operator characteristic (ROC) curve analysis to determine optimal values for excluding and confirming cardiometabolic metflammation. The thalassemia cohort exhibited a statistically significant higher concentration of FABP4 compared to the control group (p-value < 0.001). Positive correlations were found between FABP4 and ferritin serum levels above 800 or 1000 ug/L, as well as with ALT, TGS, and LDL (p-value < 0.05). Circulating FABP4 was identified as a statistically significant risk factor for thalassemia-associated cardiometabolic comorbidities (OR = 84.00, 95%CI:18.6–378.6, p-value < 0.001). ROC analysis determined that the FABP4 exclusionary cut-off value > 2.30 ng/ml could effectively discriminate between thalassemia-associated adverse metaflammation and controls, while the FABP4 confirmatory cut-off value was > 2.58 ng/ml. In conclusion, circulating FABP4 appears to be a potential risk factor for predicting progression to cardiometabolic events in thalassemia-associated adverse metaflammation. FABP4 holds promise as a diagnostic and prognostic biomarker for disease monitoring and risk stratification. Further validation through large-scale, multicenter, prospective studies is warranted. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a chronic disease characterized by self‐destruction of insulin‐producing pancreatic β cells by cytotoxic T cell activity. However, the pathogenic mechanism of T cell infiltration remains obscure. Recently, tissue‐resident memory T (TRM) cells have been shown to contribute to cytotoxic T cell recruitment. TRM cells are found present in human pancreas and are suggested to modulate immune homeostasis. Here, the role of TRM cells in the development of T1D is investigated. The presence of TRM cells in pancreatic islets is observed in non‐obese diabetic (NOD) mice before T1D onset. Mechanistically, elevated fatty acid‐binding protein 4 (FABP4) potentiates the survival and alarming function of TRM cells by promoting fatty acid utilization and C‐X‐C motif chemokine 10 (CXCL10) secretion, respectively. In NOD mice, genetic deletion of FABP4 or depletion of TRM cells using CD69 neutralizing antibodies resulted in a similar reduction of pancreatic cytotoxic T cell recruitment, a delay in diabetic incidence, and a suppression of CXCL10 production. Thus, targeting FABP4 may represent a promising therapeutic strategy for T1D. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the effect of FABP4 gene on lipid accumulation and migration of endometrial epithelial cells in sheep. Three FABP4 interference fragments were designed and ligated with pGBplv-U6-mcherry-puro to construct interference vectors. The empty plasmid was used as the control (NC group), and the three interference recombinant plasmids were FABP4-shRNA1, FABP4-shRNA2, and FABP4-shRNA3, respectively. The recombinant plasmids were identified by enzyme digestion. After plasmid transfection, RT-qPCR was used to identify the interference efficiency. Western Blot was used to further verify the interference effect of the vector. The vector was transfected into endometrial epithelial cells cultured in vitro. The accumulation of lipid droplets was detected by BODIPY method. The triglyceride content in the cells was detected by detection kit. RT-qPCR was used to detect genes related to lipid metabolism, proliferation and migration. Cell scratch test was used to detect cell migration. The results showed that all vectors can effectively interfere with the expression of the FABP4 gene, with the FABP4-shRNA2 vector showing the best interference effect. After interfering with the expression of the FABP4 gene in endometrial epithelial cells, compared with the NC group, the ability of cells to aggregate lipid droplets decreased, the content of triglycerides was reduced, the expression of mRNA, related to cellular lipid metabolism and proliferation and migration decreased, and the speed of scratch healing was reduced. After reducing the expression of the FABP4 gene in endometrial epithelial cells, the level of cellular lipid accumulation and the ability of cells to migrate decreased. The study indicates that the FABP4 gene may play an important role in the pregnancy of sheep and the normal development of embryos, and it is worth further in-depth study in breeding practice. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most common cancer in women diagnosed in the U.S. and worldwide. Obesity increases breast cancer risk without clear underlying molecular mechanisms. Our studies demonstrate that circulating adipose fatty acid binding protein (A-FABP, or FABP4) links obesity-induced dysregulated lipid metabolism and breast cancer risk, thus potentially offering a new target for breast cancer treatment. Methods: We immunized FABP4 knockout mice with recombinant human FABP4 and screened hybridoma clones with specific binding to FABP4. The potential effects of antibodies on breast cancer cells in vitro were evaluated using migration, invasion, and limiting dilution assays. Tumor progression in vivo was evaluated in various types of tumorigenesis models including C57BL/6 mice, Balb/c mice, and SCID mice. The phenotype and function of immune cells in tumor microenvironment were characterized with multi-color flow cytometry. Tumor stemness was detected by ALDH assays. To characterize antigen-antibody binding capacity, we determined the dissociation constant of selected anti-FABP4 antibodies via surface plasmon resonance. Further analyses in tumor tissue were performed using 10X Genomics Visium spatial single cell technology. Results: Herein, we report the generation of humanized monoclonal antibodies blocking FABP4 activity for breast cancer treatment in mouse models. One clone, named 12G2, which significantly reduced circulating levels of FABP4 and inhibited mammary tumor growth, was selected for further characterization. After confirming the therapeutic efficacy of the chimeric 12G2 monoclonal antibody consisting of mouse variable regions and human IgG1 constant regions, 16 humanized 12G2 monoclonal antibody variants were generated by grafting its complementary determining regions to selected human germline sequences. Humanized V9 monoclonal antibody showed consistent results in inhibiting mammary tumor growth and metastasis by affecting tumor cell mitochondrial metabolism. Conclusions: Our current evidence suggests that targeting FABP4 with humanized monoclonal antibodies may represent a novel strategy for the treatment of breast cancer and possibly other obesity- associated diseases. [ABSTRACT FROM AUTHOR]

A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in murine macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cell lines, which promotes cancer cell migration in vitro and metastasis in vivo. Notably, a deficiency of FABP4 in murine macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor with poor prognosis. A better understanding of mechanisms concerned in glioma invasion might be critical for treatment optimization. Given that epithelial-mesenchymal transition in tumor cells is closely associated with glioma progression and recurrence, identifying pivotal mediators in GBM EMT process is urgently needed. As a member of Fatty acid binding protein (FABP) family, FABP4 serves as chaperones for free fatty acids and participates in cellular process including fatty acid uptake, transport, and metabolism. In this study, our data revealed that FABP4 expression was elevated in human GBM samples and correlated with a mesenchymal glioma subtype. Gain of function and loss of function experiments indicated that FABP4 potently rendered glioma cells increased filopodia formation and cell invasiveness. Differential expression genes analysis and GSEA in TCGA dataset revealed an EMT-related molecular signature in FABP4-mediated signaling pathways. Cell interaction analysis suggested CD36 as a potential target regulated by FABP4. Furthermore, in vitro mechanistic experiments demonstrated that FABP4-induced CD36 expression promoted EMT via non-canonical TGFβ pathways. An intracranial glioma model was constructed to assess the effect of FABP4 on tumor progression in vivo. Together, our findings demonstrated a critical role for FABP4 in the regulation invasion and EMT in GBM, and suggest that pharmacological inhibition of FABP4 may represent a promising therapeutic strategy for treatment of GBM.

The purpose of the current study was to elucidate the physiological roles of intraocularly present fatty acid-binding protein 4 (FABP4). Using four representative intraocular tissue-derived cell types, including human non-pigmented ciliary epithelium (HNPCE) cells, retinoblastoma (RB) cells, adult retinal pigment epithelial19 (ARPE19) cells and human ocular choroidal fibroblast (HOCF) cells, the intraocular origins of FABP4 were determined by qPCR analysis, and the intracellular functions of FABP4 were investigated by seahorse cellular metabolic measurements and RNA sequencing analysis using a specific inhibitor for FABP4, BMS309403. Among these four different cell types, FABP4 was exclusively expressed in HOCF cells. In HOCF cells, both mitochondrial and glycolytic functions were significantly decreased to trace levels by BMS309403 in a dose-dependent manner. In the RNA sequencing analysis, 67 substantially up-regulated and 94 significantly down-regulated differentially expressed genes (DEGs) were identified in HOCF cells treated with BMS309403 and those not treated with BMS309403. The results of Gene Ontology enrichment analysis and ingenuity pathway analysis (IPA) revealed that the DEGs were most likely involved in G-alpha (i) signaling, cAMP-response element-binding protein (CREB) signaling in neurons, the S100 family signaling pathway, visual phototransduction and adrenergic receptor signaling. Furthermore, upstream analysis using IPA suggested that NKX2-1 (thyroid transcription factor1), HOXA10 (homeobox A10), GATA2 (gata2 protein), and CCAAT enhancer-binding protein A (CEBPA) were upstream regulators and that NKX homeobox-1 (NKX2-1), SFRP1 (Secreted frizzled-related protein 1) and TREM2 (triggering receptor expressed on myeloid cells 2) were causal network master regulators. The findings in this study suggest that intraocularly present FABP4 originates from the ocular choroid and may be a critical regulator for the cellular homeostasis of non-adipocyte HOCF cells. [ABSTRACT FROM AUTHOR]

The fatty acid-binding protein 4 (FABP4) plays a crucial role in the transportation and metabolism of fatty acids. It binds to long-chain fatty acids and facilitates their transport within cells. FABP4 is involved in lipid metabolism, insulin sensitivity, inflammation, and energy homeostasis. This study was conducted to assess the association between the FABP4 gene and growth traits in Karakul and Awassi sheep. A PCR-single strand conformation polymorphism (SSCP) protocol was utilized to assess the polymorphism of FABP4 PCR products with growth traits measured at birth, three, six, nine, and twelve-month intervals. One non-synonymous SNP was identified in the second exon, in which threonine was converted to aspartate in the 61st position in FABP4 (p.61Thr > Asp). This novel SNP showed significant associations with all growth traits measured at all age intervals. The results showed that lambs with the TT genotype exhibited higher growth traits than those with the GT and GG genotypes, respectively. The conducted prediction showed a clearly deleterious effect of p.61Thr > Asp on FABP4 structure, which was accompanied by reduced fatty acid binding efficiency. Owing to the predicted damaging effects caused by p.61Thr > Asp on FABP, lower levels of lipid transport and its consequent increased weight gain and other growth trait indices are expected. Therefore, a putative mechanism through which lambs with these genotypes exhibit higher growth traits is proposed. The FABP4 gene is suggested as a promising marker to improve growth traits in Karakul and Awassi sheep. However, more research is required to validate this mechanism. [ABSTRACT FROM AUTHOR]

Objective: Cardiovascular diseases (CVD) are the primary cause of death worldwide. Therefore, this investigation aimed to evaluate the effect of arsenic exposure and genetic polymorphism (rs1800469) on cardiovascular risk biomarkers levels in a Mexican adult population. Methods: Then, a cross-sectional study was completed, including 155 adults. Urinary arsenic (UAs) levels were analyzed as an exposure biomarker, and assessed cardiovascular risk biomarkers were: serum ADMA and FABP4 concentrations and atherogenic indices (Castelli risk index and atherogenic index of plasma). Gentrification of TGF-β C509T polymorphism (rs1800469) was determined by real-time polymerase chain reaction (PCR) using TaqMan probes. Results: UAs levels ranged from 11.5 to 175 µg/g creatinine. The allele frequency for TGF-β C509T polymorphism was 0.37 and 0.63 for the C and T alleles, respectively. Mean serum ADMA and FABP4 levels were 1.35 ± 0.35 µmol/L and 22.0 ± 9.50 ng/mL, respectively. Also, statistically significant associations (p < 0.05) were detected between the exposure biomarker (UAs) and the cardiovascular risk biomarkers (ADMA and FABP4). Similarly, a strong relationship was detected between the TGF-β C509T polymorphism and assessed cardiovascular risk biomarkers (ADMA and FABP4). In addition, a gene-environmental interaction was found. Conclusion: Our findings suggest a gene-environment interaction with an enhanced effect on CVD biomarkers. [ABSTRACT FROM AUTHOR]

Adipocyte P2 (aP2), also known as FABP4, is an adipokine that adipose tissue produces and expresses in macrophages. Its primary role is to facilitate the transportation of fatty acids across cell membranes. Numerous studies have reported associations between FABP4 and the development of metabolic disorders. However, there is limited knowledge regarding FABP4 expression in diabetes and obesity, especially about different age groups, genders, and ethnicities. This study aims to investigate the association between FABP4 levels, diabetes mellitus, and obesity within various ethnic groups. We measured plasma FABP4 concentrations in a cohort of 2083 patients from the KDEP study and gathered anthropometric data. Additionally, we collected and analyzed clinical, biochemical, and glycemic markers using multivariate regression analysis. The average FABP4 concentration was significantly higher in female participants than in males (18.8 ng/mL vs. 14.4 ng/mL, p < 0.001, respectively), and in those over 50 years old compared to those under 50 years of age (19.3 ng/mL vs. 16.2 ng/mL, p < 0.001, respectively). In this study, significant positive associations were found between the plasma level of FABP4 and obesity markers: BMI (r = 0.496, p < 0.001), hip circumference (r = 0.463, p < 0.001), and waist circumference (WC) (r = 0.436, p < 0.001). Similar observations were also seen with glycemic markers, which included HbA1c (r = 0.126, p < 0.001), fasting blood glucose (FBG) (r = 0.184, p < 0.001), fasting insulin (r = 0.326, p < 0.001), and HOMA-IR (r = 0.333, p < 0.001). Importantly, these associations remained significant even after adjusting for age, gender, and ethnicity. Furthermore, FABP4 levels were negatively associated with male gender (β: −3.85, 95% CI: −4.92, −2.77, p < 0.001), and positively associated with age (β: 0.14, 95% CI: 0.096, 0.183, p < 0.001), BMI (β: 0.74, 95% CI: 0.644, 0.836, p < 0.001), and fasting insulin (β: 0.115, 95% CI: 0.091, 0.138, p < 0.001). In this study, plasma FABP4 levels were significantly higher in diabetic and obese participants, and they were strongly influenced by age, gender, and ethnicity. These findings suggest that FABP4 may serve as a valuable prognostic and diagnostic marker for obesity and diabetes, particularly among female patients, individuals over 50 years old, and specific ethnic groups. [ABSTRACT FROM AUTHOR]

Purpose of Review: Fatty acid-binding protein 4 (FABP4) plays a role in lipid metabolism and cardiovascular health. In this paper, we cover FABP4 biology, its implications in atherosclerosis from observational studies, genetic factors affecting FABP4 serum levels, and ongoing drug development to target FABP4 and offer insights into future FABP4 research. Recent Findings: FABP4 impacts cells through JAK2/STAT2 and c-kit pathways, increasing inflammatory and adhesion-related proteins. In addition, FABP4 induces angiogenesis and vascular smooth muscle cell proliferation and migration. FABP4 is established as a reliable predictive biomarker for cardiovascular disease in specific at-risk groups. Genetic studies robustly link PPARG and FABP4 variants to FABP4 serum levels. Considering the potential effects on atherosclerotic lesion development, drug discovery programs have been initiated in search for potent inhibitors of FABP4. Summary: Elevated FABP4 levels indicate an increased cardiovascular risk and is causally related to acceleration of atherosclerotic disease, However, clinical trials for FABP4 inhibition are lacking, possibly due to concerns about available compounds' side effects. Further research on FABP4 genetics and its putative causal role in cardiovascular disease is needed, particularly in aging subgroups. [ABSTRACT FROM AUTHOR]

Objective: To investigate the impacts of fatty acid binding protein 4 （FABP4） silencing on endoplasmic reticulum stress（ ERS） and insulin resistance（ IR） in gestational diabetes mellitus（ GDM） rats by regulating protein kinase R-like endoplasmic reticulum kinase （PERK）/eukaryotic initiation factor 2α （eIF2α）/transcription factor 4 （ATF4）/C/EBP homologous protein （CHOP） signaling pathway. Methods: GDM rat model was established by intraperitoneal injection of streptozotocin （STZ）. Rats were injected with FABP4 siRNA plasmid （si-FABP4）, negative control plasmid （NC） and PERK activator （CCT020312） via tail vein, and were randomly grouped into Normal group, GDM group, GDM+NC group, GDM+si-FABP4 group and GDM+si-FABP4+CCT020312 group. The levels of FABP4, blood lipids, inflammatory markers and oxidative stress markers in pancreatic tissue were detected, the expressions of PERK/eIF2α/ATF4/CHOP signaling pathway-related proteins in pancreatic tissue were detected. HTR-8/SVneo cells were divided into 5 groups: Control group, high glucose （HG） group, HG+NC group, HG+si-FABP4 group, HG+si-FABP4+CCT020312 group. After 24 h, the expressions of FABP4 and PERK/eIF2α/ATF4/CHOP signaling pathway related proteins were detected. Results: Compared with Normal group, the level of FABP4 in the serum and pancreatic tissue of the GDM group were obviously up-regulated（ P<0.05）. FABP4 silencing obviously reduced FBG and IR, decreased the levels of blood lipids, CRP, TNF-α, IL-6 and MDA, and increased the levels of SOD and CAT（ P<0.05）. Furthermore, FABP4 silencing attenuated pancreatic and placental tissue damages. After CCT020312 up-regulated the phosphorylation levels of PERK and eIF2α and the protein expressions of ATF4 and CHOP, the inhibitory effects of FABP4 silencing on IR, inflammation, oxidative stress, and pancreatic and placental damages in GDM rats were reversed （P<0.05）. FABP4 was up-regulated in HTR-8/SVneo cells induced by HG, and silencing FABP4 inhibited the protein expression of the PERK/eIF2α/ATF4/CHOP pathway, while CCT020312 reversed this change （P<0.05）. Conclusion: FABP4 silencing improves IR and ERS in GDM rats by inhibiting inflammation and oxidative stress, and the mechanism is related to the inhibition of PERK/eIF2α/ATF4/CHOP signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract Type 1 diabetes (T1D) is a chronic disease characterized by self‐destruction of insulin‐producing pancreatic β cells by cytotoxic T cell activity. However, the pathogenic mechanism of T cell infiltration remains obscure. Recently, tissue‐resident memory T (TRM) cells have been shown to contribute to cytotoxic T cell recruitment. TRM cells are found present in human pancreas and are suggested to modulate immune homeostasis. Here, the role of TRM cells in the development of T1D is investigated. The presence of TRM cells in pancreatic islets is observed in non‐obese diabetic (NOD) mice before T1D onset. Mechanistically, elevated fatty acid‐binding protein 4 (FABP4) potentiates the survival and alarming function of TRM cells by promoting fatty acid utilization and C‐X‐C motif chemokine 10 (CXCL10) secretion, respectively. In NOD mice, genetic deletion of FABP4 or depletion of TRM cells using CD69 neutralizing antibodies resulted in a similar reduction of pancreatic cytotoxic T cell recruitment, a delay in diabetic incidence, and a suppression of CXCL10 production. Thus, targeting FABP4 may represent a promising therapeutic strategy for T1D.

Background/Objectives: Moringa oleifera is a matrix plant with the high potential to cure several diseases with its medicinal and ethnopharmacological value and nutraceutical properties. In this study, we investigated the chemical and biological properties of this plant cultivated in our local region. Methods: Leaves, roots, seeds, stem bark, and twigs of oleifera were extracted and evaluated bioactivities targeting intracellular lipid accumulation and adipocyte differentiation in 3T3-L1 preadipocytes, and UHPLC-ESI-Orbitrap-MS/MS-Based molecular networking guided isolation and dereplication of metabolites from these extracts. Results: Five extracts of different organs of M. oleifera significantly stimulated intracellular lipid accumulation and adipocyte differentiation in 3T3-L1 preadipocytes in a concentration-dependent manner. These extracts markedly increased the expression of genes related to adipogenesis and lipogenesis. Notably, these extracts promoted peroxisome proliferator-activated receptor γ (PPARγ) activity and the expression of its target genes, including phosphoenolpyruvate carboxykinase, fatty acid-binding protein 4, and perilipin-2. These adipogenic and lipogenic effects of Moringa extracts through the regulation of PPARγ activity suggests their potential efficacy in preventing or treating type 2 diabetes. Furthermore, chemical investigation revealed high contents of phytonutrients as rich sources of secondary metabolites including glycosides, flavones, fatty acids, phenolics, and other compounds. In addition, in silico studies on major components of these extracts revealed the bioavailability of major components through their binding affinity to respective proteins targeting adipocyte differentiation.

Objective: To investigate the relationship between serum interleukin-1β (IL-1β), fatty acid binding protein 4 (FABP4),stimulated by retinoic acid 6 (STRA6) and type 2 diabetes mellitus (T2DM) combined with dry eye disease (DED) . Methods: 129 patients with T2DM combine with DED (T2DM combine with DED group), 117 patients with simple T2DM (simple T2DM group) and 85healthy volunteers (control group) admitted to The Fourth Affiliated Hospital of Nanjing Medical University from June 2020 to June2023 were selected, patients with T2DM combine with DED were divided into mild group (61 cases), moderate group (36 cases) and severe group (32 cases) according to the severity of DED. The levels of serum IL-1β, FABP4 and STRA6 were detected by enzyme-linked immunosorbent assay. The influencing factors of T2DM combine with DED were analyzed by multivariate logistic regression analysis,and the predictive value of serum IL-1β, FABP4 and STRA6 levels for T2DM combine with DED were analyzed by ROC curve. Results:The levels of serum IL-1β, FABP4 and STRA6 in T2DM combine with DED group were higher than those in simple T2DM group and control group, and the levels of serum IL-1β, FABP4 and STRA6 in simple T2DM group were higher than those in control group (P＜0.05) . The levels of serum IL-1β, FABP4 and STRA6 in severe group were higher than those in moderate group and mild group, and the levels of serum IL-1β, FABP4 and STRA6 in moderate group were higher than those in mild group (P＜0.05) . Multivariate logistic regression analysis showed that prolonged course of T2DM and elevated glycated hemoglobin, IL-1β, FABP4, and STRA6 were independent risk factors for T2DM combine with DED, and elevated BUT was an independent protective factor (P＜0.05) . The area under the curve of combined prediction of serum IL-1β, FABP4 and STRA6 levels for T2DM combine with DED was 0.916, which was greater than 0.784,0.782 and 0.788 predicted by serum IL-1β, FABP4 and STRA6 levels alone. Conclusions: The levels of serum IL-1β, FABP4 and STRA6 in patients with T2DM combined with DED are increase, which are independent risk factors for T2DM combine with DED, and are relate to the severity of DED.The combined detection of serum IL-1β, FABP4 and STRA6 has a higher predictive value for T2DM combine with DED. [ABSTRACT FROM AUTHOR]

Background. Colorectal cancer (CRC) remains a major cause of cancer-related morbidity and mortality worldwide. Recently, the pathogenesis of CRC among other cancer types has been linked to lipid metabolism. Fatty acid-binding proteins (FABPs) are a protein-family expressed in multiple tissues and play a crucial role in lipid metabolism. A few recent studies have examined FABPs role in CRC. Our aims are to explore the immunohistochemical expression of fatty acid binding proteins (FABP) 4 and 7 in colorectal cancer, and correlate their expression levels with clinical, histopathological features, and survival. Methods. A retrospective review of colorectal cancer biopsies over a 5-year period was conducted in our institute. Clinical and histological data were collected. Immunohistochemical staining for FABP 4 and 7 was performed using microarray and their expression was evaluated using the Histologic score (HS). The correlations between the expression of FABP 4 and 7 and clinicopathological parameters were determined by Fisher’s exact test. The impact of the expression on the overall survival was determined using Kaplan–Meier survival analysis. Results. 125 CRC tissue biopsy blocks were included. Median follow-up time was 35 months. High FABP4 expression was observed in 107 (85.60%). For FABP7, only 8.8% of cases (11/125) showed high expression. Co-expression of FABP4 and FABP7 occurred in 11 cases (8.8%). FABP7 expression correlated with age (p = 0.001). The median overall survival of patients with high expression of FABP4 was 43.00 ± 3.01 months, whereas patients showing low/negative expression reported a survival of 24.00 ± 6.24 months(p =0.041). No statistically significant association between FABP7 high expression and the overall survival was detected (Log-Rank test, p = 0.086). Conclusion. FABP4 expression in CRC is higher than that of FABP7. FABP7 expression levels negatively correlate with the age of CRC patients. FABP4 expression is associated with a better survival in CRC. No significant association between FABP4 and 7 with tumor grade, stage, or other clinicopathological criteria has been found in this study. [ABSTRACT FROM AUTHOR]

Background: Lipid metabolism related factors, such as angiopoietin‐like protein 3 (ANGPTL3), angiopoietin‐like 4 (ANGPTL4), fatty acid‐binding protein 4 (FABP4) are newly discovered factors that can affect coronary artery disease (CAD). In this study, we aimed to investigate the relationship between CAD and these lipid metabolism factors. Hypothesis: ANGPTL3, ANGPTL4, and FABP4 may provide a new method for the control of CAD risk factors and the prevention and treatment of CAD. Methods: We enrolled 284 consecutive inpatients with suspected CAD and divided them into CAD and non‐CAD groups based on the coronary angiography results. Serum ANGPTL3, ANGPTL4, FABP4, and tumor necrosis factor‐α (TNF‐α) levels were estimated using the enzyme‐linked immunosorbent assay. Multivariate logistic regression was used to assess the risk factors for CAD. The receiver operating characteristic curve was used to determine the cutoff and diagnostic values. Results: The serum TNF‐α, FABP4, ANGPTL3, and ANGPTL4 values showed a significant difference between the CAD and non‐CAD groups (p <.05). After adjusting for confounding factors, the FABP4, ANGPTL3, and ANGPTL4 levels were independently associated with CAD (p <.05). The ANGPTL3 expression level was an independent risk factor for CAD in patients with hypertension, but not in those without hypertension. The ANGPTL3 > 67.53 ng/mL, ANGPTL4 > 29.95 ng/mL, and FABP4 > 1421.25 ng/L combination had the highest diagnostic value for CAD. Conclusion: ANGPTL3, ANGPTL4, and FABP4 were identified as independent risk factors for CAD and have valuable clinical implications for the diagnosis and treatment of CAD. [ABSTRACT FROM AUTHOR]

Background & Objective: Cervical cancer spreads to the pelvic lymph nodes, leading to a high incidence of cancer recurrence and unfavorable survival rates. Therefore, there is an urgent need to detect new predictive biomarkers for the early assessment of pelvic lymph node status in patients with cervical cancer. The current study aimed to assess the expression of FABP4, GINS2, and CBX7 in cervical cancer tissue to detect their prognostic and predictive roles in developing lymph node metastases in patients with that cancer type. Methods: We collected the tissues from patients with cervical cancer and evaluated the expression of FABP4, GINS2, and CBX7 using immunohistochemistry. We evaluated the association between their expression and clinicopathological and prognostic parameters. Results: A high expression of FABP4 and GINS2 and a low expression of CBX7 were found to be positively associated with the old age group, large tumor size, high grade and lymphovascular involvement, para-uterine organ infiltration, advanced FIGO stage, chemotherapeutic resistance, and tumor recurrence. Conclusion: We demonstrated the oncogenic roles of FABP4 and GISN2 in addition to the on-co-suppressive roles of CBX7 in cervical cancer and their association with poor clinicopathological criteria and poor survival. Our results may indicate that FABP4, GISN2, and CBX7 could be considered predictive biomarkers of the occurrence of lymph node metastases in the cancer of the cervix preoperatively, which could be beneficial in the accurate preoperative design therapy. [ABSTRACT FROM AUTHOR]

Abstract Background The incidence and prevalence of nonalcoholic fatty liver disease related hepatocellular carcinoma (NAFLD-HCC) are rapidly increasing worldwide. This study aimed to identify biomarker genes for prognostic prediction model of NAFLD-HCC hepatectomy by integrating text-mining, clinical follow-up information, transcriptomic data and experimental validation. Methods The tumor and adjacent normal liver samples collected from 13 NAFLD-HCC and 12 HBV-HCC patients were sequenced using RNA-Seq. A novel text-mining strategy, explainable gene ontology fingerprint approach, was utilized to screen NAFLD-HCC featured gene sets and cell types, and the results were validated through a series of lab experiments. A risk score calculated by the multivariate Cox regression model using discovered key genes was established and evaluated based on 47 patients’ follow-up information. Results Differentially expressed genes associated with NAFLD-HCC specific tumor microenvironment were screened, of which FABP4 and VWF were featured by previous reports. A risk prediction model consisting of FABP4, VWF, gender and TNM stage were then established based on 47 samples. The model showed that overall survival in the high-risk score group was lower compared with that in the low-risk score group (p = 0.0095). Conclusions This study provided the landscape of NAFLD-HCC transcriptome, and elucidated that our model could predict hepatectomy prognosis with high accuracy.

Abstract Background Ligamentum flavum (LF) hypertrophy is the main cause of lumbar spinal canal stenosis (LSCS). Previous studies have shown that LF hypertrophy tissue exhibits abnormal lipid accumulation, but the regulatory mechanism remains unclear. The objective of this study was to explore the function and potential mechanism of ACSM5 in LF lipid accumulation. Methods To assess the ACSM5 expression levels, lipid accumulation and triglyceride (TG) level in LF hypertrophy and normal tissue, we utilized RT-qPCR, western blot, oil red O staining, and TG assay kit. The pearson correlation coefficient assay was used to analyze the correlation between ACSM5 levels and lipid accumulation or TG levels in LF hypertrophy tissue. The role of ACSM5 in free fatty acids (FFA)-induced lipid accumulation in LF cells was assessed in vitro, and the role of ACSM5 in LF hypertrophy in mice was verified in vivo. To investigate the underlying mechanisms of ACSM5 regulating lipid accumulation in LF, we conducted the mRNA sequencing, bioinformatics analysis, and rescue experiments. Results In this study, we found that ACSM5, which was significantly down-regulated in LF tissues, correlated with lipid accumulation. In vitro cell experiments demonstrated that overexpression of ACSM5 significantly inhibited FFA-induced lipid accumulation and fibrosis in LF cells. In vivo animal experiments further confirmed that overexpression of ACSM5 inhibited LF thickening, lipid accumulation, and fibrosis. Mechanistically, ACSM5 inhibited lipid accumulation of LF cells by inhibiting FABP4-mediated PPARγ signaling pathway, thereby improving hypertrophy and fibrosis of LF. Conclusions our findings elucidated the important role of ACSM5 in the regulation of LF lipid accumulation and provide insight into potential therapeutic interventions for the treatment of LF hypertrophy. This study further suggested that therapeutic strategies targeting lipid deposition may be an effective potential approach to treat LF hypertrophy-induced LSCS.

Background: To explore the prospective role of serum fatty acid-binding protein 4 (FABP4) in the outcomes of peritoneal dialysis (PD) patients. Methods: A prospective observational study was conducted with 159 patients on PD. Demographic and clinical data at baseline were collected from medical records. Biochemical data were recorded based on blood samples measured in a central laboratory. Serum FABP4 concentrations were determined using enzyme-linked immunosorbent assay. Body composition was measured using a Body Composition Monitor. Abdominal lateral plain radiography was used to evaluate vascular calcification. The primary endpoints were all-cause and cardiovascular death. Results: The median of serum FABP4 concentration was 154.6 ng/mL (interquartile range, 132.8-269.7 ng/mL). Increased serum FABP4 was associated with increased vascular calcification proportion, time on dialysis, body mass index, high-sensitivity C-reactive protein (hs-CRP), intact parathyroid hormone (iPTH), triglycerides, body fat mass, and body fat percentage (p < 0.05). Increased serum FABP4 was associated with decreased residual kidney Kt/V urea (p < 0.05). Patients with hs-CRP= 3 mg/L had significantly higher serum FABP4 than those with hs-CRP< 3 mg/L (p < 0.05). Patients with vascular calcification had significantly higher serum FABP4 than those without vascular calcification (p < 0.05). During a median follow-up of 58.0 months, 58 all-cause deaths and 26 cardiovascular deaths occurred. High serum FABP4 levels were independently predictive for all-cause [hazard ratio (HR), 1.003; 95% confidence interval (CI), 1.001-1.005; p = 0.016] and cardiovascular death (HR, 1.005; 95% CI, 1.001-1.008; p = 0.006) in PD patients. Conclusions: Increased serum FABP4 levels can independently predict all-cause and cardiovascular death in patients on PD. [ABSTRACT FROM AUTHOR]

Both lipid accumulation and inflammatory response in lesion macrophages fuel the progression of atherosclerosis, leading to high mortality of cardiovascular disease. A therapeutic strategy concurrently targeting these two risk factors is promising, but still scarce. Oridonin, the bioactive medicinal compound, is known to protect against inflammatory response and lipid dysfunction. However, its effect on atherosclerosis and the underlying molecular mechanism remain elusive. Here, we showed that oridonin attenuated atherosclerosis in hyperlipidemic ApoE knockout mice. Meanwhile, we confirmed the protective effect of oridonin on the oxidized low‐density lipoprotein (oxLDL)‐induced foam macrophage formation, resulting from increased cholesterol efflux, as well as reduced inflammatory response. Mechanistically, the network pharmacology prediction and further experiments revealed that oridonin dramatically facilitated the expression of peroxisome proliferator‐activated receptor gamma (PPARγ), thereby regulating liver X receptor‐alpha (LXRα)‐induced ATP‐binding cassette transporter A1 (ABCA1) expression and nuclear factor NF‐kappa‐B (NF‐κB) translocation. Antagonist of PPARγ reversed the cholesterol accumulation and inflammatory response mediated by oridonin. Besides, RNA sequencing analysis revealed that fatty acid binding protein 4 (FABP4) was altered responding to lipid modulation effect of oridonin. Overexpression of FABP4 inhibited PPARγ activation and blunted the benefit effect of oridonin on foam macrophages. Taken together, oridonin might have potential to protect against atherosclerosis by modulating the formation and inflammatory response in foam macrophages through FABP4/PPARγ signalling. [ABSTRACT FROM AUTHOR]

Introduction: Parkinson’s disease (PD), as a common neurodegenerative disease, currently has no effective therapeutic approaches to delay or stop its progression. There is an urgent need to further define its pathogenesis and develop new therapeutic targets. An increasing number of studies have shown that members of the sirtuin (SIRT) family are differentially involved in neurodegenerative diseases, indicating their potential to serve as targets in therapeutic strategies. Mitochondrial SIRT4 possesses multiple enzymatic activities, such as deacetylase, ADP ribosyltransferase, lipoamidase, and deacylase activities, and exhibits different enzymatic activities and target substrates in different tissues and cells; thus, mitochondrial SIRT4 plays an integral role in regulating metabolism. However, the role and mechanism of SIRT4 in PD are not fully understood. This study aimed to investigate the potential mechanism and possible regulatory targets of SIRT4 in 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. Methods: The expression of the SIRT4 protein in the MPTP-induced PD mouse mice or key familial Parkinson disease protein 7 knockout (DJ-1 KO) rat was compared against the control group by western blot assay. Afterwards, quantitative proteomics and bioinformatics analyses were performed to identify altered proteins in the vitro model and reveal the possible functional role of SIRT4. The most promising molecular target of SIRT4 were screened and validated by viral transfection, western blot assay and reverse transcription quantitative PCR (RT-qPCR) assays. Results: The expression of the SIRT4 protein was found to be altered both in the MPTP-induced PD mouse mice and DJ-1KO rats. Following the viral transfection of SIRT4, a quantitative proteomics analysis identified 5,094 altered proteins in the vitro model, including 213 significantly upregulated proteins and 222 significantly downregulated proteins. The results from bioinformatics analyses indicated that SIRT4 mainly affected the ribosomal pathway, propionate metabolism pathway, peroxisome proliferator-activated receptor (PPAR) signaling pathway and peroxisome pathway in cells, and we screened 25 potential molecular targets. Finally, only fatty acid binding protein 4 (FABP4) in the PPAR signaling pathway was regulated by SIRT4 among the 25 molecules. Importantly, the alterations in FABP4 and PPARγ were verified in the MPTP-induced PD mouse model. Discussion: Our results indicated that FABP4 in the PPAR signaling pathway is the most promising molecular target of SIRT4 in an MPTP-induced mouse model and revealed the possible functional role of SIRT4.This study provides a reference for future drug development and mechanism research with SIRT4 as a target or biomarker. [ABSTRACT FROM AUTHOR]

Background: Ligamentum flavum (LF) hypertrophy is the main cause of lumbar spinal canal stenosis (LSCS). Previous studies have shown that LF hypertrophy tissue exhibits abnormal lipid accumulation, but the regulatory mechanism remains unclear. The objective of this study was to explore the function and potential mechanism of ACSM5 in LF lipid accumulation. Methods: To assess the ACSM5 expression levels, lipid accumulation and triglyceride (TG) level in LF hypertrophy and normal tissue, we utilized RT-qPCR, western blot, oil red O staining, and TG assay kit. The pearson correlation coefficient assay was used to analyze the correlation between ACSM5 levels and lipid accumulation or TG levels in LF hypertrophy tissue. The role of ACSM5 in free fatty acids (FFA)-induced lipid accumulation in LF cells was assessed in vitro, and the role of ACSM5 in LF hypertrophy in mice was verified in vivo. To investigate the underlying mechanisms of ACSM5 regulating lipid accumulation in LF, we conducted the mRNA sequencing, bioinformatics analysis, and rescue experiments. Results: In this study, we found that ACSM5, which was significantly down-regulated in LF tissues, correlated with lipid accumulation. In vitro cell experiments demonstrated that overexpression of ACSM5 significantly inhibited FFA-induced lipid accumulation and fibrosis in LF cells. In vivo animal experiments further confirmed that overexpression of ACSM5 inhibited LF thickening, lipid accumulation, and fibrosis. Mechanistically, ACSM5 inhibited lipid accumulation of LF cells by inhibiting FABP4-mediated PPARγ signaling pathway, thereby improving hypertrophy and fibrosis of LF. Conclusions: our findings elucidated the important role of ACSM5 in the regulation of LF lipid accumulation and provide insight into potential therapeutic interventions for the treatment of LF hypertrophy. This study further suggested that therapeutic strategies targeting lipid deposition may be an effective potential approach to treat LF hypertrophy-induced LSCS. [ABSTRACT FROM AUTHOR]

Background: The incidence and prevalence of nonalcoholic fatty liver disease related hepatocellular carcinoma (NAFLD-HCC) are rapidly increasing worldwide. This study aimed to identify biomarker genes for prognostic prediction model of NAFLD-HCC hepatectomy by integrating text-mining, clinical follow-up information, transcriptomic data and experimental validation. Methods: The tumor and adjacent normal liver samples collected from 13 NAFLD-HCC and 12 HBV-HCC patients were sequenced using RNA-Seq. A novel text-mining strategy, explainable gene ontology fingerprint approach, was utilized to screen NAFLD-HCC featured gene sets and cell types, and the results were validated through a series of lab experiments. A risk score calculated by the multivariate Cox regression model using discovered key genes was established and evaluated based on 47 patients' follow-up information. Results: Differentially expressed genes associated with NAFLD-HCC specific tumor microenvironment were screened, of which FABP4 and VWF were featured by previous reports. A risk prediction model consisting of FABP4, VWF, gender and TNM stage were then established based on 47 samples. The model showed that overall survival in the high-risk score group was lower compared with that in the low-risk score group (p = 0.0095). Conclusions: This study provided the landscape of NAFLD-HCC transcriptome, and elucidated that our model could predict hepatectomy prognosis with high accuracy. [ABSTRACT FROM AUTHOR]

Background: Sepsis causes several immunological and metabolic alterations that induce oxidative stress. The modulation of fatty acid-binding protein 4 (FABP4) has been shown to worsen this condition. Extract of cogon grass root (ECGR) contains flavonoids and isoeugenol compounds that exhibit anti-inflammatory and antioxidant properties. This study aimed to assess the effects of ECGR on FABP4 and oxidative stress–related factors in a sepsis mouse model. Methods: Twenty-nine male mice ( Mus musculus) of the Deutsche Denken Yoken strain were divided into four groups: group 1, control; group 2, mice treated with 10 μL/kg body weight (BW) lipopolysaccharide (LPS); and groups 3 and 4, mice pre-treated with 90 and 115 mg/kg BW, respectively, and then treated with 10 μL/kg BW LPS for 14 d. Blood, liver, lymph, and cardiac tissue samples were collected and subjected to histological and complete blood examinations. Antioxidant (Glutathione peroxidase 3 (GPx3) and superoxide dismutase), FABP4 levels, and immune system-associated biomarker levels (TNF-α, IL-6 and IL-1β ) were measured. Results: Significant increases in platelet levels (p = 0.03), cardiomyocyte counts (p =0.004), and hepatocyte counts (p = 0.0004) were observed in group 4 compared with those in group 2. Conversely, compared with those in group 2, there were significant decreases in TNF-α expression in group 3 (p = 0.004), white pulp length and width in group 4 (p = 0.001), FABP4 levels in groups 3 and 4 (p = 0.015 and p = 0.012, respectively), lymphocyte counts in group 4 (p = 0.009), and monocyte counts (p = 0.000) and polymorphonuclear cell counts in the livers (p = 0.000) and hearts (p = 0.000) of groups 3 and 4. GPx3 activity was significantly higher in group 3 than in group 1 (p = 0.04). Conclusions: ECGR reduces FABP4 level and modulating oxidative stress markers in sepsis mouse model.

The purpose of the current study was to elucidate the physiological roles of intraocularly present fatty acid-binding protein 4 (FABP4). Using four representative intraocular tissue-derived cell types, including human non-pigmented ciliary epithelium (HNPCE) cells, retinoblastoma (RB) cells, adult retinal pigment epithelial19 (ARPE19) cells and human ocular choroidal fibroblast (HOCF) cells, the intraocular origins of FABP4 were determined by qPCR analysis, and the intracellular functions of FABP4 were investigated by seahorse cellular metabolic measurements and RNA sequencing analysis using a specific inhibitor for FABP4, BMS309403. Among these four different cell types, FABP4 was exclusively expressed in HOCF cells. In HOCF cells, both mitochondrial and glycolytic functions were significantly decreased to trace levels by BMS309403 in a dose-dependent manner. In the RNA sequencing analysis, 67 substantially up-regulated and 94 significantly down-regulated differentially expressed genes (DEGs) were identified in HOCF cells treated with BMS309403 and those not treated with BMS309403. The results of Gene Ontology enrichment analysis and ingenuity pathway analysis (IPA) revealed that the DEGs were most likely involved in G-alpha (i) signaling, cAMP-response element-binding protein (CREB) signaling in neurons, the S100 family signaling pathway, visual phototransduction and adrenergic receptor signaling. Furthermore, upstream analysis using IPA suggested that NKX2-1 (thyroid transcription factor1), HOXA10 (homeobox A10), GATA2 (gata2 protein), and CCAAT enhancer-binding protein A (CEBPA) were upstream regulators and that NKX homeobox-1 (NKX2-1), SFRP1 (Secreted frizzled-related protein 1) and TREM2 (triggering receptor expressed on myeloid cells 2) were causal network master regulators. The findings in this study suggest that intraocularly present FABP4 originates from the ocular choroid and may be a critical regulator for the cellular homeostasis of non-adipocyte HOCF cells.

Background: Sepsis causes several immunological and metabolic alterations that induce oxidative stress. The modulation of fatty acid-binding protein 4 (FABP4) has been shown to worsen this condition. Extract of cogon grass root (ECGR) contains flavonoids and isoeugenol compounds that exhibit anti-inflammatory and antioxidant properties. This study aimed to assess the effects of ECGR on FABP4 and oxidative stress–related factors in a sepsis mouse model. Methods: Twenty-nine male mice (Mus musculus) of the Deutsche Denken Yoken strain were divided into four groups: group 1, control; group 2, mice treated with 10 μL/kg body weight (BW) lipopolysaccharide (LPS); and groups 3 and 4, mice pre-treated with 90 and 115 mg/kg BW, respectively, and then treated with 10 μL/kg BW LPS for 14 d. Blood, liver, lymph, and cardiac tissue samples were collected and subjected to histological and complete blood examinations. Antioxidant (Glutathione peroxidase 3 (GPx3) and superoxide dismutase), FABP4 levels, and immune system-associated biomarker levels (TNF-α, IL-6 and IL-1β) were measured. Results: Significant increases in platelet levels (p = 0.03), cardiomyocyte counts (p =0.004), and hepatocyte counts (p = 0.0004) were observed in group 4 compared with those in group 2. Conversely, compared with those in group 2, there were significant decreases in TNF-α expression in group 3 (p = 0.004), white pulp length and width in group 4 (p = 0.001), FABP4 levels in groups 3 and 4 (p = 0.015 and p = 0.012, respectively), lymphocyte counts in group 4 (p = 0.009), and monocyte counts (p = 0.000) and polymorphonuclear cell counts in the livers (p = 0.000) and hearts (p = 0.000) of groups 3 and 4. Gpx3 activity was significantly higher in group 3 than in group 1 (p = 0.04). Conclusions: ECGR reduces FABP4 level and modulating oxidative stress markers in sepsis mouse model.

Fatty acid-binding protein-4 (FABP4), commonly known as adipocyte-fatty acid-binding protein (A-FABP), is a pleiotropic adipokine that broadly affects immunity and metabolism. It has been increasingly recognized that FABP4 dysfunction is associated with various metabolic syndromes, including obesity, diabetes, cardiovascular diseases, and metabolic inflammation. However, its explicit roles within the context of women's reproduction and pregnancy remain to be investigated. In this review, we collate recent studies probing the influence of FABP4 on female reproduction, pregnancy, and even fetal health. Elevated circulating FABP4 levels have been found to correlate with impaired reproductive function in women, such as polycystic ovary syndrome and endometriosis. Throughout pregnancy, FABP4 affects maternal–fetal interface homeostasis by affecting both glycolipid metabolism and immune tolerance, leading to adverse pregnancy outcomes, including miscarriage, gestational obesity, gestational diabetes, and preeclampsia. Moreover, maternal FABP4 levels exhibit a substantial linkage with the metabolic health of offspring. Herein, we discuss the emerging significance and potential application of FABP4 in reproduction and pregnancy health and delve into its underlying mechanism at molecular levels. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX), an effective and broad‐spectrum anthracycline antibiotic, is widely used in the treatment of numerous malignancies. However, dose‐dependent cardiotoxicity limits the clinical application of DOX, and the molecular mechanisms are still unknown. In this study, we used the BK receptor B1/B2 double‐knockout (B1B2‐/‐) mice to observe the role of BK receptor in cardiotoxicity induced by DOX and the underlying mechanisms. DOX induced myocardial injury with increased serum levels of AST, CK, and LDH, upregulated tissue expression of bradykinin B1/B2 receptor, FABP4 and iNOS, and downregulated expression of eNOS. However, these altered releases of myocardial enzyme and the expression level of iNOS were significantly prevented in the B1B2‐/‐ mice. We concluded that the activation of both B1 and B2 receptors of BK were involved in the DOX‐induced acute myocardial injury, possibly mediated through iNOS signaling pathways. [ABSTRACT FROM AUTHOR]

Abstract Foamy macrophages containing prominent cytoplasmic lipid droplets (LDs) are found in a variety of infectious diseases. However, their role in Streptococcus uberis-induced mastitis is unknown. Herein, we report that S. uberis infection enhances the fatty acid synthesis pathway in macrophages, resulting in a sharp increase in LD levels, accompanied by a significantly enhanced inflammatory response. This process is mediated by the involvement of fatty acid binding protein 4 (FABP4), a subtype of the fatty acid-binding protein family that plays critical roles in metabolism and inflammation. In addition, FABP4 siRNA inhibitor cell models showed that the deposition of LDs decreased, and the mRNA expression of Tnf, Il1b and Il6 was significantly downregulated after gene silencing. As a result, the bacterial load in macrophages increased. Taken together, these data demonstrate that macrophage LD formation is a host-driven component of the immune response to S. uberis. FABP4 contributes to promoting inflammation via LDs, which should be considered a new target for drug development to treat infections.

Introduction. In most patients with colorectal cancer (CRC), the tumor develops against the background of metabolically healthy obesity or metabolic syndrome (more than 60 % of patients), the key pathogenetic moment of which is developing hyperinsulinemia. Metabolic changes are also characteristic of patients with colon polyps (CP), which are currently considered as the most significant precancerous diseases. It has been shown that fractions of small extracellular vesicles (EVs) of adipocyte origin are specifically enriched in extracellular matrix proteins, including matrix metalloproteinases (MMPs), chaperones, and some metabolic enzymes involved in the synthesis of lipids and carbohydrates. This was the reason for choosing exosomal markers in our study. Comparison of protein expression on CD9- and FABP-4 positive vesicles will be useful to explain some clinical issues, such as the effectiveness of thermoradiotherapy or radiotherapy in obese CRC patients; for a more substantiated search for vesicular prognostic markers in obese cancer patients. However, taking into account the lack of data in the literature on the level of MMPs and HSPs expression in the composition of the total pool of EVs and in the composition of FABP4-positive EVs in patients with PTC and CRC patients, the aim of the work was formulated.Aim. Study of the level of MMPs and heat shock proteins (HSPs) on CD9- and FABP4-positive EVs in patients with CP and CRC in relation to metabolic status.Materials and methods. The study included 12 patients with CRC (T2-4N0-2M0; mean age 59.6 ± 1.6 years) who were treated at the Department of Abdominal Oncology of the Cancer Research Institute of the Tomsk National Research Medical Center from 2019 to 2021. The comparison group included 10 patients with CP. The level of proteins on the surface of CD9- and FABP4-positive EVs was studied using flow cytometry.Results. MMP9-positive EVs were detected more often in CRC patients than in CP patients, however, MMP9+MMP2+TIMP-positive EVs were significantly more frequently detected in CP patients. Among the studied heat shock proteins, HSP60 was most often expressed on the surface of EVs, and HSP60-positive EVs were detected on the surface of CD9-positive exosomes in patients with PTC much more often than in CRC. In patients with CRC, compared with patients with СP, among FABP4-positive EVs, the proportion of triple-positive EVs and EVs with the MMP9+MMP2-TIMP1+ phenotype significantly increases, which in general may indicate overexpression of MMP9 and TIMP1 by adipocytes or marcrophages of adipose tissue in patients with CRC. Correlation analysis revealed multiple correlations of individual phenotypes of CD9-positive EVs in patients with CRC with body mass index and serum high density lipoprotein cholesterol levels, while the phenotypes of FABP4-positive EVs were associated mainly with triglyceride levels.Conclusions. The phenotypes of CD9-positive and FABP4-positive circulating EVs are promising as predictors for clarifying cancer risk in patients with colon polyps, as well as in terms of explaining the effectiveness of the treatment of CRC patients with obesity or metabolic syndrome.

Objective(s): Cardiac fibrosis is a key biological process of cardiac remodeling and heart failure. Fatty acid-binding protein 4 (FABP4) is a lipid-binding protein that can regulate glucose and lipid homeostasis, and its expression was elevated in heart failure. However, whether FABP4 is involved in cardiac fibrosis remains unknown. Materials and Methods: The cardiac fibrosis model was established in male C57BL/6 mice with subcutaneously infused angiotensin II (Ang-II) (2.8 mg/kg/day) for 4 weeks. DMSO or FABP4 inhibitor BMS309403 (50 mg/kg/day) was intraperitoneally injected for 4 weeks. Ang II-infused mice, FABP4 inhibitor (BMS309403) injected mice, and ventricular tissue were used for morphological studies, and histological and biochemical analyses (FABP4 protein composition and expression).Results: Ang II infusion increased FABP4 mRNA and protein expression in the mouse ventricular tissue. After treatment with FABP4 inhibitor BMS309403 for 4 weeks, mice showed improved cardiac structure and function as detected by echocardiography. BMS309403 suppressed cardiac and systemic inflammatory response, reduced collagen deposition, and mRNA expression of collagen type I (COL1A1) and collagen type III (COL3A1) in Ang II-infused mice. BMS309403 also reduced the number of α-smooth muscle actin (α-SMA)+cells and decreased the mRNA expression of α-SMA, matrix metalloproteinases-2 (MMP-2), MMP-9, and transforming growth factor-β (TGF‑β) in ventricular tissue.Conclusion: The inhibitory effect of BMS309403 on cardiac fibrosis might be associated with inhibition of NLRP3 inflammasome activation, which Ang II activated. Thus, our data speculated that inhibition of FABP4 could significantly induce cardiac fibrosis.

The majority of colorectal cancer patients (CRCPs) develop tumors on the background of "metabolically healthy obesity" or metabolic syndrome. The aim of the work was to study the levels of matrix metalloproteinases (MMPs) and heat shock proteins (HSPs) on the surface of blood plasma CD9-positive and FABP4-positive small extracellular vesicles (sEVs) from CRCPs depending on metabolic status and tumor angiogenesis, as well as to evaluate the sEVs markers as predictors of the effectiveness of thermoradiotherapy. In CRCPs, compared with patients with colorectal polyps (CPPs), the proportion of triple positive EVs and EVs with the MMP9+MMP2-TIMP1+ phenotype increased significantly among FABP4-positive EVs (adipocyte-derived EVs), which in general may indicate the overexpression of MMP9 and TIMP1 by adipocytes or adipose tissue macrophages in CRCPs. The results obtained have prospects for use as markers to clarify cancer risk in CPPs. One can assume that for CRCPs with metabolic syndrome or metabolically healthy obesity, it is the FABP4+MMP9+MMP2-TIMP1- population of circulating sEVs that is the most optimal biomarker reflecting tumor angiogenesis. Determining this population in the blood will be useful in monitoring patients after treatment for the early detection of tumor progression. CD9+MMP9+MMP2-TIMP1- and MMP9+MMP2-TIMP1+ subpopulations of circulating sEVs are the most promising predictors of the efficacy of thermoradiation therapy because their levels at baseline differ significantly in CRCPs with different tumor responses. [ABSTRACT FROM AUTHOR]

Mingyu Gu,1,2,&ast; Yi Lin,2,&ast; Xianying Gai,3,&ast; Xiaohui Wei,2 Chunhua Lu,4 Yufan Wang,2 Xiaoying Ding,2,&ast; Yongde Peng,1,2 Yuhang Ma2 1Department of Endocrinology and Metabolism, Shanghai General Hospital of Nanjing Medical University, Shanghai, 200080, People’s Republic of China; 2Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, People’s Republic of China; 3Department of Endocrinology, Shanghai Sijing Hospital, Shanghai, 201601, People’s Republic of China; 4Community Health Service Center of Sijing, Shanghai, 201601, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yongde Peng, Department of Endocrinology and Metabolism, Shanghai General Hospital of Nanjing Medical University, 100 Haining Road, Shanghai, 200080, People’s Republic of China, Email pengyongde0908@126.com Yuhang Ma, Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, People’s Republic of China, Email mayuhang5992@163.comObjective: To explore the relationship between the level of fatty acid-binding protein 4 (FABP4) and reversion from prediabetes to normal glucose tolerance (NGT).Methods: A two-year retrospective cohort study was conducted on 398 participants with complete information. These 398 participants were divided into an NGT group and an abnormal glucose metabolism (AGM) group after 2 years of follow-up. The baseline level of FABP4 was determined, and the role of FABP4 in predicting reversion from prediabetes to NGT was investigated using an unconditional logistic regression model.Results: Over the two-year follow-up period, 37.4% (149/398) of the participants reverted from prediabetes to NGT. The participants with AGM had a higher baseline level of FABP4 than those with NGT. The baseline level of FABP4 was significantly negatively correlated with reversion from prediabetes to NGT. After adjusting for age, sex, body mass index and waist-to-hip ratio, the level of fasting blood glucose (FBG) [odds ratio (OR) 0.336, 95% confidence interval (CI) (0.196– 0.576)], 2-h post-challenge blood glucose (2hBG) [OR 0.697, 95% CI (0.581– 0.837)], and FABP4 [OR 0.960, 95% CI (0.928– 0.993)] at baseline were significant independent predictors of reversion from prediabetes to NGT. The area under the curve (AUC) value of the receiver operating characteristic curve for FABP4 was 0.605 (95% CI: 0.546– 0.665), and the AUC for FABP4 combined with FBG and 2hBG was 0.716 (95% CI: 0.663– 0.769).Conclusion: A higher baseline level of FABP4 was positively correlated with an adverse profile of diabetes risk factors and negatively correlated with reversion from prediabetes to NGT. FABP4, FBG and 2hBG were predictors of reversion from prediabetes to NGT.Keywords: fatty acid-binding protein 4, FABP4, prediabetes, normal glucose tolerance, abnormal glucose metabolism

Introduction. Obesity is associated with a high risk of developing concomitant diseases such as: metabolic syndrome, type 2 diabetes mellitus (DM2), cardiovascular pathology. FABP4 (fatty acid binding protein) is the specific lipid chaperone and an important protein for the function of adipose tissue and is one of the adipocytokines secreted by adipose tissue.The objective of the study was to investigate the FABP4 gene expression in subcutaneous and visceral adipose tissue (SAT and VAT) in patients with obesity and DM2.Methods and materials. SAT and VAT samples were obtained during bariatric surgery (N=43, BMI>35): obese with DM2 (N=21), obese without DM2 (N=22). Samples for the control group without obesity (N=15, BMI

Ordinary small molecule de novo drug design is time-consuming and expensive. Recently, computational tools were employed and proved their efficacy in accelerating the overall drug design process. Molecular dynamics (MD) simulations and a derivative of MD, steered molecular dynamics (SMD), turned out to be promising rational drug design tools. In this paper, we report the first application of SMD to evaluate the binding properties of small molecules toward FABP4, considering our recent interest in inhibiting fatty acid binding protein 4 (FABP4). FABP4 inhibitors (FABP4is) are small molecules of therapeutic interest, and ongoing clinical studies indicate that they are promising for treating cancer and other diseases such as metabolic syndrome and diabetes. [ABSTRACT FROM AUTHOR]

In dairy cattle, identifying polymorphisms that contribute to complex economical traits such as residual feed intake (RFI) is challenging and demands accurate genotyping. In this study, we compared imputed genotypes (n = 192 cows) to those obtained using the TaqMan and high-resolution melting (HRM) methods (n = 114 cows), for mutations in the FABP4 gene that had been suggested to have a large effect on RFI. Combining the whole genome sequence (n = 19 bulls) and the cows' BovineHD BeadChip allowed imputing genotypes for these mutations that were verified by Sanger sequencing, whereas, an error rate of 11.6% and 10.7% were encountered for HRM and TaqMan, respectively. We show that this error rate seriously affected the linkage-disequilibrium analysis that supported this gene candidacy over other BTA14 gene candidates. Thus, imputation produced superior genotypes and should also be regarded as a method of choice to validate the reliability of the genotypes obtained by other methodologies that are prone to genotyping errors due to technical conditions. These results support the view that RFI is a complex trait and that searching for the causative sequence variation underlying cattle RFI should await the development of statistical methods suitable to handle additive and epistatic interactions. [ABSTRACT FROM AUTHOR]

Subjects with type 2 diabetes mellitus (T2D) are at increased risk for heart failure (HF). The cardiac-specific (FABP3) and adipose-tissue-specific (FABP4) types of the fatty acid binding proteins have been associated with both all-cause and cardiovascular (CV) mortality. The aim of this study was to explore the prognosis value of FABP3 and FABP4 in ambulatory subjects with chronic HF (CHF), with and without T2D. A prospective study involving 240 ambulatory CHF subjects was performed. Patients were followed-up for a mean of 5.78 ± 3.30 years and cause of death (if any) was recorded. Primary endpoints were defined as all-cause and CV death, and a composite endpoint that included CV death or hospitalization for HF was included as a secondary endpoint. Baseline serum samples were obtained and the serum FABP3 and FABP4 concentrations were assessed by sandwich enzyme-linked immunosorbent assay. Survival analysis was performed with multivariable Cox regressions, using Fine and Gray competing risks models when needed, to explore the prognostic value of FABP3 and FABP4 concentrations, adjusting for potential confounders. Type 2 diabetes mellitus was highly prevalent, accounting for 47.5% for total subjects with CHF. Subjects with T2D showed higher mortality rates (T2D: 69.30%; non-T2D: 50.79%, p = 0.004) and higher serum FABP3 (1829.3 (1104.9–3440.5) pg/mL vs. 1396.05 (820.3–2362.16) pg/mL, p = 0.007) and FABP4 (45.5 (27.6–79.8) ng/mL vs. 34.1 (24.09–55.3) ng/mL, p = 0.006) concentrations compared with non-T2D CHF subjects. In the whole study cohort, FABP3 was independently associated with all-cause death, and both FABP3 and FABP4 concentrations were associated with CV mortality. The predictive values of these two molecules for all-cause (FABP3: HR 1.25, 95% CI 1.09–1.44; p = 0.002. FABP4: HR 2.21, 95% CI 1.12–4.36; p = 0.023) and CV mortality (FABP3: HR 1.28, 95% CI 1.09–1.50; p = 0.002. FABP4: HR 4.19, 95% CI 2.21–7.95; p < 0.001) were only statistically significant in the subgroup of subjects with T2D. Notably, FABP4 (HR 2.07, 95% CI 1.11–3.87; p = 0.022), but not FABP3, also predicted the occurrence of the composite endpoint (death or hospitalization for HF) only in subjects with T2D. All these associations were not found in CHF subjects without T2D. Our findings support the usefulness of serum FABP3 and FABP4 concentrations as independent predictors for the occurrence of all-cause and CV mortality in ambulatory subjects with CHF with T2D. [ABSTRACT FROM AUTHOR]

Hypertriglyceridemia (HTG) has been associated with an increased risk of pancreatitis and cardiovascular disease. Adipose tissue plays a major role in lipid metabolism, mobilization and distribution. We have compared the histological and transcriptomic profiles of the subcutaneous (SAT) and visceral (VAT) adipose tissues from subjects with severe obesity undergoing bariatric surgery with (Ob-HTG, n = 37) and without HTG (Ob-NTG, n = 67). Mean age and BMI were 51.87 ± 11.21 years, 45.78 ± 6.96 kg/m2 and 50.03 ± 10.17 years, 44.04 ± 4.69 kg/m2, respectively. The Ob-HTG group showed higher levels of glycosylated hemoglobin, fasting plasma glucose, high-sensitivity C-reactive protein and prevalence of hypertension. The degree of fibrosis was increased by 14% in SAT from the Ob-HTG group (p = 0.028), while adipocyte size distribution was comparable. Twenty genes were found differentially expressed in SAT and VAT between study groups. Among them, only SAT expression of FABP4 resulted significantly associated with circulating triglyceride levels after adjusting for other covariates and independently explained 5% of the variance in triglyceride levels in the combined model. This relationship was not found in the cohort of lean or overweight patients with normotriglyceridemia (non-Ob, n = 21). These results emphasize the contribution of SAT to triglyceride concentrations in obesity and indicate that FABP4 may be a potential drug target for the treatment of HTG. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH) increases the risk for liver cirrhosis. Noninvasive tests for NAFLD/NASH exist, but they are unreliable and thus liver biopsy remains the standard for diagnosis and new noninvasive diagnostic approaches are of great interest. The aim of this study was to test whether the serum levels of fatty acid-binding protein-4 (FABP4) and matrix metalloproteinase-9 (MMP9) could be used as a diagnostic tool for NASH. Methods: Patients who underwent bariatric surgery and simultaneous liver biopsy were identified. Biopsies were assigned a NAFLD activity score (NAS). MMP9- and FABP4- Enzyme-linked Immunosorbent Assays (ELISAs) on serum samples were performed. The serum levels of FABP4/MMP9 were compared and different models to predict NASH were developed. Results: A total of 84 patients were included, 28 patients (33.3%) were diagnosed with NASH. Higher concentrations of MMP9 in NASH patients (p < 0.01) were detected. FABP4 concentrations were not significantly increased. A moderate correlation between the NAS and MMP9 concentrations (r = 0.32, P < 0.01) was observed. The neural network model fit best with the dataset, with an area under the curve (AUC) of 83% and an accuracy of 88%. Conclusion: Serum MMP9 levels are increased in patients with NASH and should routinely be measured in patients with obesity, but further investigations are needed to improve noninvasive NASH diagnosis. [ABSTRACT FROM AUTHOR]