Fatty Acid Binding Protein Research Articles

Clinical values of MRSI, CRP and FABP4 in the diagnosis and prognosis of acute pancreatitis.

To examine the clinical values of C-reactive protein (CRP), fatty acid-binding protein 4 (FABP4) and magnetic resonance severity index (MRSI) in acute pancreatitis (AP) cases. 70 AP patients and another 70 healthy controls were recruited, and the MRSI score was calculated. Receiver operator characteristic (ROC) curve was used for diagnostic performance analysis. FABP4 levels were elevated in AP patients, and significantly correlated with CRP and MRSI score. Serum FABP4 and MRSI score displayed high diagnostic performance for AP. FABP4, MRSI score and CRP levels were positively correlated with disease severity. MRSI score and FABP4 were independently related to patients' survival, and showed high predictive values. FABP4 may serve as a potential marker for the diagnosis of AP, with the advantages of low cost and high simplicity. The levels of FABP4 and MRSI score can predict the poor survival of the patients.

Natural linoleic acid from marine fungus Eutypella sp. F0219 blocks KEAP1/NRF2 interaction and ameliorates MASLD by targeting FABP4

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.

Comprehensive biomarker assessment for predicting severe acute kidney injury and need of kidney replacement therapy in liver transplantation patients

Background Renal dysfunction is a common complication following liver transplantation (LT). This study aimed to determine whether a comprehensive assessment of kidney function using nineteen serum and urinary biomarkers (BMs) within the first 48 h post-LT could enhance the prediction of severe acute kidney injury (AKI) and the need of kidney replacement therapy (KRT) during the first postoperative week. Methods Blood and urine (U) samples were collected during the pre- and postoperative periods. Nineteen BMs were evaluated to assess kidney health in the first 48 h after LT. Classification and regression tree (CART) cross-validation identified key predictors to determine the best BM combination for predicting outcomes. Results Among 100 LT patients, 36 developed severe AKI, and 34 required KRT within the first postoperative week. Preoperative assessment of U neutrophil gelatinase-associated lipocalin (NGAL) and liver-type fatty acid-binding protein (L-FABP) predicted the need for KRT with 75% accuracy. The combined assessment of U osmolality (OSM), U kidney injury molecule 1 (KIM-1), and tissue inhibitor of metalloproteinase (TIMP-1) within 48 h post-LT predicted severe AKI with 80% accuracy. U-OSM alone, measured within 48 h post-LT, had an accuracy of 83% for predicting KRT need, outperforming any BM combination. Conclusions Combined BM analysis can accurately predict severe AKI and KRT needs in the perioperative period of LT. U-OSM alone proved to be an effective tool for monitoring the risk of severe AKI, available in most centers. Further studies are needed to assess its impact on AKI progression postoperatively. Registered at Clinical Trials (clinicaltrials.gov) in March 24th, 2014 by title ‘Acute Kidney Injury Biomarkers: Diagnosis and Application in Pre-operative Period of Liver Transplantation (AKIB)’ and identifier NCT02095431.

Impact of smoking habit on the subgingival proteome in patients with periodontitis.

Few investigations evaluated smoking's impact on the periodontal proteome. Therefore, this study aimed to analyse the influence of tobacco on the overall periodontal proteome and the differential expression of gingival crevicular fluid (GCF) proteins using sequential window acquisition of all theoretical mass spectra (SWATH-MS). GCF samples were collected from 40 periodontitis subjects (stages III-IV). These were separated based on smoking status into smokers (17), ex-smokers (10), and non-smokers (13). Samples were analysed using SWATH-MS, and proteins were identified using the UniProt human-specific database. Data are available via ProteomeXchange with the identifier PXD043474. Principal component analysis (PCA) was employed to examine the spectral mass distribution of the proteome. Protein expression was different for a p-value<0.05 and a log2 fold change ≥0.3 (upregulated) or ≤-0.3 (downregulated). The distribution of overall proteome did not differ between non-smokers, smokers, and ex-smokers. Considering protein expression, 23 were differentially expressed in smokers vs. non-smokers (16 upregulated and 7 downregulated), 17 in ex-smokers vs. non-smokers (2 upregulated and 15 downregulated), and only 8 in smokers vs. ex-smokers (7 upregulated and 1 downregulated). Smoking increased the expression of proteins related to epithelial hyperkeratinization (keratins type II cytoskeletal 4, type I cytoskeletal 13 and type I cytoskeletal 19, cornulin, and fatty acid-binding protein 5). However, multiple immunoglobulins were underexpressed when comparing smokers and ex-smokers to non-smokers. Although smoking does not significantly modify the overall GCF proteome associated with periodontitis, it alters the expression of several proteins compared to never-smokers and ex-smokers. Smoking is a critical risk factor for the development and progression of periodontitis. However, evidence of the effect of smoking on the subgingival proteome is scarce. Therefore, this study aimed to determine the impact of smoking on the overall proteome and differential expression of gingival crevicular fluid (GCF) proteins using the sequential window acquisition of all theoretical mass spectra (SWATH-MS) proteomic technique. For this purpose, GCF samples were collected from 40 subjects with periodontitis, of which 17 were smokers, 10 were ex-smokers, and 13 were non-smokers. These samples were analysed by SWATH-MS, and proteins were identified using the UniProt human-specific database. Analysis of the overall proteome showed that its distribution was not significantly different between smokers, ex-smokers, and non-smokers. However, several proteins were found to be differentially expressed according to the smoking status. Smoking can increase the expression of several keratins and proteins related to hyperkeratinization of the epithelium. However, in ex-smokers, these proteins return to similar levels to those of non-smokers. Moreover, smoking may induce a lower expression of proteins related to adaptive immunity, such as immunoglobulins. This immunosuppressive effect may persist in ex-smokers.

FABP1 induces lipogenesis by regulating the processing of SREBP1 in hepatocytes of large yellow croaker (Larimichthys crocea).

Fatty acid-binding protein 1 (FABP1) plays an important role in regulating fatty acid metabolism in liver, which is a potential therapeutic target for diseases such as non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms are not well defined. Using complementary experimental models, we discovered FABP1 induction in hepatocytes as a primary mediator of lipogenesis when exposed to fatty acids, especially saturated fatty acids (SFAs). In the feeding trial, palm oil led to excess lipid accumulation in the liver of large yellow croaker (Larimichthys crocea), accompanied by significant induction of FABP1. In cultured cells, palmitic acid (PA), a kind of SFA, triggered the fabp1 expression and increased triglyceride (TG) contents. Knockdown of FABP1 dampened PA-induced TG accumulation through mitigated lipogenesis. The overexpression of FABP1 showed the opposite result. Furthermore, the inactivation of FABP1 led to induction in insulin-induced gene 1 (INSIG1) expression, which attenuated the processing of sterol regulatory element-binding protein 1 (SREBP1) by down-regulating the nuclear-localized SREBP1. These results revealed a previously unrecognized function of FABP1 in response to PA, providing additional evidence for targeting FABP1 in the treatment of NAFLD caused by SFA.

Intestinal fatty acid-binding protein (I-FABP) as biomarker of ischemic damage in experimentally induced 12-h small bowel obstruction.

Laboratory tests have low diagnostic specificity for strangulated intestinal obstruction. The diagnostic potential of the intestinal fatty acid-binding protein (I-FABP) expressed in the tips of the intestinal villi continues to be explored. The number of white blood cells, blood plasma levels of L-lactate, C-reactive protein (CRP) and I-FABP were measured in rats with experimentally induced 12-h strangulated and non-strangulated intestinal obstruction. The results of the laboratory tests were compared with the changes in the morphology of the intestinal wall. The studied diagnostic markers, except for CRP, were elevated by 12-h L-lactate and I-FABP concentrations were significantly higher in the strangulated obstruction group than in other groups. L-lactate (cutoff value: 3.01mmol/L) had 86.1% sensitivity and 66.7% specificity for strangulated obstruction (AUC 0.815, p < 0.001). I-FABP levels above 5.432ng/ml indicated strangulated obstruction with 83.33% sensitivity and 88.9% specificity (AUC 0.906, p < 0.001). Villi destruction was observed at 2h in the strangulated obstruction group. I-FABP levels peaked at 4h and plateaued at 12h. Functional changes were observed in the non-strangulated group; they were accompanied by a significant increase in I-FABP concentrations that lasted until 12h. Compared with traditional diagnostic markers of strangulated intestinal obstruction, I-FABP demonstrated higher accuracy in the first 12h, although its concentrations reached the plateau already at 4h and did not increase thereafter. The functional changes in small bowel wall in non-strangulated obstruction were accompanied by continuous increase in I-FABP concentrations up to 12h, which may have influenced the diagnostic accuracy of the marker.

Intestinal fatty acid binding protein is associated with infarct size and cardiac function in acute heart failure following myocardial infarction

BackgroundIn acute heart failure (HF), reduced cardiac output, vasoconstriction and congestion may damage the intestinal mucosa and disrupt its barrier function. This could facilitate the leakage of bacterial products into...

The Role of Matrix Stiffness And Viscosity on Lipid Phenotype And Fat Lineage Potential.

Autologous fat transfer is a common procedure that patients undergo to rejuvenate large soft tissue defects. However, these surgeries are complicated by limited tissue sources, donor-site morbidity, and necrosis. While the biofabrication of fat tissue can serve as a clinical option for reconstructive surgery, the influence of matrix mechanics, specifically stiffness and viscosity, on adipogenesis requires further elucidation. Additionally, the effects of these mechanical parameters on metabolic and thermogenic fat potential haveyet to be investigated. In this study, gelatinmethacryloyl (GelMA) polymers with varying degrees of methacrylation (DoM) were fabricated to create matrices with different stiffnesses and viscosities. Human adipose-derived mesenchymal stem cells were then encapsulated in mechanically tunable GelMA and underwent adipogenesis to investigate the effects of matrix mechanics on lipid phenotype and fat potential. Mechanical testing confirmed that GelMA stiffness was regulated by DoM and weight composition, whereas viscosity was determined by the latter. Further work revealed that while lipid phenotype became more enriched as matrix stiffness and viscosity declined, the potential toward metabolic and thermogenic fat appeared to be more viscous dependent rather than stiffness dependent. In addition, fatty acid binding protein 4 and uncoupling protein 1 gene expression exhibited viscous-dependent behavior despite comparable levels of peroxisome proliferator-activated receptor gamma. However, despite the superior role of viscosity, lipid quantity and mitochondrial abundance demonstrated stiffness-dependent behavior. Overall, this work revealed that matrix viscosity played a more superior role than stiffness in driving adipogenesis and distinguishing between metabolic and thermogenic fat potential. Ultimately, this differentiation in fat production is important for engineering ideal adipose tissue for large soft tissue defects.

FABP4 deficiency ameliorates alcoholic steatohepatitis in mice via inhibition of p53 signaling pathway

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.

Pyrroloquinoline Quinone Alleviates Intestinal Inflammation and Cell Apoptosis via the MKK3/6-P38 Pathway in a Piglet Model.

This study investigates the underlying mechanism through which dietary supplementation of pyrroloquinoline quinone disodium (PQQ) alleviates intestinal inflammation and cell apoptosis in piglets challenged with lipopolysaccharide (LPS). Seventy-two barrows were divided into three groups: control (CTRL), LPS challenged (LPS), and LPS challenged with PQQ supplementation (PQQ + LPS). On d 7, 11, and 14, piglets received intraperitoneal injections of LPS or 0.9% of NaCl (80 μg/kg). After a 4 h interval following the final LPS injection on d 14, blood samples were obtained, and all piglets were euthanized for harvesting jejunal samples. The results showed that dietary supplementation of PQQ improved the damage of intestinal morphology, increased the down-regulated tight junction proteins, and reduced the increase of serum diamine oxidase activity, the intestinal fatty acid binding protein, and TNF-α levels in piglets challenged with LPS (p < 0.05). The proteomics analysis revealed a total of 141 differentially expressed proteins (DEPs), consisting of 64 up-regulated DEPs and 77 down-regulated DEPs in the PQQ + LPS group compared to the LPS group. The KEGG pathway analysis indicated enrichment of the tight junction pathway and the apoptosis pathway (p < 0.05). Compared to the LPS group, the piglets in the PQQ + LPS group had increased levels of Bcl-2 protein, reduced positive apoptosis signals, and a decrease in the abundance of MKK 3/6 and p-p38 proteins (p < 0.05). In conclusion, dietary supplementation of PQQ could alleviate jejunal inflammatory damage and cell apoptosis in piglets challenged with LPS through the MKK3/6-p38 signaling pathway.

Study of Intestinal Fatty Acid Binding Protein-2 in Cirrhotic Patients and its Relation to Chronic Use of Proton Pump Inhibitors in Decompensated Cirrhosis

Study of Intestinal Fatty Acid Binding Protein-2 in Cirrhotic Patients and its Relation to Chronic Use of Proton Pump Inhibitors in Decompensated Cirrhosis

Docetaxel-Induced Cell Death Is Regulated by a Fatty Acid-Binding Protein 12-Slug-Survivin Pathway in Prostate Cancer Cells.

Chemotherapy is an important treatment option for advanced prostate cancer, especially for metastatic prostate cancer (PCa). Resistance to first-line chemotherapeutic drugs such as docetaxel often accompanies prostate cancer progression. Attempts to overcome resistance to docetaxel by combining docetaxel with other biological agents have been mostly unsuccessful. A better understanding of the mechanisms underlying docetaxel resistance may provide new avenues for the treatment of advanced PCa. We have previously found that the fatty acid-binding protein 12 (FABP12)-PPARγ pathway modulates lipid-related bioenergetics and PCa metastatic transformation through induction of Slug, a master driver of epithelial-to-mesenchymal transition (EMT). Here, we report that the FABP12-Slug axis also underlies chemoresistance in PCa cells. Cell sensitivity to docetaxel is markedly suppressed in FABP12-expressing cells, along with induction of Survivin, a typical apoptosis inhibitor, and inhibition of cleaved PARP, a hallmark of programmed cell death. Importantly, Slug depletion down-regulates Survivin and restores cell sensitivity to docetaxel in FABP12-expressing cells. Finally, we also show that high levels of Survivin are associated with poor prognosis in PCa patients, with FABP12 status determining its prognostic significance. Our research identifies a FABP12-Slug-Survivin pathway driving docetaxel resistance in PCa cells, suggesting that targeting FABP12 may be a precision approach to improve chemodrug efficacy and curb metastatic progression in PCa.

Heart-type fatty acid binding protein (H-FABP) as an early biomarker in sepsis-induced cardiomyopathy: a prospective observational study

BackgroundSepsis-induced cardiomyopathy (SICM) is a common and life-threatening complication of sepsis, significantly contributing to elevated mortality. This study aimed to identify crucial indicators for the prompt and early assessment of SICM.MethodsPatients diagnosed with sepsis or SICM within 24 h of intensive care unit (ICU) admission were enrolled in this prospective observational study. Patients were assigned to the training set, validation set and external test set. The primary endpoint was 7-day ICU mortality, and the secondary endpoint was 28-day ICU mortality. Three machine learning algorithms were utilized to identify relevant indicators for diagnosing SICM, incorporating 64 indicators including serum biomarkers associated with cardiac, renal, and liver function, lipid metabolism, coagulation, and inflammation. Internal and external validations were performed on the screening results. Patients were then stratified based on the cut-off value of the most diagnostically effective biomarker identified, and their prognostic outcomes were observed and analyzed.ResultsA total of 270 patients were included in the training and validation set, and 52 patients were included in the external test set. Age, sex, and comorbidities did not significantly differ between the sepsis and SICM groups (P > 0.05). The support vector machine (SVM) algorithm identified six indicators with an accuracy of 84.5%, the random forest (RF) algorithm identified six indicators with an accuracy of 81.9%, and the logistic regression (LR) algorithm screened out seven indicators. Following rigorous selection, a diagnostic model for sepsis-induced cardiomyopathy was established based on heart-type fatty acid binding protein (H-FABP) (OR 1.308, 95% CI 1.170–1.462, P < 0.001) and retinol-binding protein (RBP) (OR 1.020, 95% CI 1.006–1.034, P < 0.05). H-FABP alone exhibited the highest diagnostic performance in both the internal (AUROC 0.689, P < 0.05) and external sets (AUROC 0.845, P < 0.05). Patients with SICM were further stratified based on an H-FABP diagnostic cut-off value of 8.335 ng/mL. Kaplan–Meier curve analysis demonstrated that elevated H-FABP levels at admission were associated with higher 7-day ICU mortality in patients with SICM (P < 0.05).ConclusionsThis study revealed that H-FABP concentrations measured within 24 h of patient admission could serve as a crucial biomarker for the early and rapid diagnosis and short-term prognostic evaluation of SICM.

Genetic polymorphisms in FABP2, CYP2E1, and TP53 genes are potentially associated with colorectal cancer susceptibility

Colorectal cancer (CRC) is among the most prevalent cancers with a high mortality rate. Both genetic and environmental factors contribute to CRC development. This study aimed to assess the association of single nucleotide polymorphisms (SNPs) in the fatty acid binding protein-2 (rs1799883), Cytochrome P450 2E1 (rs3813865), TP53 (rs1042522), and Murine double minute 2 (rs1042522) genes with CRC. A cross-sectional case–control study was conducted at the Institute of Molecular Biology and Biotechnology from May 2020 to March 2021, involving CRC patients (N = 100) and controls (N = 100) recruited from the Multan district in Pakistan. Polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) and tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) were employed to investigate the studied SNPs. The association of SNPs in all genes with CRC was examined either individually or in various combinations. Genotypes at three SNPs, rs1799883 in FABP2, rs3813865 in CYP2E1, and rs1042522 in TP53, were found to be associated with the development of CRC, while rs1042522 in MDM2 was not. Patients who were married, smoked, lacked exercise habits or had a family history of CRC were at a greater risk of acquiring the disease. FABP2 gene rs1799883, CYP2E1 gene rs3813865, and TP53 gene rs1042522 polymorphisms are significant in the development of CRC in Pakistani participants.

Feeding intolerance after pediatric cardiac surgery is associated with dysbiosis, barrier dysfunction, and reduced short-chain fatty acids.

Congenital heart disease (CHD) is the most common birth defect, occurring in roughly 40,000 U.S. births annually. Malnutrition and feeding intolerance (FI) in CHD range from 30% to 42% and are associated with longer hospitalization and increased mortality. Cardiopulmonary bypass (CPB) required for surgical repair of CHD induces a systemic inflammatory response worsening intestinal dysbiosis and leading to intestinal epithelial barrier dysfunction (EBD), possibly contributing to postoperative FI. The objective of this study was to determine the relationship of postoperative FI with intestinal microbiome, short-chain fatty acids (SCFAs), and EBD in pediatric CHD after cardiac surgery. This was a prospective study of patients aged 0-15 years undergoing cardiac surgery with CPB. Samples were collected preoperatively and postoperatively to evaluate the gut microbiome, plasma EBD markers, short-chain fatty acids (SCFAs), and plasma cytokines. Clinical data were collected to calculate a FI score and evaluate patient status postoperatively. We enrolled 26 CPB patients and identified FI (n = 13). Patients with FI had unique microbial shifts with the reduced SCFA-producing organisms Rothia, Clostridium innocuum, and Intestinimonas. Patients who developed FI had associated elevations in the plasma EBD markers claudin-2 (P < 0.05), claudin-3 (P < 0.01), and fatty acid binding protein (P < 0.01). Patients with FI had reduced plasma and stool SCFAs. Mediation analysis showed the microbiome functional shift was associated with reductions in stool butyric and propionic acid in patients with FI. In conclusion, we provide novel evidence that intestinal dysbiosis, markers of EBD, and SCFA depletion are associated with FI. These data will help identify mechanisms and therapeutics to improve clinical outcomes following pediatric cardiac surgery.NEW & NOTEWORTHY Feeding intolerance contributes to postoperative morbidity following pediatric cardiac surgery. The intestinal microbiome and milieu play a vital role in gut function. Short-chain fatty acids are gut and cardioprotective metabolites produced by commensal bacteria and help maintain appropriate barrier function. Depletion of these metabolites and barrier dysfunction contribute to postoperative feeding intolerance following cardiac surgery. Identifying mechanistic targets to improve the intestinal milieu with the goal of improved nutrition and clinical outcomes is critical.

Proteomic Correlates and Prognostic Significance of Kidney Injury in Heart Failure With Preserved Ejection Fraction.

Kidney disease is common in heart failure with preserved ejection fraction (HFpEF). However, the biologic correlates and prognostic significance of kidney injury (KI), in HFpEF, beyond the estimated glomerular filtration rate (eGFR), are unclear. Using baseline plasma samples from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, we measured the following KI biomarkers: cystatin-C, fatty acid-binding protein-3, Beta-2 microglobulin, neutrophil gelatinase-associated lipocalin, and kidney-injury molecule-1. Factor analysis was used to extract the common variability underlying these biomarkers. We assessed the relationship between the KI-factor score and the risk of death or HF-related hospital admission in models adjusted for the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. We also assessed the relationship between the KI factor score and ~5000 plasma proteins, followed by pathway analysis. We validated our findings among HFpEF participants in the Penn Heart Failure Study. KI was associated with the risk of death or HF-related hospital admission independent of the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. Both the risk score and eGFR were no longer associated with death or HF-related hospital admission after adjusting for the KI factor score. KI was predominantly associated with proteins and biologic pathways related to complement activation, inflammation, fibrosis, and cholesterol homeostasis. KI was associated with 140 proteins, which reproduced across cohorts. Findings regarding biologic associations and the prognostic significance of KI were also reproduced in the validation cohort. KI is associated with adverse outcomes in HFpEF independent of baseline eGFR. Patients with HFpEF and KI exhibit a plasma proteomic signature indicative of complement activation, inflammation, fibrosis, and impaired cholesterol homeostasis.

Activation of pregnane X receptor sensitizes alcoholic steatohepatitis by transactivating fatty acid binding protein 4

Alcoholic steatohepatitis (ASH) is a liver disease characterized by steatosis, inflammation, and necrosis of the liver tissue as a result of excessive alcohol consumption. Pregnane X receptor (PXR) is a xenobiotic nuclear receptor best known for its function in the transcriptional regulation of drug metabolism and disposition. Clinical reports suggested that the antibiotic rifampicin, a potent human PXR activator, is a contraindication in alcoholics, but the mechanism was unclear. In this study, we showed that the hepatic expression of fatty acid binding protein 4 (FABP4) was uniquely elevated in ASH patients and a mouse model of ASH. Pharmacological inhibiting FABP4 attenuated ASH in mice. Furthermore, treatment of mice with the mouse PXR agonist pregnenolon-16α-carbonitrile (PCN) induced the hepatic and circulating levels of FABP4 and exacerbated ASH in a PXR-dependent manner. Our mechanism study established FABP4 as a transcriptional target of PXR. Treatment with andrographolide, a natural compound and dual inhibitor of PXR and FABP4, alleviated mice from ASH. In summary, our results showed that the PXR–FABP4 gene regulatory axis plays an important role in the progression of ASH, which may have accounted for the contraindication of rifampicin in patients of alcoholic liver disease. Pharmacological inhibition of PXR and/or FABP4 may have its promise in the clinical management of ASH.

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.

FABP4 Enhances Lipidic and Fibrotic Cardiac Structural and Ca2+ Dynamic Changes.

Adipocyte FABP4 (fatty acid-binding protein 4) is augmented in the epicardial stroma of patients with long-standing persistent atrial fibrillation. Because this molecule is released mainly by adipocytes, our objective was to study its role in atrial cardiomyopathy, focusing our attention on fibrosis, metabolism, and electrophysiological changes. These results might clarify the role of adiposity as a mediator of atrial cardiomyopathy. We used several preclinical cellular models, epicardial and subcutaneous stroma primary cell cultures from patients undergoing open heart surgery, human atrial fibroblasts, atrial cardiomyocytes derived from human induced pluripotent stem cells and isolated from adult mice, and Nav1.5 transfected Chinese hamster ovary cells. Fibrosis, glucose, mitochondrial and adipogenesis activity, gene expression, and proteomics were determined by wound healing, enzymatic, colorimetric, fluorescence assays, real-time quantitative polymerase chain reaction, and TripleTOF proteomics. Molecular changes were analyzed by Raman confocal microspectroscopy, calcium dynamics by confocal microscopy, and ion currents by patch clamp. Epicardial, subcutaneous, and atrial fibroblasts and cardiomyocytes were incubated with FABP4 at 100 ng/mL. Our results showed that FABP4 induced fibrosis, glucose metabolism, and lipid accumulation on epicardial and subcutaneous stroma cells and atrial fibroblasts. Besides, it modified lipid content and calcium dynamics in atrial cardiomyocytes without effects on INa. FABP4 exerts fibrotic and metabolic changes on epicardial stroma and modifies lipid content and calcium dynamic on atrial cardiomyocytes. These results suggest its possible role as an atrial cardiomyopathy mediator.

Effects of high temperature short time (HTST) pasteurization on milk and whey during commercial whey protein concentrate production

Two pasteurization steps are often used in the preparation of whey protein concentrate (WPC) before evaporation into a dry product. The Pasteurized Milk Ordinance (PMO) in the United States requires that raw bovine milk be pasteurized using a process that meets minimum heat treatment requirements to achieve reductions in pertinent microorganisms. In addition, WPC produced from USDA-approved plants must comply with CFR Subpart B §58.809, which dictates that all fluid whey used in the manufacture of dry whey products shall be pasteurized before being condensed. These heat treatments are effective at inactivating the most thermally resistant bacterium, such as Coxiella burnetii; however, they can also alter milk proteins-inducing denaturation, aggregation and reduced bioactivity. Though the impact of thermal treatments on whey proteins has been examined, the specific influence of 2 high-temperature-short-time (HTST) pasteurization steps on the retention of proteins in WPC remains unknown. This study aimed to investigate the effect of commercial-scale HTST pasteurization of both raw milk and the resulting sweet whey on the products' overall protein profile. Three distinct batches of raw milk (RM) and corresponding pasteurized milk (PM), the resulting whey (RW) and pasteurized whey (PW) produced at commercial scale were analyzed. Assessments of denaturation were conducted through solubility testing at pH 4.6 and hydrophobicity evaluation via anilinonaphthalene-1-sulfonic acid assay (ANS). Additionally, enzyme-linked immunosorbent assay (ELISA), PAGE (PAGE) and liquid chromatography tandem mass spectroscopy (LC-MS/MS) were employed to compare the retention of key bioactive proteins before and after each HTST pasteurization step. The percentage of soluble whey protein decreased from RM to PM and from RW to PW, but no significant differences were observed via hydrophobicity assay. ELISA revealed a significant reduction in key bioactive proteins, such as lactoferrin, immunoglobulin A and immunoglobulin M, but not immunoglobulin G, after HTST pasteurization of RM and RW. PAGE and LC-MS/MS revealed a significant decrease in the retention of lactoferrin and key milk fat globular membrane proteins, such as xanthine dehydrogenase oxidase/xanthine oxidase, lactadherin and fatty acid binding protein. Additionally, xanthine oxidase activity was significantly reduced after HTST pasteurization of milk and whey. This research helps to identify the limitations of the current processing techniques used in the dairy industry and could lead to innovation in improving the retention of bioactive proteins.