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151. Acute Renal Failure - A Serious Complication in Patients After Kidney Transplantation

Author

Sanja Radojevic-Skodric, Lj. Bogdanovic, Milena Radunovic, Milica Prostran, Gordana Basta-Jovanovic, S. Simic-Ogrizovic, and R. Naumovic

Subjects
Pathology, medicine.medical_specialty, Bioinformatics, Fatty Acid-Binding Proteins, Biochemistry, Proinflammatory cytokine, 03 medical and health sciences, Acute renal failure, L-FABP, 0302 clinical medicine, Lipocalin-2, Drug Discovery, medicine, Humans, Transplantation, Homologous, 030212 general & internal medicine, Hepatitis A Virus Cellular Receptor 1, NGAL, KIM-1, Cystatin C, Kidney transplantation, Pharmacology, Kidney, medicine.diagnostic_test, biology, business.industry, Organic Chemistry, Acute kidney injury, Interleukin-18, Complement System Proteins, Acute Kidney Injury, medicine.disease, Kidney Transplantation, 3. Good health, Transplantation, medicine.anatomical_structure, 030220 oncology & carcinogenesis, biology.protein, Molecular Medicine, Biomarker (medicine), Renal biopsy, business, IL-18, Biomarkers
Abstract

Free radical-mediated injury releases proinflammatory cytokines and activates innate immunity. It has been suggested that the early innate response and the ischemic tissue damage play roles in the development of adaptive responses, which may lead to acute kidney rejection. Various durations of hypothermic kidney storage before transplantation add to ischemic tissue damage. The final stage of ischemic injury occurs during reperfusion that develops hours or days after the initial insult. Repair and regeneration processes occur together with cellular apoptosis, autophagy and necrosis and a favorable outcome is expected if regeneration prevails. Along the entire transplantation time course, there is a great demand for novel immune and nonimmune injury biomarkers. The use of these markers can be of great help in the monitoring of kidney injury in potential kidney donors, where acute kidney damage can be overlooked, in predicting acute transplant dysfunction during the early post-transplant periods, or in predicting chronic changes in long term followup. Numerous investigations have demonstrated that biomarkers that have the highest predictive value in acute kidney injury include NGAL, Cystatin C, KIM-1, IL-18, and L-FABP. Most investigations show that the ideal biomarker to fulfill all the needs in renal transplant has not been identified yet. Although, in many animal models, new biomarkers are emerging for predicting acute and chronic allograft damage, in human allograft analysis they are still not routinely accepted and renal biopsy still remains the gold standard.

Published
2015

152. Biomarcadores precoces de fracaso renal agudo tras angiografía coronaria o cirugía cardiaca en pacientes con síndrome coronario o fallo cardiaco agudo

Author

Torregrosa Maicas, Isidro Antonio, Sáez Tormo, Guillermo, Miguel Carrasco, Alfonso, Montoliu Félix, Carmina, and Departament de Bioquímica i Biologia Molecular

Subjects
fracaso renal agudo, UNESCO::CIENCIAS MÉDICAS, ngal, interleucina 18, cistatina-c, kim-1, CIENCIAS MÉDICAS [UNESCO], angiografía coronaria, cirugía cardiaca, l-fabp
Abstract

Introducción. El fracaso renal agudo es una complicación frecuente tras la cirugía cardiaca y la angiografía coronaria y tiene un marcado impacto sobre el pronóstico porque conlleva una mayor utilización de recursos, prolonga la estancia hospitalaria, aumenta la mortalidad y puede conducir a la enfermedad renal crónica. El diagnóstico de fracaso renal agudo se basa fundamentalmente en la detección del incremento de la creatinina sérica, que es tardío y no refleja adecuadamente el filtrado glomerular en el paciente agudo. En los últimos años diferentes grupos han intentado identificar nuevos marcadores para el diagnóstico temprano del fracaso renal agudo, pero aún quedan importantes cuestiones por resolver. Objetivo. Evaluar la utilidad de NGAL, IL-18, KIM-1 y L-FABP en orina y cistatina-C en suero para la detección precoz del fracaso renal agudo en pacientes con síndrome coronario o fallo cardiaco agudo y sometidos a cirugía cardiaca o angiografía coronaria y explorar la posible aplicación de un nuevo biomarcador, la proteína Klotho en orina, como biomarcador precoz del FRA en las poblaciones anteriores. Métodos. Se incluyó un total de 193 pacientes adultos ingresados en la unidad de cuidados intensivos por síndrome coronario o fallo cardiaco agudo y a los que se realizó una angiografía coronaria con o sin angioplastia o implantación de endoprótesis o una cirugía cardiaca valvular o de revascularización. El criterio de valoración fue la aparición de fracaso renal agudo definido como un aumento de la creatinina sérica igual o mayor del 50% durante los siete días posteriores a la cirugía, siguiendo los criterios RIFLE. Las muestras de sangre y orina para la determinación de los biomarcadores se recogieron 12 horas tras la intervención. La determinación de NGAL, IL-18, KIM-1 y L-FABP en orina se realizó por ELISA y la de cistatina-C en suero por nefelometría. La utilidad de los biomarcadores para el diagnóstico precoz del fracaso renal agudo definido según los criterios RIFLE se evaluó mediante curvas ROC. Para el estudio de la proteína Klotho en orina se seleccionaron 60 pacientes de la población anterior y para determinar si existía correlación entre los niveles de Klotho en orina y la presencia de fracaso renal agudo se realizó la prueba de Spearman. Resultados. Se incluyó un total de 193 pacientes, 144 en el grupo de angiografía y 49 en el de cirugía cardiaca. Veinte pacientes desarrollaron fracaso renal agudo en el primer grupo y 15 en el segundo. En el grupo de angiografía el área bajo la curva ROC (AUC) para los distintos biomarcadores fue: NGAL: 0.958, Cistatina-C: 0.869, IL-18: 0.727, KIM-1, 0.713 y L-FABP: 0.642 y en el de cirugía cardiaca: NGAL: 0.916, Cistatina-C: 0.675, IL-18: 0.676, KIM-1: 0.716 y L-FABP: 0.743. En el grupo de pacientes analizado no existía correlación entre los niveles de Klotho en orina y la presencia de fracaso renal agudo. Conclusiones. De entre todos los biomarcadores estudiados para el diagnóstico precoz del fracaso renal agudo en pacientes adultos con síndrome coronario o fallo cardiaco agudo y sometidos a angiografía coronaria o cirugía cardíaca, NGAL en orina a las 12 horas de la intervención es el que ha demostrado una mayor utilidad, con un capacidad predictiva superior a cistatina-C en suero e IL-18, KIM-1 y L-FABP en orina. Klotho en orina medido por ELISA no parece ser un buen candidato para ser usado como biomarcador precoz de fracaso renal agudo.

Published
2015

156. Lípidos nucleares: topología y metabolismo

Author

Juan Pablo Layerenza and Ves Losada, Ana

Subjects
L-FABP, lípidos nucleares, Células, Biología, gotas lipídicas, Lípidos, lípidos neutros, Ácidos Grasos, Núcleo Celular, Ciencias Exactas
Abstract

El núcleo es una de las características distintivas que definen a las células eucariotas, permite una compartamentalización que es crítica para procesos que se desarrollan dentro del mismo, como la replicación, transcripción, splicing de pre-mRNA y ensamblado de ribosomas. Los Lípidos Neutros (LN) nucleares son fuentes alternativas de ácidos grasos (FA) y colesterol para membranas, vías de señalización y ligandos de factores de transcripción. Los objetivos de la presente tesis fueron: 1) Determinar la organización estructural y espacial de los lípidos nucleares. 2) Determinar el o los mecanismos de incorporación de los ácidos grasos (FA) exógenos en los lípidos nucleares. Como modelo experimental se trabajó con núcleos y matrices nucleares aislados de hígado de rata. La pureza de las fracciones aisladas se determinó mediante ensayos morfológicos y bioquímicos y se corroboró la alta pureza e integridad de cada fracción. Mediante análisis bioquímicos tradicionales se determinó la composición lipídica nuclear y se pudo concluir que los lípidos nucleares se ubican en dos localizaciones principales, la doble membrana nuclear compuesta de glicerofosfolípidos, esfingolípidos y colesterol; y dentro del núcleo, los lípidos endonucleares están enriquecidos en triacilglicéridos (TAG) y ésteres de colesterol (CE). En particular, los LN nucleares se organizan en la matríz nuclear como Gotas Lipídicas nucleares (nLD), que serían análogas a las gotas lípidicas citosólicas (cLD). Esta hipótesis fue corroborada al observar nLD en el interior de núcleos y matrices aislados de hígado de rata, en hepatocitos de rata y en células HepG2, mediante microscopía de campo claro y de fluorescencia en muestras tratadas con coloraciones específicas para lípidos. Las nLD se caracterizan por ser esferas, de número limitado por núcleo y estar separadas espacialmente de los dominios nucleares nucleolo, Speckles y Paraspeckles y lámina nucleas. Poseen además diámetros menores a los de las cLD. Se elaboró un protocolo para aislar nLD de los demás componentes nucleares y se corroboró la presencia de gotas de lípidos en la fracción aislada por microscopía de campo claro y electrónica con tinciones específicas. Las nLD son estructuras supramoleculares nucleares compuestas principalmente por CE, C, TAG y proteínas, con una baja proporción de lípidos polares. Las nLD constituyen un nuevo dominio nuclear donde los LN se almacenan y organizan y seguramente participan en la homeostasis lipídica nuclear. Las nLD podrían actuar como un sistema buffer endonuclear proveyendo o incorporando lípidos y proteínas involucrados en diferentes procesos. Se determinó que la membrana nuclear corresponde a una zona de fluidez mayor a la de la membrana plasmática y la matriz nuclear es más rígida, utilizando la sonda Laurdan y microscopía de 2 fotones. Para evaluar el mecanismo de incorporación FA exógenos en los lípidos nucleares se incubaron núcleos con distintos [14C]FA y se analizó la incorporación de la radiactividad en los lípidos. Los FA saturados y polinosaturados exógenos estudiados se incorporan como FA y se esterifican en los lípidos nucleares. Los FA no se esterifican directamente a los pooles lipídicos nucleares sino que primero deben ser convertidos en ésteres de CoA. Este proceso es llevado a cabo por acción de acil-CoA sintetasas. Los ácidos 16:0, 18:0, 18:1n-9, 18:2n-6 y 20:4n-6 se esterifican en los lípidos nucleares. Los FA ensayados se incorporan como FA libre tanto en núcleos, membranas nucleares aisladas, matrices nucleares como en las nLD y se esterifican en los lípidos de las mismas (LP y LN en los núcleos, matrices y nLD y LP en las membranas nucleares). Sin embargo, los FA no se esterifican en lípidos de nLD aisladas en las condiciones ensayadas, esto pude deberse a que se necesiten componentes nucleares que se pierden durante el aislamiento o que no haya remodelado de FA dentro de la gota. La L-FABP participa en la movilización y transporte de FA nucleares. Existe un transporte reverso de FA unidos a L-FABP desde los pooles lipídicos nucleares y endonucleares (matrices nucleares) hacia el citosol. La L-FABP moviliza al 20:4n-6, 18:0 y 18:1n-9 fuera del núcleo hacia otros compartimentos celulares. Estimula la movilización y redistribución de los mismos dentro del núcleo entre los diferentes pooles lipídicos. En especial, determina un incremento de 20:4n-6 esterificado en PI. El PI de la matriz nuclear forma parte del activo sistema de transducción de señales del núcleo, y la L-FABP estaría favoreciendo la adecuada composición de este fosfolípido. El 20:4n-6 movilizado por la L-FABP de los pooles endonucleares, podría ser el ligando de factores de transcripción, en particular del PPARα, dado que existe colocalización entre PPARα y L-FABP., Los resultados obtenidos de esta tesis fueron premiados en las Jornadas de Lípidos 2012 de la Facultad de Farmacia y Bioquímica de la Universidad de Buenos Aires (UBA)., Facultad de Ciencias Exactas

Published
2013

157. Biomarkers of acute kidney injury in pediatric cardiac surgery

Author

Nikola Kocev, Amira Peco-Antic, Jelena Kotur-Stevuljevic, Jasmina Ivanisevic, Ivana Ivanisevic, Irena Vulicevic, Milica Miljković, and Slobodan Ilic

Subjects
Male, Clinical Biochemistry, 030232 urology & nephrology, Urine, 030204 cardiovascular system & hematology, urologic and male genital diseases, law.invention, L-FABP, 0302 clinical medicine, law, Hepatitis A Virus Cellular Receptor 1, NGAL, Child, Cardiopulmonary Bypass, Membrane Glycoproteins, biology, Cardiopulmonary bypass, Acute kidney injury, General Medicine, Acute Kidney Injury, female genital diseases and pregnancy complications, Lipocalins, 3. Good health, Cardiac surgery, Child, Preschool, Receptors, Virus, Female, medicine.medical_specialty, Adolescent, Urology, Renal function, Fatty Acid-Binding Proteins, 03 medical and health sciences, Lipocalin-2, Renal Dialysis, Proto-Oncogene Proteins, medicine, Humans, Cystatin C, Receiver operating characteristic, business.industry, Infant, medicine.disease, Surgery, Aortic cross-clamp, biology.protein, business, Biomarkers, Acute-Phase Proteins
Abstract

Objectives Acute kidney injury (AKI) is a significant problem in children undergoing cardiopulmonary bypass (CPB). The aims of this study were to assess the diagnostic validity of serum CysC (sCysC), serum neutrophil gelatinase lipocalin (sNGAL), urine neutrophil gelatinase lipocalin (uNGAL), urine kidney injury molecule (uKIM)-1, and urine liver fatty acid-binding protein (uL-FABP) to predict AKI presence and severity in children undergoing CPB. Design and methods We performed a prospective single-center evaluation of sCysC, sNGAL, uNGAL, uKIM-1 and uL-FABP at 0, 2, 6, 24 and 48 h postoperatively in children undergoing CPB during cardiac surgery. AKI was defined as ≥ 25% decrease in the estimated creatinine clearance (eCCl) from pre-operative baseline at 48 h after surgery. Results Of the 112 patients, 18 patients (16.1%) developed AKI; four of them needed acute dialysis treatment and three AKI patients died. In the AKI compared to the non-AKI group, sCysC at 2 h, and uNGAL and uL-FABP at 2–48 h were significantly increased, as well as CPB, aortic cross clamp time and length of hospital stay. Biomarkers increased with worsening AKI severity. At 2 h after CPB the best accuracy for diagnosis of AKI had uL-FABP and sCysC with area under the receiver operator curve (AUC) of 0.89 and 0.73, respectively. At 6 and 24 h after CPB the best AUC was found for uL-FABP (0.75 and 0.87 respectively) and for uNGAL (0.70 and 0.93, respectively). Conclusions sCysC, uNGAL and uL-FABP are reliable early predictors for AKI after CPB. By allowing earlier timing of injury and earlier intervention, they could improve AKI outcome.

Published
2013

158. L-FABP can be an early marker of acute kidney injury in children

Author

Jelena Kotur-Stevuljevic, Nikola Kocev, Đorđe Hercog, Irena Vulicevic, Amira Peco-Antic, Vladimir Milovanovic, Ivana Ivanisevic, and Aleksandra Stefanović

Subjects
Male, Nephrology, medicine.medical_specialty, medicine.medical_treatment, Urinary system, 030232 urology & nephrology, Urology, 030204 cardiovascular system & hematology, Fatty Acid-Binding Proteins, law.invention, Peritoneal dialysis, 03 medical and health sciences, chemistry.chemical_compound, L-FABP, 0302 clinical medicine, law, Internal medicine, Cardiopulmonary bypass, Humans, Medicine, Renal replacement therapy, Children, Creatinine, Cardiopulmonary Bypass, business.industry, Acute kidney injury, Infant, Postoperative complication, Acute Kidney Injury, medicine.disease, 3. Good health, Surgery, chemistry, Case-Control Studies, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, business
Abstract

Acute kidney injury (AKI) is a common postoperative complication following cardiopulmonary bypass (CPB) surgery. New biomarkers to identify patients with early AKI (before increases in serum creatinine) are needed to facilitate appropriate treatment. This study aimed to test the role of urinary liver fatty-acid-binding protein (L-FABP) as an early biomarker for AKI in children undergoing CPB surgery. This is a case–control study of children undergoing CPB. AKI was defined as 50 % increase in serum creatinine at 48 h after surgery. For each patient, five serum and urine samples were obtained corresponding to time 0 h (presurgery) and 2, 6, 24, and 48 h after surgery. Twenty-seven patients, median age 360 days, were enrolled. AKI developed in 11 patients (41 %); three needed renal replacement therapy (peritoneal dialysis); there were two deaths. There were significant differences between patients with and without AKI in L-FABP levels at 2, 6, and 48 h after surgery, length of hospital stay, and CPB time; there were no differences in gender, patient age, and body weight. L-FABP was normalized to urinary creatinine concentration at all time points, with area under the receiver operator curve (AUC ROC) 0.867 at 2 and 6 h postoperatively. Correlation coefficient between L-FABP and length of hospital stay after surgery was statistically significant (r = 0.722, p value = 0.000). Our results suggest that urinary L-FABP can be used to diagnose AKI earlier than rise in serum creatinine in children undergoing CPB.

Published
2013

159. Protective effects of L-type fatty acid-binding protein (L-FABP) in proximal tubular cells against glomerular injury in anti-GBM antibody-mediated glomerulonephritis

Author

Yasuhiko Kanaguchi, Takeshi Sugaya, Yasuhiko Tomino, Ken Osaki, Satoshi Horikoshi, and Yusuke Suzuki

Subjects
medicine.medical_treatment, Fatty Acids, Nonesterified, medicine.disease_cause, Kidney Tubules, Proximal, Mice, L-FABP, Glomerulonephritis, Transforming Growth Factor beta, II. Scientific Papers, Medicine, oxidative stress, Chemokine CCL2, Mice, Inbred BALB C, Survival Rate, Proteinuria, Cytokine, Nephrology, tubulointerstitial damage, Mesangial proliferative glomerulonephritis, Cytokines, Tumor necrosis factor alpha, Female, medicine.symptom, medicine.medical_specialty, Blotting, Western, Inflammation, Mice, Transgenic, Cysteine Proteinase Inhibitors, Fatty Acid-Binding Proteins, Real-Time Polymerase Chain Reaction, Fatty acid-binding protein, Proinflammatory cytokine, Angiotensin Receptor Antagonists, Internal medicine, Animals, Humans, RNA, Messenger, Autoantibodies, Transplantation, Aldehydes, business.industry, Tumor Necrosis Factor-alpha, Original Articles, medicine.disease, Mice, Inbred C57BL, PPAR gamma, Endocrinology, Experimental Nephrology, Mice, Inbred CBA, Nephritis, Interstitial, business, Oxidative stress
Abstract

Background. In glomerulonephritis (GN), an overload of free fatty acids (FFA) bound to albumin in urinary protein may induce oxidative stress in the proximal tubules. Human liver-type fatty acid-binding protein (hL-FABP) expressed in human proximal tubules, but not rodents, participates in intracellular FFA metabolism and exerts anti-oxidative effects on the progression of tubulointerstitial damage. We examined whether tubular enhancement of this anti-oxidative action modulates the progression of glomerular damage in immune-mediated GN in hL-FABP chromosomal gene transgenic (Tg) mice. Methods. Anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM GN) was induced in Tg and wild-type mice (WT). Proteinuria, histopathology, polymorphonuclear (PMN) influx, expression of tubulointerstitial markers for oxidative stress 4-hydroxy-2-Nonenal (HNE) and fibrosis (α-smooth muscle actin), proximal tubular damage (Kim-1), Peroxisome Proliferator-Activated Receptor γ (PPAR γ) and inflammatory cytokines [Monocyte Chemotactic Protein-1, tumor necrosis factor-alpha (TNF-α) and Transforming growth factor beta (TGF-β)] were analyzed. The mice were also treated with an angiotensin type II receptor blocker (ARB). Results. The urinary protein level in Tg mice decreased significantly during the acute phase (∼Day 5). Tg mice survived for a significantly longer time than WT mice, with an attenuation of tubulointerstitial damage score and expression of each tubulointerstitial damage marker observed at Day 7. Expression of inflammatory cytokines on Day 7 was higher in WT mice than Tg mice and correlated strongly with PPARγ expression in WT mice, but not in Tg mice. Interestingly, Tg mice showed insufficient PMN influx at 3 and 6 h, with simultaneous elevation of urinary L-FABP and reduction in HNE expression. The two strains of mice showed different types of glomerular damage, with mild mesangial proliferation in Tg mice and severe endothelial swelling with vascular thrombosis in WT mice. The glomerular damage in Tg mice was improved by administration of an ARB. Conclusions. The present experimental model suggests that tubular enhancement of L-FABP may protect mice with anti-GBM GN from progression of both tubulointerstitial and glomerular injury.

Published
2011

160. Role of liver fatty acid binding protein in fatty liver cell culture model

Author

Gong, Yuewen (Pharmacy) Minuk, Gerald Y (Pharmacology and Therapeutics), Burczynski, Frank J (Pharmacy), Chen, Yufei, Gong, Yuewen (Pharmacy) Minuk, Gerald Y (Pharmacology and Therapeutics), Burczynski, Frank J (Pharmacy), and Chen, Yufei

Abstract

Liver fatty acid binding protein has been reported to possess antioxidant properties in the liver. The aim of this study was to investigate the effect of this protein in a nonalcoholic fatty liver disease (NAFLD) cell culture model. Rat hepatoma cells were treated with an oleate:palmitate (2:1) mixture for either 1 and 2 days, or further treated with 500 µM clofibrate to induce L-FABP expression. Intracellular lipid accumulation was quantitated by Nile Red. Lipotoxicity was determined using the WST-1 assay. Dichlorofluorescein (DCF) was utilized to assess intracellular reactive oxidative species (ROS) level. Measurement of lipotoxicity showed statistical decreases in cell viability as lipid concentrations increased in a dose-dependent manner. NAFLD cell cultures showed characteristic cellular damage from increased ROS levels in fatty acid treated cells. All groups treated with clofibrate showed statistically increased intracellular L-FABP levels and reduced ROS levels. The results lead to the conclusion that clofibrate induces L-FABP expression and in this manner suppresses hepatocellular ROS generation.

Published
2012

162. Performance of Serum Creatinine and Kidney Injury Biomarkers for Diagnosing Histologic Acute Tubular Injury.

Author

Moledina DG, Hall IE, Thiessen-Philbrook H, Reese PP, Weng FL, Schröppel B, Doshi MD, Wilson FP, Coca SG, and Parikh CR

Subjects
Acute Kidney Injury diagnosis, Acute Kidney Injury pathology, Adult, Area Under Curve, Biomarkers metabolism, Cohort Studies, Cross-Sectional Studies, Female, Humans, Kidney Transplantation, Kidney Tubules pathology, Male, Middle Aged, Prospective Studies, ROC Curve, Severity of Illness Index, Acute Kidney Injury metabolism, Creatinine blood, Fatty Acid-Binding Proteins urine, Hepatitis A Virus Cellular Receptor 1 metabolism, Interleukin-18 urine, Lipocalin-2 urine, Tissue Donors
Abstract

Background: The diagnosis of acute kidney injury (AKI), which is currently defined as an increase in serum creatinine (Scr) concentration, provides little information on the condition's actual cause. To improve phenotyping of AKI, many urinary biomarkers of tubular injury are being investigated. Because AKI cases are not frequently biopsied, the diagnostic accuracy of concentrations of Scr and urinary biomarkers for histologic acute tubular injury is unknown., Study Design: Cross-sectional analysis from multicenter prospective cohort., Settings & Participants: Hospitalized deceased kidney donors on whom kidney biopsies were performed at the time of organ procurement for histologic evaluation., Predictors: (1) AKI diagnosed by change in Scr concentration during donor hospitalization and (2) concentrations of urinary biomarkers (neutrophil gelatinase-associated lipocalin [NGAL], liver-type fatty acid-binding protein [L-FABP], interleukin 18 [IL-18], and kidney injury molecule 1 [KIM-1]) measured at organ procurement., Outcome: Histologic acute tubular injury., Results: Of 581 donors, 98 (17%) had mild acute tubular injury and 57 (10%) had severe acute tubular injury. Overall, Scr-based AKI had poor diagnostic performance for identifying histologic acute tubular injury and 49% of donors with severe acute tubular injury did not have AKI. The area under the receiver operating characteristic curve (AUROC) of change in Scr concentration for diagnosing severe acute tubular injury was 0.58 (95% CI, 0.49-0.67) and for any acute tubular injury was 0.52 (95% CI, 0.45-0.58). Compared with Scr concentration, NGAL concentration demonstrated higher AUROC for diagnosing both severe acute tubular injury (0.67; 95% CI, 0.60-0.74; P=0.03) and any acute tubular injury (0.60; 95% CI, 0.55-0.66; P=0.005). In donors who did not have Scr-based AKI, NGAL concentrations were higher with increasing severities of acute tubular injury (subclinical AKI). However, compared with Scr concentration, AUROCs for acute tubular injury diagnosis were not significantly higher for urinary L-FABP, IL-18, or KIM-1., Limitations: The spectrum of AKI cause in deceased donors may be different from that of a general hospitalized population., Conclusions: Concentrations of Scr and kidney injury biomarkers (L-FABP, IL-18, and KIM-1) lack accuracy for diagnosing acute tubular injury in hospitalized deceased donors. Although urinary NGAL concentration had slightly higher discrimination for acute tubular injury than did Scr concentration, its overall AUROC was still modest., (Published by Elsevier Inc.)

Published
2017
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163. Output of liver fatty acid-binding protein (L-FABP) in bile

Author

Nicole Domingo, Joël Grillasca, Philippe Besnard, Huguette Lafont, Laurent Foucaud, Richard Planells, Isabelle Niot, Laboratoire de Physiologie de la Nutrition, Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Unité de Recherche sur le Transport des Lipides, Institut National de la Santé et de la Recherche Médicale (INSERM), and Dijon, Institut Agro

Subjects
Male, medicine.drug_class, Nerve Tissue Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Fatty Acid-Binding Proteins, Myelin P2 Protein, Fatty acid-binding protein, Mice, 03 medical and health sciences, chemistry.chemical_compound, L-FABP, Cytosol, Biosynthesis, Immunochemistry, medicine, Animals, Humans, Bile, Rats, Wistar, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, 0303 health sciences, Liver fatty acid binding protein, Bile acid, Tumor Suppressor Proteins, Fatty Acids, 030302 biochemistry & molecular biology, Gallbladder, Cell Biology, Molecular biology, G protein-coupled bile acid receptor, Neoplasm Proteins, Rats, Molecular Weight, Blot, Liver, Biochemistry, chemistry, Cytoplasm, lipids (amino acids, peptides, and proteins), Carrier Proteins, Fatty Acid-Binding Protein 7
Abstract

International audience; Liver fatty acid-binding protein (L-FABP) is a small cytoplasmic molecule highly expressed in the liver. Since L-FABP exhibits affinities for several biliary components, its presence in bile was explored by Western blotting and competitive ELISA in various mammalian species. A L-FABP-like immunoreactivity was consistently found in both hepatic and gallbladder bile. A close molecular identity between this 14 kDa biliary protein and the purified L-FABP was assessed by immunological analyses and high performance capillary electrophoresis. Pharmacological induction of hepatic L-FABP biosynthesis led to a similar increase in biliary L-FABP levels showing a close relationships between the cytosolic and biliary contents of this protein. Finally, a correlation between the presence of L-FABP in bile and both bile flow and bile acid release was found. These data suggest an output of L-FABP in bile in normal conditions which might be coupled with the physiological release of biliary components.

Published
1999

164. Follow Up of Value of the Intrarenal Resistivity Indices and Different Renal Biomarkers for Early Identification of Diabetic Nephropathy in Type 1 Diabetic Patients.

Author

Dayem SAE, Bohy AEME, Hamed M, and Ahmed S

Abstract

Aim: To evaluate intrarenal resistivity index (RI) and different biomarkers of diabetic nephropathy (DN) with clinical signs of DN and its progression over time as early detection of DN., Patients and Methods: This longitudinal study included 48 type 1 diabetic patients who were studied at baseline and after three years. A blood sample was taken for assessment of glycosylated haemoglobin (HbA1), lipid profile and a urine sample was taken for assessment of albumin/creatinine ratio, Neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty acid binding protein (L-FABP) and kidney injury molecule-1 (Kim-1) at baseline and after three years. Forty diabetic patients did renal Doppler at baseline & after three years., Results: HbA1, waist/hip ratio, albumin/creatinine ratio, lipid profile, NGAL, KIM-1, L-FABP and resistivity index (RI) were significantly increased in follow-up. Twenty patients (41.7%) showed progression to albuminuria. RI showed a significant increase in follow-up study. ROC curve showed that RI and NGAL had the highest sensitivity (100%), followed by L-FABP (90%) and lastly KIM-1 (63.6%) in the prediction of DN., Conclusion: High RI, NGAL, KIM-1 & L-FABP can be considered as early markers of diabetic nephropathy in type 1 diabetics and are associated with its progression over time, independent of albuminuria.

Published
2017
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165. [Effects of Gubentongluo Formula on Oxidative Stress Reflected by Expressions of PPARα and L-FABP in Mice with IgA Nephropathy].

Author

Li WW, Huang D, Shen PC, Wu Q, Sun C, Wang XX, and He LQ

Subjects
Animals, Glomerulonephritis, IGA metabolism, Mice, Mice, Inbred C57BL, Random Allocation, Drugs, Chinese Herbal pharmacology, Fatty Acid-Binding Proteins metabolism, Glomerulonephritis, IGA drug therapy, Oxidative Stress, PPAR alpha metabolism
Abstract

Objectives: To determine the underlying mechanism of Gubentongluo Formula in the treatment of IgA nephropathy (IgAN)., Methods: C57BL/6 mice were randomly divided into four groups: normal group ( n =10), IgAN group ( n =10), control group ( n =10) and treatment group ( n =10). Mice in the normal and IgAN groups were intragastricly administered with normal saline for 12 weeks; while those in the control and treatment groups were given fenofibrate [30 mg/(kg!$d) and Gubentongluo Formula [1.67 mL/(g!$d)], respectively. Urinary albumin was detected at week 0 and 12. At week 12, protein expressions of peroxisome proliferstor activated receptor α (PPARα), liver fatty acid-binding proteins (L-FABP), 4-hydroxy-2-nonenal (4-HNE), and hemeoxygenase-1(HO-1) in renal tissues were determined by Western blot; mRNA expressions of PPARα and L-FABP in renal tissues were determined by florescent quantitative reverse transcription-polymerase chain reaction (qRT-PCR)., Results: At week 12, higher levels of urinary albumin, pathological injuries in glomerular mesangial area, and lower expressions of protein and mRNA of PPARα and L-FABP were found in mice in the IgAN group compared with those in the normal group ( P <0.01). The levels of those indicators decreased in those treated with fenofibrate and Gubentongluo Formule, but still higher than the normal controls ( P <0.01). The mice treated with Gubentongluo Formula had more significant improvement than those treated with fenofibrate ( P <0.05)., Conclusion: [CM(155.3mm]Gubentongluo formula can improve proteinuria and pathological injuries in glomerular mesangial area of IgAN mice, due to reduction of oxidative stress in renal tissues through regulating the expressions of PPARα and L-FABP.

Published
2017

166. Biomarkers for Early Diagnosis of Acute Kidney Injury: Current Progress and Clinical Prospects.

Author

Huang HF, Zhou JY, and Chen JH

Subjects
Acute Kidney Injury blood, Acute Kidney Injury pathology, Acute Kidney Injury urine, Biomarkers blood, Biomarkers urine, Creatinine blood, Critical Illness, Early Diagnosis, Glomerular Filtration Rate, Humans, Interleukin-18 blood, Predictive Value of Tests, Sodium-Hydrogen Exchanger 3, Urinalysis, Acute Kidney Injury diagnosis, Cystatin C blood, Fatty Acid-Binding Proteins urine, Hepatitis A Virus Cellular Receptor 1 metabolism, Interleukin-18 urine, Lipocalin-2 urine, Sodium-Hydrogen Exchangers urine
Abstract

Acute kidney injury (AKI) is one of the most common complications in critically ill patients, resulting in high morbidity and mortality. AKI usually occurs after major surgery, severe infection or drug-induced nephrotoxicity and is associated with prolonged hospital stays, increased costs and adverse clinical outcomes. The diagnosis of AKI is currently based on decreased glomerular filtration rate (GFR) and urine output, and increased serum creatinine. Novel biomarkers are required for early identification of patients with AKI to allow timely therapy and improve patient outcomes. With the advent of proteomics and genomics techniques, a vast array of biomarkers are now available in clinical practice., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Published
2017
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167. Liver fatty acid-binding protein in two cases of human lipid storage

Author

Maurizio Rosa, Rosalba Carrozzo, A. Galassi, Corrado Angelini, Lodovica Vergani, Andrea Martinuzzi, Marina Fanin, and Andrea Appi

Subjects
Male, medicine.medical_specialty, Adolescent, Clinical chemistry, Clinical Biochemistry, Enzyme-Linked Immunosorbent Assay, Biology, Fatty Acid-Binding Proteins, Antibodies, Lipid Metabolism, Inborn Errors, Pathogenesis, L-FABP, multisystemic lipid storage, Internal medicine, FABP, fatty liver, Reye's syndrome, medicine, Animals, Humans, Molecular Biology, chemistry.chemical_classification, Liver Diseases, Reye Syndrome, Tumor Suppressor Proteins, Fatty liver, Fatty acid, Lipid metabolism, Cell Biology, General Medicine, Metabolism, Middle Aged, medicine.disease, Neoplasm Proteins, Endocrinology, chemistry, Liver, lipids (amino acids, peptides, and proteins), Female, Carrier Proteins, Fatty Acid-Binding Protein 7, Chickens, Intracellular
Abstract

FABPs in the various tissues play an important role in the intracellular fatty acid transport and metabolism. Reye's syndrome (RS) and multisystemic lipid storage (MLS) are human disorders characterized by a disturbance of lipid metabolism of unknown etiology. We investigated for the first time L-FABP in these two conditions. Affinity purified antibodies against chicken L-FABP were raised in rabbits, and found to cross-react specifically with partially purified human L-FABP. L-FABP content in liver samples of two patients with RS and MLS was investigated by immuno-histochemistry, SDS-PAGE and ELISA. L-FABP immuno-histochemistry showed increased reactivity in the liver of RS patient and normal reactivity in MLS liver. L-FABP increase in RS liver was confirmed by densitometry of SDS-PAGE and ELISA method. By these two methods the increase amounted to 180% and 199% (p less than 0.02), respectively, as compared to controls. A possible role of L-FABP in the pathogenesis of RS is discussed.

Published
1990

168. Urinary levels of early kidney injury molecules in children with vitamin B12 deficiency.

Author

Güneş A, Aktar F, Tan İ, Söker M, Uluca Ü, Balık H, and Mete N

Subjects
Adolescent, Biomarkers urine, Child, Child, Preschool, Cross-Sectional Studies, Female, Humans, Infant, Kidney Diseases etiology, Male, Vitamin B 12 Deficiency complications, Kidney Diseases urine, Vitamin B 12 Deficiency urine
Abstract

The aim of this study was to investigate urine early kidney injury molecules, including human kidney injury molecule-1 (KIM-1), liver-type fatty-acid binding protein (L-FABP), N-acetyl-b-D-glucosaminidase A (NAG), and neutrophil gelatinase-associated lipocalin (NGAL) in children with vitamin B12 (cobalamin) deficiency (CD). Twelve children with vitamin B12 deficiency and 20 healthy matched controls were included. Hematologic parameters, serum urea, creatinine (Cr), electrolytes, B12 and folate levels were recorded. Estimated glomerular filtration rate (eGFR) was calculated. Urine protein, electrolytes, andurinary early markers were measured. Patients with CD had significantly higher urine electrolyte/Cr ratios (p <0.05). Significantly higher urinary KIM-1/Cr, L-FABP/Cr, NAG/Cr and NGAL/Cr were found in CD group (p <0.05). Significant negative correlations were found between levels of serum B12 and urinary markers in the patients (p <0.05). Increased urinary kidney injury molecules and electrolytes in children with B12 deficiency suggest a possible subclinical renal dysfunction, which cannot be determined by conventional kidney function tests., (Sociedad Argentina de Pediatría.)

Published
2016
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169. Microarray analysis of gene expression in liver, adipose tissue and skeletal muscle in response to chronic dietary administration of NDGA to high-fructose fed dyslipidemic rats.

Author

Zhang H, Shen WJ, Li Y, Bittner A, Bittner S, Tabassum J, Cortez YF, Kraemer FB, and Azhar S

Abstract

Nordihydroguaiaretic acid (NDGA), the main metabolite of Creosote Bush, has been shown to have profound effects on the core components of metabolic syndrome, including lowering of blood glucose, free fatty acids and triglyceride levels, attenuating elevated blood pressure in several rodent models of dyslipidemia, and improving body weight, insulin resistance, diabetes and hypertension. In the present study, a high-fructose diet fed rat model of hypertriglyceridemia, dyslipidemia, insulin resistance and hepatic steatosis was employed to investigate the global transcriptional changes in the lipid metabolizing pathways in three insulin sensitive tissues: liver, skeletal muscle and adipose tissue in response to chronic dietary administration of NDGA. Sprague-Dawley male rats (SD) were fed a chow (control) diet, high-fructose diet (HFrD) or HFrD supplemented with NDGA (2.5 g/kg diet) for eight weeks. Dietary administration of NDGA decreased plasma levels of TG, glucose, and insulin, and attenuated hepatic TG accumulation. DNA microarray expression profiling indicated that dietary administration of NDGA upregulated the expression of certain genes involved in fatty acid oxidation and their transcription regulator, PPARα, decreased the expression of a number of lipogenic genes and relevant transcription factors, and differentially impacted the genes of fatty acid transporters, acetyl CoA synthetases, elongases, fatty acid desaturases and lipid clearance proteins in liver, skeletal muscle and adipose tissues. These findings suggest that NDGA ameliorates hypertriglyceridemia and steatosis primarily by inhibiting lipogenesis and enhancing fatty acid catabolism in three major insulin responsive tissues by altering the expression of key enzyme genes and transcription factors involved in de novo lipogenesis and fatty acid oxidation.

Published
2016
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170. Elevation of urinary liver-type fatty acid binding protein after cardiac catheterization related to cardiovascular events.

Author

Kamijo-Ikemori A, Hashimoto N, Sugaya T, Matsui K, Hisamichi M, Shibagaki Y, Miyake F, and Kimura K

Abstract

Purpose: Contrast medium (CM) induces tubular hypoxia via endothelial damage due to direct cytotoxicity or viscosity. Urinary liver-type fatty acid binding protein (L-FABP) increases along with tubular hypoxia and may be a detector of systemic circulation injury. The aim of this study was to evaluate the clinical usefulness of detecting increases in urinary L-FABP levels due to administration of CM, as a prognostic biomarker for cardiovascular disease in patients without occurrence of CM-induced nephropathy undergoing cardiac catheterization procedure (CCP)., Methods: Retrospective longitudinal analyses of the relationship between urinary L-FABP levels and occurrence of cardiovascular events were performed (n=29). Urinary L-FABP was measured by ELISA before CCP, and at 6, 12, 24, and 48 hours after CCP., Results: Urinary L-FABP levels were significantly higher at 12 hours (P<0.05) and 24 hours (P<0.005) after CCP compared with before CCP, only in the patients with occurrence of cardiovascular events (n=17), but not in those without cardiovascular events (n=12). The parameter with the largest area under the curve (0.816) for predicting the occurrence of cardiovascular events was the change in urinary L-FABP at 24 hours after CCP. The difference in urinary L-FABP levels (ΔL-FABP ≥11.0 μg/g creatinine) between before CCP and at 24 hours after CCP was a risk factor for the occurrence of cardiovascular events (hazard ratio, 4.93; 95% confidence interval, 1.27-19.13; P=0.021)., Conclusion: Measurement of urinary L-FABP before CCP and at 24 hours after CCP in patients with mild to moderate renal dysfunction may be an important indicator for risk stratification of onset of cardiovascular events.

Published
2015
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171. Detection and evaluation of renal biomarkers in a swine model of acute myocardial infarction and reperfusion.

Author

Duan SY, Xing CY, Zhang B, and Chen Y

Subjects
Acute Kidney Injury blood, Acute Kidney Injury prevention & control, Acute Kidney Injury urine, Animals, Biomarkers blood, Biomarkers urine, Cardio-Renal Syndrome blood, Cardio-Renal Syndrome therapy, Cardio-Renal Syndrome urine, Disease Models, Animal, Fatty Acid-Binding Proteins blood, Fatty Acid-Binding Proteins urine, Interleukin-18 blood, Interleukin-18 urine, Kidney pathology, Lipocalins blood, Lipocalins urine, Myocardial Infarction blood, Myocardial Infarction therapy, Myocardial Infarction urine, Myocardial Reperfusion Injury blood, Myocardial Reperfusion Injury therapy, Myocardial Reperfusion Injury urine, Swine, Time Factors, Acute Kidney Injury metabolism, Cardio-Renal Syndrome metabolism, Kidney metabolism, Myocardial Infarction metabolism, Myocardial Reperfusion Injury metabolism
Abstract

The prevalence of type 1 cardiorenal syndrome (CRS) is increasing and strongly associated with long-term mortality. However, lack of reliable animal models and well-defined measures of renoprotection, made early diagnosis and therapy difficult. We previously successfully established the swine acute myocardial infarction (AMI) model of ischemia-reperfusion by blocking left anterior descending branch (LAD). Reperfusion was performed after 90-minute occlusion of the LAD. AMI was confirmed by ECG and left ventricular angiography (LVG). Then those 52 survived AMI reperfusion swine, including ventricular fibrillation-cardiac arrest after restoration of blood flow, were randomly divided into four groups (four/group) according to different interventions: resuscitation in room temperature, resuscitation with 500 ml saline in room temperature, resuscitation with 4°C 500 ml saline and normal control (with no intervention of resuscitation). Each group was further observed in four groups according to different time of resuscitation after ventricular arrhythmias: 1, 3, 5, 10-minute reperfusion after ventricular arrhythmias. Plasma and random urine were collected to evaluate renal function and test renal biomarkers of acute kidney injury (AKI). Our swine AMI model of ischemia-reperfusion provoked subclinical AKI with the elevation of the tubular damage biomarker, NGAL, IL-18 and L-FABP. Renal damage rapidly observed after hemodynamic instability, rather than observation after several hours as previously reported. The increasing rate of biological markers declined after interventions, however, its impact on the long-term prognosis remains to be further studied. These data show that elevation of tubular damage biomarkers without glomerular function loss may indicate appropriate timing for effective renoprotections like hypothermia resuscitation in type 1 CRS.

Published
2015

172. Human liver-type fatty acid-binding protein protects against tubulointerstitial injury in aldosterone-induced renal injury.

Author

Ichikawa D, Kamijo-Ikemori A, Sugaya T, Shibagaki Y, Yasuda T, Hoshino S, Katayama K, Igarashi-Migitaka J, Hirata K, and Kimura K

Subjects
Aldosterone administration & dosage, Angiotensinogen metabolism, Animals, Blood Pressure drug effects, Chemokine CCL2 metabolism, Collagen Type I metabolism, Collagen Type III metabolism, Disease Models, Animal, Kidney metabolism, Kidney pathology, Macrophages pathology, Male, Mice, Mice, Transgenic, Oxidative Stress, Renal Insufficiency pathology, Renal Insufficiency physiopathology, Aldosterone metabolism, Fatty Acid-Binding Proteins metabolism, Renal Insufficiency metabolism, Renin-Angiotensin System
Abstract

To demonstrate the renoprotective function of human liver-type fatty acid-binding protein (hL-FABP) expressed in proximal tubules in aldosterone (Aldo)-induced renal injury, hL-FABP chromosomal transgenic (Tg) and wild-type (WT) mice received systemic Aldo infusions (Tg-Aldo and WT-Aldo, respectively) were given 1% NaCl water for 28 days. In this model, elevation of systolic blood pressure, monocyte chemoattractant protein-1 expression, macrophage infiltration in the interstitium, tubulointerstitial damage, and depositions of type I and III collagens were observed. Elevation of systolic blood pressure did not differ in WT-Aldo vs. Tg-Aldo animals, however, renal injury was suppressed in Tg-Aldo compared with WT-Aldo mice. Dihydroethidium fluorescence was used to evaluate reactive oxidative stress, which was suppressed in Tg-Aldo compared with WT-Aldo mice. Gene expression of angiotensinogen in the kidney was upregulated, and excretion of urinary angiotensinogen was increased in WT-Aldo mice. This exacerbation was suppressed in Tg-Aldo mice. Expression of hL-FABP was upregulated in proximal tubules of Tg-Aldo mice. Urinary excretion of hL-FABP was significantly greater in Tg-Aldo than in Tg-control mice. In conclusion, hL-FABP ameliorated the tubulointerstitial damage in Aldo-induced renal injury via reducing oxidative stress and suppressing activation of the intrarenal renin-angiotensin system., (Copyright © 2015 the American Physiological Society.)

Published
2015
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173. Serum levels of interleukin-8 and gut-associated biomarkers in diagnosing necrotizing enterocolitis in preterm infants.

Author

Benkoe TM, Mechtler TP, Weninger M, Pones M, Rebhandl W, and Kasper DC

Subjects
Biomarkers blood, Enterocolitis, Necrotizing blood, Female, Humans, Infant, Infant, Newborn, Male, Prospective Studies, Enterocolitis, Necrotizing diagnosis, Fatty Acid-Binding Proteins blood, Infant, Premature blood, Interleukin-8 blood
Abstract

Background: In recent years several potential biochemical markers have been evaluated to facilitate a reliable diagnosis of necrotizing enterocolitis (NEC), but none have made progress to clinical routine. We performed a comparative assessment in premature infants to evaluate the diagnostic value of the routinely available cytokine interleukin (IL)-8, and two promising experimental biomarkers, the gut barrier proteins liver fatty acid binding protein (L-FABP) and intestinal fatty acid binding protein (I-FABP), respectively, for the diagnosis of NEC., Methods: IL-8, L-FABP, and I-FABP concentrations were analyzed in the serum of 15 infants with NEC and compared with 14 gestational age-matched infants serving as a control group., Results: Serum concentrations of I-FABP, L-FABP and IL-8 were significantly higher in infants with NEC compared with controls. IL-8 showed the highest diagnostic value with an area under the curve of 0.99, followed by L-FABP and I-FABP. In addition we found a significant correlation between IL-8 and both FABPs in infants with NEC., Conclusion: Our results further advocate the possible role of IL-8 as a specific marker for NEC. The diagnostic value of IL-8 seems to be superior to I-FABP, and similar to L-FABP. The routinely availability facilitates IL-8 as a possible candidate for further clinical investigations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Published
2014
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174. Biomarkers of Contrast-Induced Nephropathy: Which Ones and What Is Their Clinical Relevance?

Author

Malyszko J, Bachorzewska-Gajewska H, and Dobrzycki S

Abstract

Contrast-induced nephropathy, or contrast-induced acute kidney injury (AKI), is an acute impairment of renal function as manifested by an increase in serum creatinine. Different urinary and serum proteins have been intensively investigated as possible biomarkers for the early diagnosis of AKI. Promising candidate biomarkers have the ability to detect an early and graded increase in tubular epithelial cell injury and to distinguish prerenal causes of AKI from acute tubular necrosis. In this article new, emerging biomarkers of contrast-induced AKI are presented and described, of which serum neutrophil gelatinase-associated lipocalin appears to be the most promising., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Published
2014
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175. Renoprotective effect of renal liver-type fatty acid binding protein and angiotensin II type 1a receptor loss in renal injury caused by RAS activation.

Author

Ichikawa D, Kamijo-Ikemori A, Sugaya T, Shibagaki Y, Yasuda T, Katayama K, Hoshino S, Igarashi-Migitaka J, Hirata K, and Kimura K

Subjects
Animals, Humans, Male, Mice, Mice, Knockout, Mice, Transgenic, Reactive Oxygen Species metabolism, Renal Insufficiency, Chronic pathology, Sodium Chloride, Dietary administration & dosage, Fatty Acid-Binding Proteins metabolism, Receptor, Angiotensin, Type 1 biosynthesis, Renal Insufficiency, Chronic prevention & control, Renin-Angiotensin System physiology
Abstract

The aim of this study was to assess the renoprotective effect of renal human liver-type fatty acid binding protein (hL-FABP) and angiotensin II (ANG II) type 1A receptor (AT1a) loss in renal injury caused by renin-angiotensin system (RAS) activation. We established hL-FABP chromosomal transgenic mice (L-FABP(+/-)AT1a(+/+)), crossed the L-FABP(+/-)AT1a(+/+) with AT1a knockdown homo mice (L-FABP(-/-)AT1a(-/-)), and generated L-FABP(+/-)AT1a hetero mice (L-FABP(+/-)AT1a(+/-)). After the back-cross of these cubs, L-FABP(+/-)AT1a(-/-) were obtained. To activate the renal RAS, wild-type mice (L-FABP(-/-)AT1a(+/+)), L-FABP(+/-)AT1a(+/+), L-FABP(-/-)AT1a(+/-), L-FABP(+/-)AT1a(+/-), L-FABP(-/-)AT1a(-/-), and L-FABP(+/-)AT1a(-/-) were administered high-dose systemic ANG II infusion plus a high-salt diet for 28 days. In the L-FABP(-/-)AT1a(+/+), RAS activation (L-FABP(-/-)AT1a(+/+)RAS) caused hypertension and tubulointerstitial damage. In the L-FABP(+/-)AT1a(+/+)RAS, tubulointerstitial damage was significantly attenuated compared with L-FABP(-/-)AT1a(+/+)RAS. In the AT1a partial knockout (AT1a(+/-)) or complete knockout (AT1a(-/-)) mice, reduction of AT1a expression led to a significantly lower degree of renal injury compared with L-FABP(-/-)AT1a(+/+)RAS or L-FABP(+/-)AT1a(+/+)RAS mice. Renal injury in L-FABP(+/-)AT1a(+/-)RAS mice was significantly attenuated compared with L-FABP(-/-)AT1a(+/-)RAS mice. In both L-FABP(-/-)AT1a(-/-)RAS and L-FABP(+/-)AT1a(-/-)RAS mice, renal damage was rarely found. The degrees of renal hL-FABP expression and urinary hL-FABP levels increased by RAS activation and gradually decreased along with reduction of AT1a expression levels. In conclusion, in this mouse model, renal hL-FABP expression and a decrease in AT1a expression attenuated tubulointerstitial damage due to RAS activation.

Published
2014
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176. Low levels of urinary liver-type fatty acid-binding protein may indicate a lack of kidney protection during aortic arch surgery requiring hypothermic circulatory arrest.

Author

Mori Y, Sato N, Kobayashi Y, and Ochiai R

Subjects
Aged, Aged, 80 and over, Biomarkers, Creatinine blood, Female, Humans, Male, Middle Aged, Prospective Studies, Acute Kidney Injury urine, Aorta, Thoracic surgery, Fatty Acid-Binding Proteins urine, Heart Arrest, Induced, Postoperative Complications urine
Abstract

Study Objective: To examine the change in liver-type fatty acid-binding protein (L-FABP) levels in patients undergoing aortic arch surgery and the correlation between L-FABP and postoperative acute kidney injury., Design: Prospective observational study., Setting: Operating room of a general hospital., Patients: 36 adult patients., Interventions and Measurements: Urine samples were obtained to measure urinary L-FABP at initiation of cardiopulmonary bypass (CPB) and 5 minutes after termination of hypothermic circulatory arrest., Main Results: 22 (61.1%) patients developed acute kidney injury within a 48-hour period. L-FABP increases more than a thousand-fold were found. In patients who subsequently developed acute kidney injury, significant increases in L-FABP were noted from 2.9 (3.6) ng/mg of creatinine before CPB to 62.1 (995.6) ng/mg of creatinine 5 minutes after termination of circulatory arrest. Values in patients who did not develop acute kidney injury increased from 1.1 (5.7) ng/mg before CPB to 1133.0 (6358.8) ng/mg of creatinine showing a significant mean difference (P = 0.011). The area under the L-FABP receiver operating characteristic curve at 5 minutes after termination of circulatory arrest was 0.758. A cutoff value of 75.13 ng/mg of creatinine yielded both good sensitivity (1.000) and specificity (0.546) for detecting non-acute kidney injury. Patients who developed acute kidney injury after aortic arch surgery demonstrated lower levels of urinary L-FABP., Conclusions: Low levels of urinary L-FABP may indicate kidney injury and lack of renal protection., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Published
2014
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177. Fatty acid synthase mediates the epithelial-mesenchymal transition of breast cancer cells.

Author

Li J, Dong L, Wei D, Wang X, Zhang S, and Li H

Subjects
Animals, Cell Movement drug effects, Cerulenin pharmacology, Fatty Acid Synthesis Inhibitors pharmacology, Fatty Acid-Binding Proteins metabolism, Female, Gene Expression drug effects, Humans, MAP Kinase Kinase 5 genetics, MAP Kinase Kinase 5 metabolism, MCF-7 Cells, Mice, Mice, Nude, Vascular Endothelial Growth Factor A metabolism, Breast Neoplasms pathology, Epithelial-Mesenchymal Transition physiology, Fatty Acid Synthases physiology
Abstract

This study aimed to investigate the role of fatty acid synthase (FASN) in the epithelial-mesenchymal transition (EMT) of breast cancer cells. MCF-7 cells and MCF-7 cells overexpressing mitogen-activated protein kinase 5 (MCF-7-MEK5) were used in this study. MCF-7-MEK5 cells showed stable EMT characterized by increased vimentin and decreased E-cadherin expression. An In vivo animal model was established using the orthotopic injection of MCF-7 or MCF-7-MEK5 cells. Real-time quantitative PCR and western blotting were used to detect the expression levels of FASN and its downstream proteins liver fatty acid-binding protein (L-FABP) and VEGF/VEGFR-2 in both in vitro and in vivo models (nude mouse tumor tissues). In MCF-7-MEK5 cells, significantly increased expression of FASN was associated with increased levels of L-FABP and VEGF/VEGFR-2. Cerulenin inhibited MCF-7-MEK5 cell migration and EMT, and reduced FASN expression and down-stream proteins L-FABP, VEGF, and VEGFR-2. MCF-7-MEK5 cells showed higher sensitivity to Cerulenin than MCF-7 cells. Immunofluorescence revealed an increase of co-localization of FASN with VEGF on the cell membrane and with L-FABP within MCF-7-MEK5 cells. Immunohistochemistry further showed that increased percentage of FASN-positive cells in the tumor tissue was associated with increased percentages of L-FABP- and VEGF-positive cells and the Cerulenin treatment could reverse the effect. Altogether, our results suggest that FASN is essential to EMT possibly through regulating L-FABP, VEGF and VEGFR-2. This study provides a theoretical basis and potential strategy for effective suppression of malignant cells with EMT.

Published
2014
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178. A 5-hydroxytryptamine receptor antagonist, sarpogrelate, reduces renal tubulointerstitial fibrosis by suppressing PAI-1.

Author

Hamasaki Y, Doi K, Maeda-Mamiya R, Ogasawara E, Katagiri D, Tanaka T, Yamamoto T, Sugaya T, Nangaku M, and Noiri E

Subjects
Adenine adverse effects, Animals, Cells, Cultured, Disease Models, Animal, Fatty Acid-Binding Proteins urine, Fibrosis, In Vitro Techniques, Kidney Tubules metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nephritis, Interstitial chemically induced, Regional Blood Flow drug effects, Serotonin metabolism, Serotonin Antagonists therapeutic use, Succinates therapeutic use, Transforming Growth Factor beta1 metabolism, Up-Regulation drug effects, Kidney Tubules drug effects, Kidney Tubules pathology, Nephritis, Interstitial metabolism, Nephritis, Interstitial prevention & control, Plasminogen Activator Inhibitor 1 metabolism, Serotonin Antagonists pharmacology, Succinates pharmacology
Abstract

A selective 5-hydroxytryptamine (5-HT) 2A receptor antagonist sarpogrelate (SG) blocks serotonin-induced platelet aggregation. It has been used clinically for the treatment of peripheral arterial disease. SG might be able to improve chronic ischemia, which contributes to renal fibrosis progression by maintaining renal microcirculation. This study investigated whether SG suppresses renal fibrosis. C57BL/6 mice fed a 0.2% adenine-containing diet for 6 wk developed severe tubulointerstitial fibrosis with kidney dysfunction. Subsequent SG treatment (30 mg·kg(-1)·day(-1)) for 4 wk improved these changes significantly by increasing peritubular blood flow in the fibrotic area, as evaluated by intravital microscopy and decreasing fibrin deposition. Urinary L-type fatty acid-binding protein, up-regulated by renal hypoxia, was also reduced by SG. Additionally, results showed that mRNA expression of plasminogen activator inhibitor-1 (PAI-1), which is known to promote fibrosis by mediating and enhancing transforming growth factor (TGF)-β1 signaling, was suppressed by SG treatment in the kidney. In vitro experiments using cultured murine proximal tubular epithelial (mProx) cells revealed that incubation with TGF-β1 and 5-HT increased PAI-1 mRNA expression; SG significantly reduced it. In conclusion, SG reduces renal fibrosis not only by the antithrombotic effect of maintaining peritubular blood flow but also by suppressing PAI-1 expression in renal tubular cells.

Published
2013
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179. Liver-type fatty acid binding protein interacts with hepatocyte nuclear factor 4α.

Author

McIntosh AL, Petrescu AD, Hostetler HA, Kier AB, and Schroeder F

Subjects
Animals, COS Cells, Cell Line, Tumor, Chlorocebus aethiops, Fatty Acid-Binding Proteins chemistry, Gene Expression Regulation, Hepatocyte Nuclear Factor 4 chemistry, Hepatocyte Nuclear Factor 4 genetics, Protein Binding, Protein Structure, Secondary, Rats, Fatty Acid-Binding Proteins metabolism, Hepatocyte Nuclear Factor 4 metabolism
Abstract

Hepatocyte nuclear factor 4α (HNF4α) regulates liver type fatty acid binding protein (L-FABP) gene expression. Conversely as shown herein, L-FABP structurally and functionally also interacts with HNF4α. Fluorescence resonance energy transfer (FRET) between Cy3-HNF4α (donor) and Cy5-L-FABP (acceptor) as well as FRET microscopy detected L-FABP in close proximity (~80 Å) to HNF4α, binding with high affinity Kd ~250-300 nM. Circular dichroism (CD) determined that the HNF4α/L-FABP interaction altered protein secondary structure. Finally, L-FABP potentiated transactivation of HNF4α in COS7 cells. Taken together, these data suggest that L-FABP provides a signaling path to HNF4α activation in the nucleus., (Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Published
2013
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180. Adiponectin activates the AMPK signaling pathway to regulate lipid metabolism in bovine hepatocytes.

Author

Chen H, Zhang L, Li X, Li X, Sun G, Yuan X, Lei L, Liu J, Yin L, Deng Q, Wang J, Liu Z, Yang W, Wang Z, Zhang H, and Liu G

Subjects
Animals, Cattle, Cells, Cultured, Signal Transduction drug effects, Triglycerides metabolism, AMP-Activated Protein Kinases metabolism, Adiponectin pharmacology, Hepatocytes drug effects, Hepatocytes metabolism, Lipid Metabolism drug effects
Abstract

Adiponectin (Ad) plays a crucial role in hepatic lipid metabolism. However, the regulating mechanism of hepatic lipid metabolism by Ad in dairy cows is unclear. Hepatocytes from a newborn female calf were cultured in vitro and treated with different concentrations of Ad and BML-275 (an AMPKα inhibitor). The results showed that Ad significantly increased the expression of two Ad receptors. Furthermore, the phosphorylation and activity of AMPKα, as well as the expression levels and transcriptional activity of peroxisome proliferator activated receptor-α (PPARα) and its target genes involved in lipid oxidation, showed a corresponding trend of upregulation. However, the expression levels and transcriptional activity of sterol regulatory element binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP) decreased in a similar manner. When BML-275 was added, the p-AMPKα level as well as the expression and activity of PPARα and its target genes were significantly decreased. However, the expression levels of SREBP-1c, ChREBP and their target genes showed a trend of upregulation. Furthermore, the triglyceride (TG) content was significantly decreased in the Ad-treated groups. These results indicate that Ad activates the AMPK signaling pathway and mediates lipid metabolism in bovine hepatocytes cultured in vitro by promoting lipid oxidation, suppressing lipid synthesis and reducing hepatic lipid accumulation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Published
2013
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181. Impact of hematopoietic cyclooxygenase-1 deficiency on obesity-linked adipose tissue inflammation and metabolic disorders in mice.

Author

Saraswathi V, Ramnanan CJ, Wilks AW, Desouza CV, Eller AA, Murali G, Ramalingam R, Milne GL, Coate KC, and Edgerton DS

Subjects
Adiponectin blood, Animals, Biomarkers blood, Biomarkers metabolism, Blotting, Western, Cyclooxygenase 1 blood, Cyclooxygenase 1 genetics, Diet, High-Fat, Eating, Female, Fluorescent Antibody Technique, Inflammation metabolism, Kidney metabolism, Kidney pathology, Leptin blood, Liver metabolism, Liver pathology, Mice, Mice, Knockout, Obesity enzymology, Obesity etiology, Real-Time Polymerase Chain Reaction, Weight Gain, Adipose Tissue enzymology, Adipose Tissue pathology, Bone Marrow Cells enzymology, Bone Marrow Transplantation, Cyclooxygenase 1 deficiency, Macrophages, Obesity complications
Abstract

Objective: Adipose tissue (AT)-specific inflammation is considered to mediate the pathological consequences of obesity and macrophages are known to activate inflammatory pathways in obese AT. Because cyclooxygenases play a central role in regulating the inflammatory processes, we sought to determine the role of hematopoietic cyclooxygenase-1 (COX-1) in modulating AT inflammation in obesity., Materials/methods: Bone marrow transplantation was performed to delete COX-1 in hematopoietic cells. Briefly, female wild type (wt) mice were lethally irradiated and injected with bone marrow (BM) cells collected from wild type (COX-1+/+) or COX-1 knock-out (COX-1-/-) donor mice. The mice were fed a high fat diet for 16 weeks., Results: The mice that received COX-1-/- bone marrow (BM-COX-1-/-) exhibited a significant increase in fasting glucose, total cholesterol and triglycerides in the circulation compared to control (BM-COX-1+/+) mice. Markers of AT-inflammation were increased and were associated with increased leptin and decreased adiponectin in plasma. Hepatic inflammation was reduced with a concomitant reduction in TXB2 levels. The hepatic mRNA expression of genes involved in lipogenesis and lipid transport was increased while expression of genes involved in regulating hepatic glucose output was reduced in BM-COX-1-/- mice. Finally, renal inflammation and markers of renal glucose release were increased in BM-COX-1-/- mice., Conclusion: Hematopoietic COX-1 deletion results in impairments in metabolic homeostasis which may be partly due to increased AT inflammation and dysregulated adipokine profile. An increase in renal glucose release and hepatic lipogenesis/lipid transport may also play a role, at least in part, in mediating hyperglycemia and dyslipidemia, respectively., (Published by Elsevier Inc.)

Published
2013
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182. Endoscopic duodenal-jejunal bypass liner rapidly improves plasma parameters of nonalcoholic fatty liver disease.

Author

de Jonge C, Rensen SS, Koek GH, Joosten MF, Buurman WA, Bouvy ND, and Greve JW

Subjects
Adolescent, Adult, Aged, Female, Humans, Liver Function Tests, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Treatment Outcome, Young Adult, Anastomosis, Surgical methods, Bariatric Surgery methods, Fatty Liver surgery, Plasma chemistry
Abstract

Bariatric surgery reduces nonalcoholic fatty liver disease (NAFLD). We investigated the effects of duodenal-jejunal bypass liner (DJBL), nonsurgical bariatric device, on plasma parameters of NAFLD. Seventeen obese subjects with type 2 diabetes received the DJBL for 24 weeks. Before, during, and after DJBL implantation, we determined plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (γ-GT), albumin, caspase-cleaved cytokeratin-18 (CK-18), and liver fatty acid-binding protein (L-FABP). At baseline, subjects had increased levels of AST (35 ± 4 IU/L), ALT (54 ± 5 IU/L), and γ-GT (66 ± 14 IU/L), compared with healthy individuals; subjects' mean concentrations of caspase-cleaved CK-18 and L-FABP were 214.4 ± 35.6 U/L and 29.3 ± 2.6 ng/mL, respectively. Three months after implantation of DJBL, all NAFLD-related parameters had decreased from baseline (AST, 28 ± 3 IU/L; ALT, 32 ± 2 IU/L; γ-GT, 44 ±7 IU/L; caspase-cleaved CK-18, 140.6 ± 16.3U/L; and L-FABP, 18.2 ± 1.5 ng/mL; all P < .05). After 6 months, levels of ALT and γ-GT had further decreased (ALT, 28 ± 2 IU/L and γ-GT, 35 ± 5 IU/L), whereas levels of AST, caspase-cleaved CK-18, and L-FABP had stabilized (P = not significant). Six months after DJBLs were removed, levels of ALT (37 ± 3 IU/L), γ-GT (42 ± 5 IU/L), and caspase-cleaved CK-18 (124.5 ± 12.5U/L) were still reduced (P < .05), whereas AST and L-FABP had returned to near baseline levels (P = not significant). Therefore, in obese subjects, DJBL reduces plasma parameters of NAFLD. ClinicalTrials.gov, Number: NCT00985114., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Published
2013
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183. Effects of leptin on the expression of fatty acid-binding proteins in human placental cell cultures.

Author

Mousiolis AV, Kollia P, Skentou C, and Messinis IE

Subjects
CD36 Antigens genetics, CD36 Antigens metabolism, Cells, Cultured, Fatty Acid-Binding Proteins genetics, Female, Humans, Lipid Metabolism drug effects, Pregnancy, Fatty Acid-Binding Proteins metabolism, Gene Expression Regulation drug effects, Leptin pharmacology, Placenta cytology
Abstract

The present study aimed to evaluate the protein expression of the transmembrane translocase FAT/CD36 and cytoplasmic H-FABP and L-FABP in human trophoblast tissue and evaluate the effects of exogenous leptin upon differential expression of each biomolecule; consequently, it aimed to derive information regarding the effects of leptin upon the expression of proteins implicated in fatty acid metabolism. Protein and total RNA were isolated from 72 samples of trophoblast tissue obtained from chorionic villous sampling. Of these, 36 samples were evaluated for protein (supernatant and pellet fraction separated) and the other 36 for total RNA expression. For each subgroup of samples, 12 were treated immediately and 24 were cultured. Half of the cultured samples were treated with 10 ng/-ml exogenously added leptin and the other half were untreated. Western blotting and PCR techniques were used for the evaluation of biomolecule expression. Our results were obtained from samples at a mean gestational week of 12+5 (n=72; min, 11+0; max, 14+1 gw; SD,0.89). In promptly treated samples we observed the presence of FAT/‌CD36 protein and absence of cytoplasmic FABPs. In the latter, only mRNA transcription of H-FABP was noted. A cytoplasmic pool of FAT/CD36 was also noted in the supernatant fraction of proteins. For cultured samples, when leptin was added, a statistically significant increase in FAT/CD36 protein expression was observed (n=24, p<0.001; mean difference, 0.219; SD, 0.0315; CI, -0.284 to -0.154). In our study we demonstrated the protein and mRNA expression of biomolecules implicated in fatty acid metabolism in human placenta. A cytoplasmic pool of the transmembrane protein FAT/CD36 was noted. Leptin caused the increase in FAT/CD36 protein expression in the cultured samples. Therefore, we conclude that leptin has an immediate effect and plays a role in lipid metabolism in human placenta.

Published
2012
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184. Microarray analysis of gene expression in liver, adipose tissue and skeletal muscle in response to chronic dietary administration of NDGA to high-fructose fed dyslipidemic rats

Author

Alex Bittner, Fredric B. Kraemer, Haiyan Zhang, Juveria Tabassum, Salman Azhar, Wen-Jun Shen, Stefanie Bittner, Yuan Cortez, and Yihang Li

Subjects
0301 basic medicine, medicine.medical_specialty, Steatosis, medicine.medical_treatment, Endocrinology, Diabetes and Metabolism, Adipose tissue, Medicine (miscellaneous), Biology, 03 medical and health sciences, chemistry.chemical_compound, L-FABP, Malony-CoA decarboxylase, Insulin resistance, Internal medicine, medicine, Beta oxidation, 2. Zero hunger, chemistry.chemical_classification, Hypertriglyceridemia, Nutrition and Dietetics, Triglyceride, Insulin, Research, Lipogenesis, Fatty acid, medicine.disease, 3. Good health, 030104 developmental biology, Endocrinology, chemistry, Fatty acid oxidation, Metabolic syndrome, CD36
Abstract

Nordihydroguaiaretic acid (NDGA), the main metabolite of Creosote Bush, has been shown to have profound effects on the core components of metabolic syndrome, including lowering of blood glucose, free fatty acids and triglyceride levels, attenuating elevated blood pressure in several rodent models of dyslipidemia, and improving body weight, insulin resistance, diabetes and hypertension. In the present study, a high-fructose diet fed rat model of hypertriglyceridemia, dyslipidemia, insulin resistance and hepatic steatosis was employed to investigate the global transcriptional changes in the lipid metabolizing pathways in three insulin sensitive tissues: liver, skeletal muscle and adipose tissue in response to chronic dietary administration of NDGA. Sprague-Dawley male rats (SD) were fed a chow (control) diet, high-fructose diet (HFrD) or HFrD supplemented with NDGA (2.5 g/kg diet) for eight weeks. Dietary administration of NDGA decreased plasma levels of TG, glucose, and insulin, and attenuated hepatic TG accumulation. DNA microarray expression profiling indicated that dietary administration of NDGA upregulated the expression of certain genes involved in fatty acid oxidation and their transcription regulator, PPARα, decreased the expression of a number of lipogenic genes and relevant transcription factors, and differentially impacted the genes of fatty acid transporters, acetyl CoA synthetases, elongases, fatty acid desaturases and lipid clearance proteins in liver, skeletal muscle and adipose tissues. These findings suggest that NDGA ameliorates hypertriglyceridemia and steatosis primarily by inhibiting lipogenesis and enhancing fatty acid catabolism in three major insulin responsive tissues by altering the expression of key enzyme genes and transcription factors involved in de novo lipogenesis and fatty acid oxidation.

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