Liver Fatty Acid Binding Protein Research Articles

Liver fatty acid-binding protein might be a predictive marker of clinical response to systemic treatment in psoriasis

Fatty acid-binding proteins play an inconclusive role in lipid metabolism and cardiometabolic diseases (CMDs) which are closely related with psoriasis. Aim of the study was to investigate the diagnostic value of serum liver fatty acid-binding protein (FABP1) level and associations with disease severity, inflammation or metabolic parameters and influence of systemic treatment in psoriatic patients. The study included thirty-three patients with active plaque-type psoriasis and eleven healthy volunteers. Blood samples were obtained before and after 12 weeks of therapy with methotrexate and acitretin. Serum FABP1 concentrations were analyzed by the enzyme-linked immunosorbent assay. Statistical analysis was performed for correlation of FABP1 with anthropometric, metabolic or inflammatory indices and treatment used. Serum liver-type FABP levels were significantly increased in psoriatic patients compared to the controls (p < 0.001). No statistical correlations between FABP1 and PASI (p = 0.25) was noted, however patients with severe psoriasis had the highest level of FABP1. No significance with metabolic parameters was obtained, beside a positive significant relation with BMI after therapy (p = 0.03). Liver-type FABP significantly correlated with CRP (p = 0.01) and morphotic blood elements. Systemic treatment combined resulted in significant decrease of FABP1 (p = 0.04), regardless of the drug: p = 0.1 in acitretin group, p = 0.3 in methotrexate group. Liver-type FABP might be a novel marker of psoriasis and predictor of clinical response to systemic therapy. FABP1 could be involved in CMDs risk assessment and perhaps link psoriasis with hematological disorders.

Severe Anemia Is Associated with Intestinal Injury in Preterm Neonates.

A temporal relationship has been reported between necrotizing enterocolitis, anemia, and red blood cell transfusion (RBCT) in preterm neonates. However, the mechanism underlying this association is not clearly defined. Intestinal (I-) and liver (L-) fatty acid binding proteins (FABPs) have been proposed as plasma markers for the detection of acute intestinal injury. This study aimed to investigate the effect of anemia and RBCT on intestinal injury in preterm neonates by measuring serum I-FABP and L-FABP levels. A prospective cohort study including preterm neonates with gestational age <32 weeks and/or birth weight <1,500 g and requiring erythrocyte transfusions for anemia after day 15 of life was conducted. Stable growing preterm infants with hemoglobin values ≥ 10 g/dL were taken as controls. I-FABP and L-FABP levels of the neonates with anemia were compared with levels of the control group. In addition, pretransfusion I-FABP and L-FABP levels of the neonates with anemia were compared with posttransfusion levels. In total, 39 infants transfused for anemia and 20 controls were enrolled. L-FABP levels were significantly higher in neonates with anemia compared with controls (p < 0.001), whereas I-FABP (p = 0.695) was not different. L-FABP and I-FABP levels were similar before and after transfusion in neonates with anemia. L-FABP levels before transfusion were negatively correlated with pretransfusion hemoglobin levels (p < 0.001). Anemia is associated with intestinal injury documented by increased L-FABP levels in preterm infants, and this injury is more severe with lower hemoglobin levels.

Effect of liver fatty acid binding protein (L-FABP) gene ablation on lipid metabolism in high glucose diet (HGD) pair-fed mice

Liver fatty acid binding protein (L-FABP) is the major fatty acid binding/”chaperone” protein in hepatic cytosol. Although fatty acids can be derived from the breakdown of dietary fat and glucose, relatively little is known regarding the impact of L-FABP on phenotype in the context of high dietary glucose. Potential impact was examined in wild-type (WT) and Lfabp gene ablated (LKO) female mice fed either a control or pair-fed high glucose diet (HGD). WT mice fed HGD alone exhibited decreased whole body weight gain and weight gain/kcal food consumed—both as reduced lean tissue mass (LTM) and fat tissue mass (FTM). Conversely, LKO alone increased weight gain, lean tissue mass, and fat tissue mass while decreasing serum β-hydroxybutyrate (indicative of hepatic fatty acid oxidation)—regardless of diet. Both LKO alone and HGD alone significantly altered the serum lipoprotein profile and increased triacylglycerol (TG), but in HGD mice the LKO did not further exacerbate serum TG content. HGD had little effect on hepatic lipid composition in WT mice, but prevented the LKO-induced selective increase in hepatic phospholipid, free-cholesterol and cholesteryl-ester. Taken together, these findings suggest that high glucose diet diminished the effects of LKO on the whole body and lipid phenotype of these mice.

Gut microbiota signatures and lipids metabolism profiles by exposure to polyene phosphatidylcholine.

The aim of the study was to address the causality links and identify specific features of the gut microbiota signatures contributing to host lipids metabolism in the presence or absence of polyene phosphatidylcholine (PPC) administration, and evaluate potential risk of PPC consumption. About 20 C57BL/6J mice were randomly allocated into two groups, normal diet group (CK) and PPC administration group (205.2 mg/kg). Compared with CK group, the contents of unsaturated fatty acids were increased and the saturated fatty acids were decreased in PPC group. The content of free fatty acids (FFA) and lipopolysaccharides (LPS) were significantly decreased (P < 0.05), and expression of carnitine palmitoyltransferase 1A (CPT1A), cluster of differentiation 36 (CD36), liver fatty acid binding protein (L-FABP), fatty acid transport protein 5 (FATP5), and fatty acid synthase (FASN) were significantly decreased in the mRNA and protein levels after treated by PPC (P < 0.05, P < 0.01). Also, we found that acetic acid in feces was significantly increased after consumption of PPC (P < 0.05). After PPC administration the relative abundances of Firmicutes and Clostridia were increased within the phylum level and the class level, respectively. Microbial abundances in genus level were dominated by Lachnospiraceae and Lachnospiraceae_NK4A136_group, whereas the proportion of sequences assigned to Bacteroidetes within the phylum level, class Bacteroidias and Mollicutes, order Anaeroplasmatalesl, genus Bacteroidales_S24-7_group were decreased in metagenomes of treated group with PPC and did not significantly influence on the accumulation of trimethylamine-N-oxide (TMAO). This study revealed that intake of PPC could regulate the gut microbiota signatures and lipids metabolism in mice without TMAO accumulations. © 2019 BioFactors, 45(3):439-449, 2019.

Screening of Potential PFOS Alternatives To Decrease Liver Bioaccumulation: Experimental and Computational Approaches

Perfluorooctanesulfonate (PFOS) is a persistent organic pollutant with significant bioaccumulation potential in liver tissues. Exposure to PFOS could cause increase of liver weight, induce adenomas of the liver, and cause hepatomegaly. Alternatives of PFOS might be designed and synthesized that have significantly lower liver bioaccumulation. In this study, we conducted animal exposure experiments to investigate tissue accumulations of 14 per- and polyfluoroalkyl substances. Correlation analysis demonstrated that accumulation of the compounds in rat liver had strong correlations with their binding affinities of liver fatty acid binding protein (LFABP). Thus, we combined a quantitative structure-activity relationship model with molecular dynamics (MD) simulations to develop computational models to predict the LFABP binding affinities of two newly synthesized alternatives, perfluorodecalin-2-sulfonic acid and N-diperfluorobutanoic acid. The binding characteristics of the PFOS alternatives for LFABP were elaborated to explore how the different structural modifications of molecules influenced the underlying binding mechanisms. Subsequent animal experiments demonstrated that the binding free energy calculations based on the MD simulations provided a good indicator to reflect the relative degree of liver accumulation of the PFOS alternatives in the same exposure doses and durations. Our findings from the combination of experimental exposure and computational model can provide helpful information to design potential alternatives of PFOS with weak LFABP binding capability and low liver accumulation.

Assessment of Liver Fatty Acid Binding Protein (L-FABP) as a Diagnostic Marker in Non-Alcoholic Fatty Liver Disease

Background: Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common liver disease worldwide, it causes chronic hepatitis, which leads to cirrhosis and hepatocellular carcinoma. We aimed to assess the value of liver fatty acid binding protein (L-FABP) in the diagnosis of non-alcoholic fatty liver disease in comparison to ultrasonography. Patients and Methods: Ninty subjects were enrolled in this study who attended the Hepatology, Gastroenterology and Internal medicine clinics in Benha University Hospitals between January 2017 and January 2018 and divided into group I included 70 consecutive patients with non-alcoholic fatty liver disease who were diagnosed by ultrasound with or without elevated liver enzymes and group II included 20 healthy control subjects without NAFLD (by ultrasound) with normal liver enzymes. Serum levels of L-FABP were determined by enzyme-linked immunosorbent assay. Results: NAFLD patients were slightly older than healthy subjects as mean age in group I was (37.74 ± 11.7) while in group II was (36.5 ± 11.31). There was a slight increase in NAFLD in males, there was a high prevalence of NAFLD in the urban population. L-FABP levels in NAFLD patients were higher than in the control group (levels were 188.6 ± 34.94 and 137.7 ± 13.05 ng/l respectively). A strong correlation was found between L-FABP and ALT, AST, BMI and glucose levels. Analysis of ROC curve revealed that at a level 151.1 ng/sensitivity, specificity, PPV, NPV and accuracy were 83.3%, 71.8%, 31.3%, 96.6% and 73.3% respectively with AUC 0.839 and at a level 189.5 ng/sensitivity, specificity, PPV, NPV and accuracy were 90%, 90%, 95.4%, 95.4%, 88.9% with AUC was 0.950. Conclusion: Serum L-FABP could be used as a new diagnostic biomarker for detecting NAFLD.

Quercetin decreases the triglyceride content through the PPAR signalling pathway in primary hepatocytes of broiler chickens

This study was conducted to investigate the effect of quercetin on the triglyceride (TG) content through the peroxisome proliferator-activated receptor α (PPARα) signalling pathway in broiler hepatocytes. The trial included the following five groups: control, DMSO control, 5 mg/L quercetin, 10 mg/L quercetin and 20 mg/L quercetin. Compared with the control group, the PPARα protein content was significantly increased at 24 h in the groups that received quercetin at 5, 10 and 20 mg/L (p < 0.05), whereas the PPARα mRNA expression was significantly increased at 24, 48 and 72 h (p < 0.05). Compared with the control, the content of the long-chain acyl-CoA synthetase (ACSL), apolipoprotein A1 (ApoA1), liver fatty acid–binding protein (FABP) and TG in the 5-, 10- and 20-mg/L quercetin group was significantly increased at 24, 48 and 72 h (p < 0.05). Moreover, the L-FABP and ApoA1 mRNA expression levels were significantly increased at 24, 48 and 72 h (p < 0.05). Compared with the control, the ApoC3 protein content in the 5-mg/L quercetin group was significantly decreased at 72 h (p < 0.05). Furthermore, the very-low-density lipoprotein (VLDL) contents in the 5- and 20-mg/L quercetin groups were significantly decreased at 72 h (p < 0.05). In conclusion, quercetin enhanced lipid transportation and peroxidase β-oxidation regulated by PPARα and promoted lipid decomposition regulated by PPARα, but this did not occur in a dose-dependent or time-dependent manner. Therefore, quercetin decreased the TG content in broiler hepatocytes by promoting PPARα-regulated lipid decomposition, thereby reducing lipid deposition in broilers.

Acute Kidney Injury after Cardiac Surgery: Risk Factors and Novel Biomarkers.

Acute kidney injury (AKI) is a common and severe complication after cardiac surgery. Currently, a series of novel biomarkers have favored the assessment of AKI after cardiac surgery in addition to the conventional indicators. The biomartkers, such as urinary liver fatty acid binding protein (L-FABP), urinary neutrophil gelatinase-associated lipocalin (NGAL), serum L-FABP, heart-type FABP, kidney injury molecule 1 (KIM-1), and interleukin-18 were found to be significantly higher in patients who developed AKI after cardiac surgery than those who did not. Apart from urinary interleukin-18, the novel biomarkers have been recognized as reliable indicators for predicting the diagnosis, adverse outcome, and even mortality of AKI after cardiac surgery. The timing of the renal replacement therapy is a significant predictor relating to patients’ prognoses. In patients with AKI after cardiac surgery, renal replacement therapy should be performed as early as possible in order to achieve promising outcomes. In children, AKI after cardiac surgery can be managed with peritoneal dialysis. AKI after cardiac surgery has received extensive attention as it may increase early mortality and impact long-term survival of patients as well. The purpose of this article was to analyze the changes of the pertinent biomarkers, to explore the related risk factors leading to the occurrence of AKI after cardiac surgery, and to provide a basis for the clinical prevention and reduction of AKI.

Effect of Tribulus terrestris in mercuric chloride-induced renal accumulation of mercury and nephrotoxicity in rat.

Mercury generates free radicals and subsequently increases oxidative stress, which leads to renal injury. Tribulus terrestris (TT) has good anti-inflammatory and antioxidant properties. Hydroalcoholic extract of different dose of TT was evaluated against mercuric chloride-induced nephrotoxicity. Rats (n = 6) were treated with TT at doses of 100, 200, and 300 mg/kg. Drugs were administered orally for 7 days. Single dose of mercuric chloride (5 mg/kg, intraperitoneal) on the 5th day caused significant elevation of blood urea nitrogen, serum creatinine, malondialdehyde, liver fatty acid binding protein, kidney injury molecule-1, and kidney mercury level and fall in glutathione, superoxide dismutase, glutathione peroxidase, and histopathological changes in disease control as compared to normal control group (P < 0.001). Dose of TT 200 and 300 mg/kg significantly (P < 0.001) prevented the renal injury, and mercury accumulation in kidney tissues significantly decreases in higher dose, i.e., 300 mg/kg as compared to control group. Our result indicates that the treatment of TT exerted significant protection against renal damage induced by mercuric chloride possibly due to its antioxidant and anti-inflammatory properties and by decreasing the renal accumulation of mercury.

Expression patterns of hepatic genes involved in lipid metabolism in cows with subclinical or clinical ketosis

Dairy cows with ketosis are characterized by high blood concentrations of ketone bodies and hepatic lipid metabolism disorder. The discrepancies in the abundance of mRNA encoding a variety of hepatic candidate genes in varying degrees of ketotic cows represent specific responses of the liver to the challenge of fatty acids and ketone bodies. Importantly, the expression disorder of hepatic genes involved in lipid metabolism plays a promoting role in the onset and progression of ketosis. Thus, the aim of this study was to investigate the expression patterns of genes involved in the hepatic fatty acids uptake, transport, activation, β-oxidation, synthesis, and esterification in the cows with subclinical ketosis (SCK) or clinical ketosis (CK). Twenty-four cows were selected into control [n = 8, β-hydroxybutyrate (BHB) ≤0.6 mM], SCK (n = 8, 3.0 > BHB ≥ 1.2 mM), and CK (n = 8, BHB ≥3.0 mM) groups according to the blood BHB concentration and clinical symptoms. The accumulation of hepatic lipid, as indicated by triglycerides (TG) contents and Oil Red O and hematoxylin and eosin staining, was pronouncedly exacerbated in the tCK group compared with the control and SCK groups. The hepatic mRNA expression of fatty acids transport and activation genes, liver fatty acid-binding protein (FABP1) and long-chain acyl-CoA synthetase 1 (ACSL1), were both significantly higher in the SCK and CK groups than in the control group. The expression levels of peroxisome proliferator-activated receptor α (PPARA) and its target genes, carnitine palmitoyltransferase 1A (CPT1A) and carnitine palmitoyltransferase 2 (CPT2), were significantly elevated in the SCK group but reduced in the CK group compared with control group. Furthermore, the gene expression level of sterol regulatory element-binding protein 1 (SREBP1) and the protein expression level of sterol regulatory element-binding protein 1c and its target genes acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS), and stearoyl-CoA desaturase-1 (SCD1) and TG synthesis genes diacylglycerol acyltransferase 1 (DGAT1) and diacylglycerol acyltransferase 2 (DGAT2) were significantly higher in the CK group relative to the control group. In short, the present data indicated that hepatic fatty acids uptake, transport, and activation are significantly increased in cows with SCK and CK, hepatic fatty acids β-oxidation is significantly increased in SCK cows but markedly decreased in CK cows, and hepatic fatty acids and TG synthesis are significantly increased in CK cows, thereby inducing hepatic steatosis in CK cows.

The Antioxidant Activity of Recombinant Rat Hepatic Fatty Acid Binding Protein T94A Variant.

Liver fatty acid binding protein (FABP1) is a cytoplasmic polypeptide that transports substrates throughout the cytosol and functions as an antioxidant. A common polymorphic variant, FABP1 T94A has a minor allele frequency of 26-38%, 8.3±1.9% homozygous in the human population. The purpose of this study was to mutate and isolate recombinant rat FABP1 to the T94A variant to evaluate the mutant's antioxidant activity using in vitro studies. Site-directed mutagenesis was used to generate a mutation in rat cDNA within a pGEX-6p-2 vector. This plasmid was transformed into competent cells and cultured for expression of FABP1 T94A mutant. The mutated protein was purified using GSTrap Fastflow columns within an ÄKTA FPLC system. A 2,7-dichlorofluorescein (DCF) assay was used to screen the T94A variant antioxidant activity. Additionally, Thiobarbituric Acid Reactive Substances (TBARS) assay was used in determining T94A mutant antioxidant activity in hydrophilic and lipophilic environments through the use of the azo compounds AAPH and MeO-AMVN, respectively and in the presence and absence of the long-chain fatty acid palmitate and α-bromo palmitate. Although the FABP1 T94A (20 μM) mutant significantly reduced DCF fluorescence compared to control (no protein; P< 0.001), there were no significant difference when compared to the wild-type (WT) FABP1. T94A was able to diminish the formation of malondialdehyde (MDA) in both lipophilic and hydrophilic systems. There were significant differences between T94A mutant and WT FABP1 at concentrations 1 and 10 μM (P< 0.05) in the hydrophilic milieu, however, this was not seen at 20 μM and also not seen in the lipophilic milieu at all concentrations. When T94A was pre-incubated with the long-chain fatty acids palmitate or α -bromo palmitate, MDA formation was decreased in both lipid peroxidation systems. There were no statistical differences between the WT FABP1 and T94A bound with fatty acids in both lipid peroxidation systems, however, there was a slight statistical difference when the T94A and WT FABP1 bound α-Br-PA in the AAPH lipid peroxidation system only. The T94A has antioxidant activity in both hydrophilic and lipophilic environments. The T94A variant of FABP1 does not have a loss of function in regard to acting as an antioxidant but the extent of function may be influenced by ligand binding. We conclude that populations having the minor T94A allele frequency would have similar ROS scavenging potential as those with nascent FABP1.

Evaluation of Intestinal Damage Biomarkers in Calves with Atresia Coli.

IntroductionIntestinal obstruction such as atresia coli causes pathophysiological changes in gastrointestinal tissue due to the rise of intra-abdominal pressure. The aim of this study is to determine the intestinal damage with intestinal biomarkers in calves with atresia coli.Material and MethodsThe study was conducted on 40 Holstein calves diagnosed with atresia coli with mild to moderate abdominal distention and 10 healthy Holstein calves which served as the control. Blood samples were collected from all calves, and then serum concentrations of intestinal biomarkers were estimated, namely intestinal fatty acid binding protein (IFABP), liver fatty acid binding protein (LFABP), trefoil factor 3 (TFF3), and intestinal alkaline phosphatase (IAP), using commercially available specific bovine ELISA kits. An automatic blood gas analyser was employed for determining the lactate concentration.ResultsThe concentrations of serum LFABP (P < 0.01), IFABP, TFF3, IAP, and blood lactate (P < 0.001) were significantly higher in calves with atresia coli than in healthy calves.ConclusionThe calves affected with atresia coli exhibited severe intestinal damage, and IFABP, LFABP, and TFF3 have significant diagnostic importance and play a useful role in determining the intestinal damage due to intestinal obstruction. High levels of IAP and lactate may serve as a signal for the development of intestinal injury.

Liver lipid metabolism disruption in cancer cachexia is aggravated by cla supplementation -induced inflammation

The liver is the main organ regulating metabolism. In spite of that, few studies examine liver metabolism in cachexia, a wasting syndrome associated with increased morbidity and mortality in cancer. Cachexia induces major metabolic disruption, inflammation and fat and lean mass loss. We have previously shown impairment of hepatic lipid metabolism in cancer cachexia that contributes to the aggravation of the symptoms. The present study addresses the effects of Conjugated Linoleic Acid supplementation upon liver lipid metabolism in cachectic rats. Male Wistar rats were randomly assigned to control groups (C) receiving 0.9NaCl (Placebo CP); or to groups supplemented with sunflower oil (CSF), supplemented with CLA (CCLA), or still, to tumour bearing animals (T) receiving NaCl (TP), sunflower oil (TSF), or CLA (TCLA). Supplementation (0.5ml) by gavage was carried out for 14 days. Body weight, dietary intake, glucose, cholesterol and triacylglycerol plasma content, liver glycogen and triacylglycerol content and mRNA expression of liver carnitine palmitoyltransferase I and II (CPT I and II), as well as microsomal triglyceride transfer protein (MTP), liver fatty acid-binding protein (L-FABP), peroxisome proliferator-activated receptor-alpha (PPAR-alpha), and apolipoprotein B (apoB), were assessed. Liver CPT II activity was reduced in all groups, when compared with CP. Hepatic mRNA expression of MTP, apoB and FABP was reduced in TCLA, when compared with all groups. TCLA also presented increased hepatic and plasma triacylglycerol content, when compared with all T groups. Adipose tissue-derived inflammatory factors were assessed. No differences among the groups were observed in regard to Retro Peritoneal Adipose Tissue cytokine (IL-1β, IL-6, and TNF-α) protein content and expression, with the exception of IL-10 in tumour-bearing animals. In the Epididymal Adipose Tissue, the inflammatory cytokines were augmented in TCLA, compared with all other groups. CLA supplementation fails to promote the re-establishment of hepatic lipid metabolism in tumour-bearing animals, and therefore is not recommended in cancer-related cachexia.

Structural and Functional Interaction of Δ9-Tetrahydrocannabinol with Liver Fatty Acid Binding Protein (FABP1).

Although serum Δ9-tetrahydrocannabinol (Δ9-THC) undergoes rapid hepatic clearance and metabolism, almost nothing is known regarding the mechanism(s) whereby this highly lipophilic phytocannabinoid is transported for metabolism/excretion. A novel NBD-arachidonoylethanolamide (NBD-AEA) fluorescence displacement assay showed that liver fatty acid binding protein (FABP1), the major hepatic endocannabinoid (EC) binding protein, binds the first major metabolite of Δ9-THC (Δ9-THC-OH) as well as Δ9-THC itself. Circular dichroism (CD) confirmed that not only Δ9-THC and Δ9-THC-OH but also downstream metabolites Δ9-THC-COOH and Δ9-THC-CO-glucuronide directly interact with FABP1. Δ9-THC and metabolite interaction differentially altered the FABP1 secondary structure, increasing total α-helix (all), decreasing total β-sheet (Δ9-THC-COOH, Δ9-THC-CO-glucuronide), increasing turns (Δ9-THC-OH, Δ9-THC-COOH, Δ9-THC-CO-glucuronide), and decreasing unordered structure (Δ9-THC, Δ9-THC-OH). Cultured primary hepatocytes from wild-type (WT) mice took up and converted Δ9-THC to the above metabolites. Fabp1 gene ablation (LKO) dramatically increased hepatocyte accumulation of Δ9-THC and even more so its primary metabolites Δ9-THC-OH and Δ9-THC-COOH. Concomitantly, rtPCR and Western blotting indicated that LKO significantly increased Δ9-THC's ability to regulate downstream nuclear receptor transcription of genes important in both EC ( Napepld > Daglb > Dagla, Naaa, Cnr1) and lipid ( Cpt1A > Fasn, FATP4) metabolism. Taken together, the data indicated that FABP1 may play important roles in Δ9-THC uptake and elimination as well as Δ9-THC induction of genes regulating hepatic EC levels and downstream targets in lipid metabolism.

Benign Hepatic Lesions Arising in Accessory Hepatic Lobes

Abstract An accessory hepatic lobe is an uncommon hepatic congenital anomaly that can sometimes mimic a mass lesion clinically and radiologically. Because accessory hepatic lobes are only rarely resected, detailed descriptions of their histologic features are sparse. We report the histologic and immunohistochemical features of 3 cases of resected accessory hepatic lobes, all of which contained benign hepatic lesions (2 hepatic adenomas [HAs] and 1 focal nodular hyperplasia). All accessory lobes were connected to the liver by a pedicle. Histologically, all lesions demonstrated no cytologic or architectural atypia. Based on immunohistochemical analysis, 1 HA was classified as inflammatory type (positive for C-reactive protein and serum amyloid A), and 1 was unclassified type (negative for C-reactive protein, serum amyloid A, glutamine synthetase, and β-catenin and positive for liver fatty acid–binding protein); the focal nodular hyperplasia showed the typical map-like staining pattern with glutamine synthetase. Interestingly, multiple foci of myelolipoma were identified within the unclassified-type HA. Of note, in all cases, the nonlesional hepatic parenchyma featured structural vascular abnormalities of the hepatic artery branches, including abnormal thickening of arterial branches and multiple arterial branches per single portal tract. Our findings describe, for the first time, benign hepatic lesions arising in accessory hepatic lobes and suggest that accessory lobes are perhaps prone to such benign lesions because of structural abnormalities in their vasculature.

Urine biomarkers of chronic kidney damage and renal functional decline in childhood-onset systemic lupus erythematosus.

To delineate urine biomarkers that reflect kidney structural damage and predict renal functional decline in pediatric lupus nephritis (LN). In this prospective study, we evaluated kidney biopsies and urine samples of 89 patients with pediatric LN. Urinary levels of 10 biomarkers [adiponectin, ceruloplasmin, kidney injury molecule-1, monocyte chemotactic protein-1, neutrophil gelatinase-associated lipocalin, osteopontin, transforming growth factor-ß (TGFß), vitamin-D binding protein, liver fatty acid binding protein (LFABP), and transferrin] were measured. Regression analysis was used to identify individual and combinations of biomarkers that determine LN damage status [NIH-chronicity index (NIH-CI) score ≤ 1 vs. ≥ 2] both individually and in combination, and biomarker levels were compared for patients with vs. without renal functional decline, i.e., a 20% reduction of the glomerular filtration rate (GFR) within 12months of a kidney biopsy. Adiponectin, LFABP, and osteopontin levels differed significantly with select histological damage features considered in the NIH-CI. The GFR was associated with NIH-CI scores [Pearson correlation coefficient (r) = - 0.49; p < 0.0001] but not proteinuria (r = 0.20; p > 0.05). Similar to the GFR [area under the ROC curve (AUC) = 0.72; p < 0.01], combinations of osteopontin and adiponectin levels showed moderate accuracy [AUC = 0.75; p = 0.003] in discriminating patients by LN damage status. Renal functional decline occurred more commonly with continuously higher levels of the biomarkers, especially of TGFß, transferrin, and LFABP. In combination, urinary levels of adiponectin and osteopontin predict chronic LN damage with similar accuracy as the GFR. Ongoing LN activity as reflected by high levels of LN activity biomarkers heralds renal functional decline. • Levels of osteopontin and adiponectin measured at the time of kidney biopsy are good predictors of histological damage with lupus nephritis. • Only about 20% of children with substantial kidney damage from lupus nephritis will have an abnormally low urine creatinine clearance. • Continuously high levels of biomarkers reflecting lupus nephritis activity are risk factors of declining renal function.

Somatic HNF1A mutations in the malignant transformation of hepatocellular adenomas: a retrospective analysis of data from MSK-IMPACT and TCGA

Mutations of Hepatocyte-Nuclear-Factor-1-Homeobox-A (HNF1A) gene and loss of Liver-Fatty-Acid-Binding-Protein (LFABP) are well documented in hepatocellular adenoma. However, the role of HNF1A mutations in hepatocellular carcinoma remains to be determined. In this study, all hepatocellular neoplasms evaluated by our institutional Memorial Sloan Kettering-Integrated Mutational Profiling of Actionable Clinical Targets assay or the Cancer Genome Atlas sequencing, and cases reported in the literature, were queried for HNF1A mutations. Together, 11 of 672 (1.6%) hepatocellular carcinomas harbored HNF1A mutations. The single case from our institution (n = 153) was extremely well differentiated, arising in a background of adenomatosis. Both the adenoma and carcinoma component contained the same 2 somatic HNF1A mutations (p. E32* and L214Q), with loss of LFABP. From the literature, 2 of 146 (1.4%) hepatocellular carcinomas had HNF1A mutations, and both arose in a background of adenomatosis. Information on pre-existing adenoma for the remaining cases (8/373, from The Cancer Genome Atlas) was not available. HNF1A mutations in carcinomas were associated with negative viral hepatitis status (p = .004), mutually exclusive with catenin beta-1 (CTNNB1) hotspot mutations, and trended to occur more in females (p = .06) and without cirrhosis (p = .03). Grade was not associated with HNF1A status (p = .28). Somatic HNF1A mutations occur in approximately 1% to 2% of hepatocellular carcinoma, often in a background of adenomatosis. Our findings suggest that malignant transformation of HNF1A-mutated hepatocellular adenoma occurs, albeit infrequently. Hepatocellular adenomas with HNF1A mutation or adenomatosis with loss of LFABP warrant thorough sampling and examination.

Extracorporeal Membrane Oxygenation Improving Survival and Alleviating Kidney Injury in a Swine Model of Cardiac Arrest Compared to Conventional Cardiopulmonary Resuscitation.

Background:Acute kidney injury (AKI) frequently occurs in cardiopulmonary resuscitation patients. Studies comparing the effects of extracorporeal membrane oxygenation (ECMO) with conventional cardiopulmonary resuscitation (CCPR) on AKI were rare. This study aimed to compare the effects of ECMO with those of CCPR on survival rate and AKI and explore the underlying mechanisms in a swine model of cardiac arrest (CA).Methods:Sixteen male pigs were treated with ventricular fibrillation to establish CA model and then underwent CCPR (CCPR group, n = 8) or ECMO during cardiopulmonary resuscitation (ECPR group, n = 8). The study endpoints were 6 h after return of spontaneous circulation (ROSC) or death. Serum and urine samples were collected at baseline and during the 6 h after ROSC. The biomarkers of AKI were detected by enzyme-linked immunosorbent assay. The apoptosis of renal tubular epithelial cells was discovered by transmission electron microscope (TEM) and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Apoptosis-related genes were detected by immune-staining and Western blotting. Data were compared by Student's t-test.Results:All pigs in ECPR group were successfully resuscitated with a higher 6-h survival rate (8/8) compared to CCPR group (6/8). The expressions of AKI biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), tissue inhibitor of metalloproteinase2 (TIMP2), insulin-like growth factor-binding protein 7 (IGFBP7), liver fatty acid-binding protein (LFABP), and kidney injury molecule1 (Kim-1) were all increased along with the time after ROSC in both groups and lower in ECPR group compared with CCPR group. Especially, products of urinary TIMP and IGFBP levels (TIMP*IGFBP) were significantly lower at ROSC4 (0.58 ± 0.10 ng2/ml2 vs. 1.18 ± 0.38 ng2/ml2, t = 4.33, P = 0.003) and ROSC6 (1.79 ± 0.45 ng2/ml2 vs. 3.00 ± 0.44 ng2/ml2, t = 5.49, P < 0.001); urinary LFABP was significantly lower at ROSC6 (0.74 ± 0.06 pg/ml vs. 0.85 ± 0.11 pg/ml, t = 2.41, P = 0.033); and urinary Kim-1 was significantly lower at ROSC4 (0.66 ± 0.09 pg/ml vs. 0.83 ± 0.06 pg/ml, t = 3.99, P = 0.002) and ROSC6 (0.73 ± 0.12 pg/ml vs. 0.89 ± 0.08 pg/ml, t = 2.82, P = 0.016). Under light microscope and TEM, the morphological injures in renal tissues were found to be improved in ECPR group. Moreover, apoptosis was also alleviated in ECPR group.Conclusions:Compared with CCPR, ECMO improves survival rate and alleviates AKI in a swine model of CA. The mechanism of which might be via downregulating AKI biomarkers and apoptosis in kidney.

Biomarkers of kidney injury in hypertension: conventional versus novel

Objective. The aim of the present study was to compare conventional and novel, potentially earlier biomarkers of kidney injury in patients with different severity and duration of arterial hypertension (HTN) and healthy controls. Design and methods. Urine levels of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule‑1 (KIM‑1), liver fatty-acid binding protein (L‑FABP), albuminuria and serum levels of cystatin C and creatinine were measured in 92 hypertensive patients (46 male, mean age 50,7 ± 12,2 years) and 34 healthy control subjects (16 male, mean age 49,9 ± 11,4 years). Hypertensive patients were divided into four age- and sex-matched groups according to HTN severity: 1st grade (n = 24), 2nd grade (n = 26), 3rd grade (n = 17) and resistant hypertension (n = 25). Glomerular filtration rate (GFR) was estimated by the level of serum creatinine and cystatin C by MDRD and CKD-EPI formulas. Instrumental examination included measuring office blood pressure (BP), 24‑hour ambulatory BP monitoring (ABPM, SpaceLabs 90207), applanation tonometry (SphygmoCor, Artcor Medical) with the calculation of central aortic pressure. Results. As compared to healthy control subjects, hypertensive patients were characterized by higher creatinine and albuminuria levels, and lower GFR, however, creatinine levels remained within the normal range despite the increase in the severity of HTN. Levels of albuminuria increased only in patients with severe HTN. Also as compared to healthy controls, HTN patients had significantly higher levels of cystatin C, which already was found in patients with 1st and 2nd stages of HTN, which occurs more often than an increase of creatinine and albuminuria levels. Patients with HTN had significantly lower sCys-estimated GFR and creatinine-sCys-estimated GFR. In HTN patients these biomarkers were associated with office systolic BP (SBP), central aortic systolic and diastolic (CAP) and mean 24‑hour BP level. There were no differencesin NGAL, KIM‑1 levels between the groups, however, KIM‑1 levels were associated with office SBP, mean daily 24‑hour of diastolic BP (DBP) and systolic and diastolic CAP in patients with severe HTN. At the same time, as compared with healthy controls, patients with initial HTN were characterized by higher levels of urine L‑FABP and its concentration increased in patients with severe HTN. In addition, L‑FABP levels were associated with office SBP and DBP, mean 24‑hour BP and systolic and diastolic CAP. Conclusions. The simultaneous assessment of creatinine and cystatin C levels, and the calculation of GFR using the formula CKD-EPI seems to be more accurate method for CKD stage classification in general and, in particular, in hypertensive patients; in hypertensive patients L‑FABP appears to be earlier biomarker of kidney injury, reflecting the progression of tubulointerstitial injury.

Scp-2/Scp-x ablation in Fabp1 null mice differentially impacts hepatic endocannabinoid level depending on dietary fat

Dysregulation of the hepatic endocannabinoid (EC) system and high fat diet (HFD) are associated with non-alcoholic fatty liver disease. Liver cytosol contains high levels of two novel endocannabinoid binding proteins—liver fatty acid binding protein (FABP1) and sterol carrier protein-2 (SCP-2). While Fabp1 gene ablation significantly increases hepatic levels of arachidonic acid (ARA)-containing EC and sex-dependent response to pair-fed high fat diet (HFD), the presence of SCP-2 complicates interpretation. These issues were addressed by ablating Scp-2/Scp-x in Fabp1 null mice (TKO). In control-fed mice, TKO increased hepatic levels of arachidonoylethanolamide (AEA) in both sexes. HFD impacted hepatic EC levels by decreasing AEA in TKO females and decreasing 2-arachidonoyl glycerol (2-AG) in WT of both sexes. Only TKO males on HFD had increased hepatic 2-AG levels. Hepatic ARA levels were decreased in control-fed TKO of both sexes. Changes in hepatic AEA/2-AG levels were not associated with altered amounts of hepatic proteins involved in AEA/2-AG synthesis or degradation. These findings suggested that ablation of the Scp-2/Scp-x gene in Fabp1 null mice exacerbated hepatic EC accumulation and antagonized the impact of HFD on hepatic EC levels—suggesting both proteins play important roles in regulating the hepatic EC system.