A-FABP (adipocyte fatty acid-binding protein), one of the most abundant proteins in adipocytes, plays a key role in obesity-related insulin resistance, inflammation and atherosclerosis in animals. In ...the present study, we sought to investigate the association of A-FABP with HF (heart failure) in Chinese subjects. Serum A-FABP levels were measured in 252 HF patients and 261 age-, gender- and BMI (body mass index)-matched non-HF subjects. Echocardiography was performed on each patient. The severity of HF was determined by the NYHA (New York Heart Association) classification system. After adjustments for age, gender and BMI, serum A-FABP concentrations in patients with HF were significantly higher than in non-HF patients 11.17 (6.63-19.93) ng/ml compared with 5.67 (3.20-8.87) ng/ml; P<0.001 and significantly progressed with the NYHA class (P<0.001). In addition, NT-proBNP (N-terminal pro-brain natriuretic peptide) was independently and positively correlated with A-FABP (standardized β=0.340, P<0.001) after adjusting for confounding factors. Each echocardiographic parameter, especially LVEF (left ventricular ejection fraction), was independently associated with A-FABP (all P<0.05). Multivariate logistic regression analysis demonstrated that A-FABP concentration was an independent risk factor for HF odds ratio, 6.93 (95% confidence interval, 2.49-19.30); P<0.001. Our results demonstrate that A-FABP is closely associated with HF, and raise the possibility that increased A-FABP may be causally related to the pathogenesis of heart dysfunction in humans.
Hypothyroidism impairs endothelium-dependent dilatations, while hyperthyroidism augments the production of endothelial nitric oxide. Thus, experiments were designed to determine if thyroid hormone ...causes endothelium-dependent responses, or alleviates diabetic endothelial dysfunction. Isometric tension was measured in rings with or without endothelium of arteries from normal and diabetic Sprague-Dawley rats. Release of 6-keto prostaglandin F1α and thromboxane B2 were measured by enzyme linked immunosorbent assay and protein levels endothelial nitric oxide synthase (eNOS), cyclooxygenases (COX) by immunoblotting. Triiodothyronine (T3) caused concentration-dependent (3×10−6–3×10−5M) relaxations in mesenteric (pEC50, 4.96±0.19) and femoral (pEC50, 4.57±0.35) arteries without endothelium. In femoral arteries of rats with diabetes, 5-methylamino-2-(2S,3R,5R,8S,9S)-3,5,9-trimethyl-2-(1-oxo-(1H-pyrrol-2- -yl)propan-2-yl)-1,7-dioxaspiro-(5,5)undecan-8-ylmethylbenzooxazole-4-carboxylic acid (A23187, 3×10−7 to 10−6M) caused partly endothelium-dependent contractions. After chronic T3-treatment with (10μg/kg/day; four weeks), the contractions to A23187 of preparations with and without endothelium were comparable, the thromboxane B2-release was reduced (by 38.1±9.2%). The pEC50 of 9, 11-dideoxy-11α, 9α-epoxymethanoprostaglandin F2α (U46619, TP-receptor agonist) was increased in T3-treated diabetic rats compared with controls (8.53±0.06 vs 7.94±0.09). The protein expression of eNOS increased (by 228%) but that of COX-1 decreased (by 35%) after chronic T3 treatment. In human umbilical vein endothelial cells incubated for one week with T3 (10−10–10−7M) in the presence but not in the absence of interleukin-1β (1ng/ml), the expression of eNOS was increased compared to control. In conclusion, thyroid hormone acutely relaxes mesenteric and femoral vascular smooth muscle, but given chronically reduces the release of endothelium-derived vasoconstrictor prostanoids while enhancing the responsiveness of TP receptors of vascular smooth muscle.
Abstract only Elevated plasma levels of the vasoconstrictor peptide endothelin-1 (ET-1) are associated with cardiovascular risk factors such as obesity, diabetes and hypertension, in which ...endothelium-dependent contractions are prominent. Exogenous ET-1 promotes the release of endothelium-derived contracting factors (EDCF), but the role of endogenously produced ET-1 in these processes is unknown. Therefore, mice with tie-1 promoter driven endothelium-restricted heterozygous overexpression of ppET-1 (TET+/-) and WT littermates were kept on standard chow as lean controls or administered a high fat diet for 30 weeks to induce obesity. At sacrifice, fasting glucose levels were significantly elevated in obese animals (8.3±0.3 vs. 5.3±0.2 mmol/l in lean controls, n =6, P <0.001). Isometric tension was measured in aortic and carotid arterial rings in wire myographs. In phenylephrine-contracted aortic rings, endothelium-dependent and −independent relaxations to acetylcholine and sodium nitroprusside, respectively, were unaltered between groups. In carotid arteries, the potency of phenylephrine to evoke contractions was greater in preparations from obese TET+/- mice ( pD 2 6.71±0.07 vs. lean TET+/- 6.34±0.13, n =5-6, P <0.05), whereas there was no change in the contractile response to the α 1 -adrenergic agonist by diet-induced obesity in WT littermates. The augmented EDCF responses to acetylcholine of quiescent carotid arterial rings of obese animals were further potentiated by TET+/- ( E max 51.3±1.1% vs. 40.6±1.3% KCl in WT obese, n =6, P <0.001). The production of 6-keto PGF 1α − the stable metabolite of prostacyclin − was increased significantly in preparations from obese TET+/- mice (238.4±30.0 vs. 127.0±12.7 pg/mL in obese WT littermates, n =4-6, P <0.05). In the presence of L-NAME, TP receptor activation by U46619 was more effective in obese TET+/- ( E max 151.8±5.4% vs. 126.1±4.7% KCl in WT obese, n =4-6, P <0.05). Overall, TET+/- had no effect on relaxations in obese animals, but contractile responses − EDCF-mediated ones in particular − were facilitated. The present results suggest that this is due to an increased production of vasoconstrictor prostanoids possibly combined with an augmented responsiveness of the underlying vascular smooth muscle.
Raised circulating adipocyte fatty acid-binding protein (AFABP) concentrations are associated with various adverse health conditions. However, their relationship with mortality remains to be defined, ...especially in view of the sexual dimorphism of circulating AFABP concentrations. Here we investigated prospectively whether serum AFABP concentrations predict multiple mortality outcomes in men and women alike, using a large clinic-based cohort of individuals with type 2 diabetes, a condition with raised AFABP concentrations.
Baseline serum AFABP concentrations were measured in 5305 research participants with a monoclonal antibody-based sandwich immunoassay. The role of circulating AFABP concentrations in predicting mortality outcomes was evaluated by multivariable Cox regression analysis.
Among the 5305 participants (59% men) in this study, over a median follow-up of 5 years, there were 512 deaths (19.3 deaths per 1000 person-years). Circulating AFABP concentrations, with higher levels in women at baseline, predicted all-cause mortality (
< 0.001), cardiovascular mortality (
= 0.037), and infection-related deaths (
< 0.002) among all participants. In sex-specific analyses, circulating AFABP concentration was an independent predictor of all-cause mortality in both men and women and a predictor of cancer-related deaths and infection-related deaths in men only. Furthermore, the addition of serum AFABP concentrations improved the time-dependent
statistics in predicting all-cause mortality in participants with type 2 diabetes (
= 0.008).
Circulating AFABP concentration was an independent predictor of various mortality outcomes in type 2 diabetes over and above known risk factors of reduced survival in men and women. The role of AFABP as a prognostic biomarker and therapeutic target warrants further investigation.
•Baseline A-FABP and LCN2 levels were associated with different risk factors.•Their levels were elevated in multiple new CVD and microvascular events.•Their association with these new events were ...mediated via related risk factors.•Fenofibrate did not affect LCN2 levels, but increased A-FABP levels modestly.
To investigate determinants of circulating levels of adipocyte-fatty acid binding protein (A-FABP) and lipocalin-2 (LCN2), their relationships with cardiovascular disease (CVD) and microvascular events, and effects of fenofibrate in type 2 diabetes (T2D).
A-FABP and LCN2 were quantified in baseline plasma from 2000 T2D adults in a Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial sub-study and correlates thereof determined. In a subset (n = 200) adipokines were also measured on-trial.
Female sex, older age, higher body mass index (BMI), HbA1c, insulin resistance index, triglycerides, plasma creatinine and homocysteine, shorter diabetes duration, and use of oral hypoglycaemic agents alone were independent determinants of higher A-FABP. Higher BMI, fibrinogen and homocysteine, Caucasian race, and lower fasting glucose, HDL-cholesterol, apolipoprotein A-II and estimated glomerular filtration rate were independent predictors of higher LCN2 levels. Baseline A-FABP and LCN2 levels were associated with multiple new CVD and microvascular events over 5-years, though significance was lost after risk factor adjustment. Fenofibrate increased A-FABP but did not change LCN2 levels.
Baseline plasma A-FABP and LCN2 levels were associated with concurrent CVD risk factors, and on-trial chronic complications, likely mediated via traditional risk factors. Fenofibrate increased A-FABP modestly but did not affect LCN2 levels.
Clinical Trial Registration: ISRCTN 64783481.
Following the main ideas of Wang 1, we generalize Matié's results and establish our inequalities for functions with
n
th derivatives of bounded
p-variation. All of our error bounds are sharp in the ...sense that they cannot be replaced by smaller ones.
Hepatic ischemia/reperfusion (I/R) injury is a major cause of morbidity and mortality after liver surgery. Therefore, it is important to identity reliable biomarkers to assist early diagnosis of ...hepatic I/R injury. This study aimed to investigate the potential of serum levels of fibroblast growth factor 21 (FGF21) as a biomarker for hepatic I/R injury in patients with liver transplantation. Two independent cohorts of liver transplantation patients were recruited for determination of serum levels of FGF21, ALT, and AST. The results demonstrated that serum FGF21 at 2 hours post-reperfusion in cohort-1 exhibited an approximately 20-fold elevation relative to those in healthy subjects. In blood samples dynamically collected in cohort-2, a dramatic increase in serum FGF21 levels (~25-fold) was observed at two hours after surgery, whereas the peak levels of serum ALT and AST were detected only after 24 hours. Temporal correlation analysis demonstrated a significant association of peak serum levels of FGF21 at 2 hours with the magnitude of the increase in both serum ALT and AST levels at 24 hours post transplantation. In conclusion, serum FGF21 may represent a sensitive and specific prognostic biomarker for early detection of I/R injury in patients with liver transplantation.
Aims/hypothesis
Growing evidence supports that dysregulation of adipose tissue-derived factors contributes to the pathogenesis of diabetes and its complications. Since our global gene profiling ...analysis has identified lipocalin-14 (LCN14)—a secretory protein with lipid-binding properties—as a potential adipokine highly expressed in white adipose tissue (WAT), this study aims to explore the metabolic roles of LCN14 in obese mice, and to investigate the functional mechanisms involved.
Methods
Immunoassays and western blotting were performed to determine the circulating level and tissue distribution of LCN14, respectively. Recombinant adeno-associated virus (rAAV)-mediated gene delivery was used to overexpress LCN14 in diet-induced obese (DIO) mice and the effects on glucose and lipid metabolism were examined.
Results
LCN14 is expressed predominantly in WAT. Both circulating levels of LCN14 and its expression in adipose tissues are repressed in DIO and genetically inherited diabetic (
db/db
) mice. Overexpression of LCN14 by rAAV-mediated gene delivery in DIO mice significantly increased insulin sensitivity in major metabolic tissues and ameliorated hyperglycaemia by inhibiting hepatic gluconeogenesis. The reduced hepatic glucose production is attributed to the suppressive effects of LCN14 on the expression of gluconeogenic genes and on glycerol efflux in adipocytes, possibly by reducing the expression of aquaporin-7.
Conclusions/interpretation
Reduced LCN14 expression is involved in the pathogenesis of obesity-related metabolic dysregulation. LCN14 exerts its beneficial effects on glucose homeostasis and insulin sensitivity via its actions in both adipocytes and hepatocytes.
Levels of the endothelium-derived peptide endothelin-1 (ET-1) are elevated in obese humans, and ET-1 mediated vascular tone is increased. Renal arterial smooth muscle is highly responsive to ET-1. ...Whether or not endothelium-derived ET-1 affects contractions of the renal artery under normal conditions or in obesity is unknown. The present study was designed to investigate whether or not overexpression of endogenous ET-1 in the endothelium affects the responsiveness of the main and segmental renal arteries differently in obesity.
Mice with tie-1 promoter-driven endothelium-restricted heterozygous overexpression of preproendothelin-1 were used (TEThet). Obesity was induced in TEThet mice and wild-type (WT) littermates by feeding a high fat diet for 30weeks; lean controls were kept on standard chow. The renal arteries were studied in wire myographs testing contractions (in the presence of l-NAME) to ET-1, serotonin, and U46619.
Contractions to ET-1 were comparable between groups in main renal arteries, but augmented in segmental preparations from obese mice. Serotonin-induced responses were enhanced in obese TEThet mice renal arteries compared to lean controls. Concentration–contraction curves to U46619 were shifted significantly to the left in main renal arteries of obese animals, and the maximal response was significantly increased between lean and obese TEThet mice.
These results indicate an augmented responsiveness of main renal arteries in obesity particularly to TP receptor activation. When combined with endothelial ET-1 overexpression this effect is even more pronounced, which may help to gain further insights into the mechanisms of hypertension in obesity.
Display omitted
PDF
