Jan Kiss

Fatty Acid Metabolism in the Liver, Measured by Positron Emission Tomography, Is Increased in Obese Individuals

BACKGROUND & AIMS Hepatic lipotoxicity results from and contributes to obesity-related disorders. It is a challenge to study human metabolism of fatty acids (FAs) in the liver. We combined (11)C-palmitate imaging by positron emission tomography (PET) with compartmental modeling to determine rates of hepatic FA uptake, oxidation, and storage, as well as triglyceride release in pigs and human beings. METHODS Anesthetized pigs underwent (11)C-palmitate PET imaging during fasting (n = 3) or euglycemic hyperinsulinemia (n = 3). Metabolic products of FAs were measured in arterial, portal, and hepatic venous blood. The imaging methodology then was tested in 15 human subjects (8 obese subjects); plasma (11)C-palmitate kinetic analyses were used to quantify systemic and visceral lipolysis. RESULTS In pigs, PET-derived and corresponding measured FA fluxes (FA uptake, esterification, and triglyceride FA release) did not differ and were correlated with each other. In human beings, obese subjects had increased hepatic FA oxidation compared with controls (mean +/- standard error of the mean, 0.16 +/- 0.01 vs 0.08 +/- 0.01 micromol/min/mL; P = .0007); FA uptake and esterification rates did not differ between obese subjects and controls. Liver FA oxidation correlated with plasma insulin levels (r = 0.61, P = .016), adipose tissue (r = 0.58, P = .024), and systemic insulin resistance (r = 0.62, P = .015). Hepatic FA esterification correlated with the systemic release of FA into plasma (r = 0.71, P = .003). CONCLUSIONS PET imaging can be used to measure FA metabolism in the liver. By using this technology, we found that obese individuals have increased hepatic oxidation of FA, in the context of adipose tissue insulin resistance, and increased FA flux from visceral fat. FA flux from visceral fat is proportional with the mass of the corresponding depot.

IFN-beta protects from vascular leakage via up-regulation of CD73.

Changes in endothelial permeability are crucial in the pathogenesis of many diseases. Adenosine is one of the endogenous mediators controlling endothelial permeability under normal conditions, and an endothelial cell surface enzyme CD73 is a key regulator of adenosine production. Here we report that IFN‐β is a novel inducer of CD73. We found that pretreatment with IFN‐β dramatically improved the vascular barrier function in lungs after intestinal ischemia‐reperfusion injury in wild‐type animals in vivo. IFN‐β had absolutely no protective effects in CD73‐deficient mice, which suffered from more severe lung damage than wild‐type mice, showing that IFN‐β functions strictly in a CD73‐dependent manner. Most importantly, IFN‐β treatment initiated after the ischemic period almost completely inhibited vascular leakage during the reperfusion. IFN‐β also induced the expression and activity of CD73 and concurrently decreased vascular permeability in cultured human pulmonary endothelial cells. These data show that induction of CD73 and improvement of vascular barrier are new mechanisms for the anti‐inflammatory action of IFN‐β. Moreover, IFN‐β treatment may be useful in alleviating vascular leakage induced by ischemia‐reperfusion injury.

Non-invasive estimation of hepatic blood perfusion from H2 15O PET images using tissue-derived arterial and portal input functions

PurposeThe liver is perfused through the portal vein and the hepatic artery. When its perfusion is assessed using positron emission tomography (PET) and 15O-labeled water (H215O), calculations require a dual blood input function (DIF), i.e., arterial and portal blood activity curves. The former can be generally obtained invasively, but blood withdrawal from the portal vein is not feasible in humans. The aim of the present study was to develop a new technique to estimate quantitative liver perfusion from H215O PET images with a completely non-invasive approach.MethodsWe studied normal pigs (n = 14) in which arterial and portal blood tracer concentrations and Doppler ultrasonography flow rates were determined invasively to serve as reference measurements. Our technique consisted of using model DIF to create tissue model function and the latter method to simultaneously fit multiple liver time–activity curves from images. The parameters obtained reproduced the DIF. Simulation studies were performed to examine the magnitude of potential biases in the flow values and to optimize the extraction of multiple tissue curves from the image.ResultsThe simulation showed that the error associated with assumed parameters was <10%, and the optimal number of tissue curves was between 10 and 20. The estimated DIFs were well reproduced against the measured ones. In addition, the calculated liver perfusion values were not different between the methods and showed a tight correlation (r = 0.90).ConclusionIn conclusion, our results demonstrate that DIF can be estimated directly from tissue curves obtained through H215O PET imaging. This suggests the possibility to enable completely non-invasive technique to assess liver perfusion in patho-physiological studies.

Ischemia-reperfusion injury is attenuated in VAP-1-deficient mice and by VAP-1 inhibitors

Neutrophils mediate the damage caused by ischemia‐reperfusion both at the site of primary injury and in remote organs. Vascular adhesion protein‐1 (VAP‐1) is an ectoenzyme expressed on endothelial cells and it has been shown to regulate leukocyte extravasation. Here we show for the first time using VAP‐1‐deficient mice that VAP‐1 plays a significant role in the intestinal damage and acute lung injury after ischemia‐reperfusion. Separate inhibition of VAP‐1 by small molecule enzyme inhibitors and a function‐blocking monoclonal antibody in WT mice revealed that the catalytic activity of VAP‐1 is responsible for its pro‐inflammatory action. The use of transgenic humanized VAP‐1 mice also showed that the enzyme inhibitors alleviate both the ischemia‐reperfusion injury in the gut and neutrophil accumulation in the lungs. These data thus indicate that VAP‐1 regulates the inflammatory response in ischemia‐reperfusion injury and suggest that blockade of VAP‐1 may have therapeutic value.

Quantification of liver perfusion with [15O]H2O-PET and its relationship with glucose metabolism and substrate levels

BACKGROUND/AIMS Hepatic perfusion plays an important role in liver physiology and disease. This study was undertaken to (a) validate the use of Positron Emission Tomography (PET) and oxygen-15-labeled water ([(15)O]H(2)O) to quantify hepatic and portal perfusion, and (b) examine relationships between portal perfusion and liver glucose and lipid metabolism. METHODS Liver [(15)O]H(2)O-PET images were obtained in 14 pigs during fasting or hyperinsulinemia. Carotid arterial and portal venous blood were sampled for [(15)O]H(2)O activity; Doppler ultrasonography was used invasively as the reference method. A single arterial input compartment model was developed to estimate portal tracer kinetics and liver perfusion. Endogenous glucose production (EGP) and insulin-mediated whole body glucose uptake (wbGU) were determined by standard methods. RESULTS Hepatic arterial and portal venous perfusions were 0.15+/-0.07 and 1.11+/-0.34 ml/min/ml of tissue, respectively. The agreement between ultrasonography and [(15)O]H(2)O-PET was good for total and portal liver perfusion, and poor for arterial perfusion. Portal perfusion was correlated with EGP (r=or+0.62, p=0.03), triglyceride (r=or+0.66, p=0.01), free fatty acid levels (r=or+0.76, p=0.003), and plasma lactate levels (r=or-0.81, p=0.0009). CONCLUSIONS Estimates of liver perfusion by [(15)O]H(2)O-PET compared well with those by ultrasonography. The method allowed to predict portal tracer concentrations which is essential in human studies. Portal perfusion may affect liver nutrient handling.

Non-invasive diagnosis of acute mesenteric ischaemia using PET.

PurposeAcute mesenteric ischaemia (AMI) is a lethal disease with an increasing incidence. Despite the availability of effective treatment, AMI remains a vascular emergency with over 60% mortality rate mainly due to late diagnosis. The difficulty in diagnosing this fatal condition stems from non-specific clinical and laboratory findings and lack of appropriate imaging study. Our aim was to test a non-invasive method of identifying AMI using PET.MethodsThe study was conducted in normal pigs (n = 14), sham-operated pigs (n = 4) and pigs undergoing ischaemia and reperfusion of intestine (n = 6). Liver blood flow was imaged by H215O PET and liver blood content by C15O PET. Both scans were performed during intestinal ischaemia and during reperfusion.ResultsAMI was identified by PET imaging of hepatic perfusion and blood pool. The H215O PET scan during AMI detected a 40% decrease in total liver perfusion, which was caused by a 45% reduction of portal blood flow and no alteration in arterial blood flow. Compromised hepatic perfusion during AMI was accompanied by a 75% decrease in hepatic blood pool recognized by the C15O PET scan. The striking reduction of liver blood flow and blood content persisted during reperfusion of intestine.ConclusionOur results demonstrate that AMI can be readily recognized by PET imaging of liver blood flow and blood content. Moreover, PET can be used in detection of perfusion abnormalities after revascularization. This non-invasive imaging tool could represent a novel approach to diagnose AMI.

Antioxidants combined with NO donor enhance systemic inflammation in acute lung injury in rats

Objectives. Acute lung injury and acute respiratory distress syndrome (ALI, ARDS) are well-known complications of cardiac and major vascular surgery. ARDS is associated with high mortality and no effective treatment is available. Protective effects of antioxidants or nitric oxide (NO) in experimental studies were not confirmed in clinical trials, but the potential beneficial effects of their combination are poorly known. This study was designed to investigate whether concomitant administration of NO donor and antioxidants has synergic effects on lung protection in ALI. Design. ALI was induced in rats by intestinal ischemia-reperfusion. Superoxide dismutase and catalase were administered as antioxidants and arginine as NO donor. Lung wet-dry ratio, MPO activity, tissue-air ratio, airspace hemorrhage and serum TNF-α were used as parameters of lung injury and systemic inflammation. Results. Antioxidants and arginine significantly reduced lung damage when administered separately. However, concomitant administration of antioxidants and arginine abolished the protective effects and enhanced systemic inflammation. Conclusions. Our data suggests that antioxidants and NO in combination should be avoided in clinical practice.