Proprotein Convertase Subtilisin/Kexin Type 9 as a possible mediator between inflammation and lipid metabolism
Sepsis is a severe clinical syndrome with still limited means of therapy and often poor prognosis. It has been recognized lately that sepsis and inflammation has an important impact on lipid metabolism and that the extent of hypocholesterolemia may even be a marker of severity of illness. One possible mediator between inflammation and sepsis could be proprotein convertase subtilisin kexin type 9 (PCSK9), a key regulator of plasma low-density lipoprotein cholesterol. PCSK9 is mostly produced and secreted by the liver and causes intracellular degradation of hepatic receptors for low-density lipoprotein cholesterol, thus resulting in higher plasma low-density lipoprotein cholesterol. In mouse models, PCSK9 has been shown to be induced strongly under septic conditions. On the other hand, PCSK9 deficiency seems to attenuate inflammatory reactions, which suggests an elementary pathophysiologic role of this protein in inflammation and sepsis, and even seems be a protective factor in human sepsis as well. However, PCSK9 kinetics in human sepsis is, to date, unknown.
This study aims to investigate the interaction between inflammation and lipid metabolism and the possible role of PCSK9 using the human endotoxin model in ten healthy volunteers. In this model, volunteers are infused intravenously with bacterial lipopolysaccharide (LPS) to simulate human sepsis. Immediately after the infusion of LPS, proinflammatory cytokines and other mediators are elevated just as they are in common sepsis. This widely used model thus represents a reliable method for evaluating conditions during inflammation.
In this study, LPS will be administered to ten healthy male volunteers aged 18-40 years and plasma levels of PCSK9 and other parameters will subsequently be measured to evaluate the influence of LPS on lipid metabolism and the possible role of PCSK9.
Blood samples will be centrifuged, transferred into chilled tubes and placed on ice. Plasma will be frozen at –20°C until it will be assayed. Plasma and urine sodium, potassium, creatinine and glucose will be measured via routine laboratory techniques. Hormones will be measured by commercially available kits, cytokines will be measured by immunoenzymometric assays. Serum levels of PCSK9 will be measured using a dual-monoclonal antibody sandwich ELISA. A case record form will be completed for each volunteer and data will subsequently be handled in an anonymous manner. Data will be analysed using repeated measures ANOVA.
In summary, this study aims to evaluate the interactions between sepsis and lipid metabolism using the human endotoxin model focusing on the possible role of PCSK9. Such knowledge could improve the understanding of the pathophysiology in human sepsis and may lead to the development of novel therapeutic strategies. Insights on possible interactions between inflammation and lipid metabolism could also enlighten pathophysiological pathways in metabolic syndrome and type 2 diabetes mellitus causing chronic low-grade inflammation with potential impact on various medical fields.
Methods and Skills:
Human endotoxin model
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