HEINZL Matthias

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

Publications:

Heinzl MW, Schönbacher M, Dauber EM, Panzer S, Mayr WR, Körmöczi GF. Detection of granulocyte-reactive antibodies: a comparison of different methods. Vox Sang 108: 287-293, 2015

Schönbacher M1, Heinzl MW, Dauber EM, Mayr WR, Panzer S, Körmöczi GF. Granulocyte-reactive antibodies are associated with red blood cell alloimmunization. Vox Sang 107: 200-203, 2014