Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Trieb, M.
Liver disease alters high-density lipoprotein composition, metabolism and function
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp.
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Marsche Gunther
- Stadlbauer-Köllner Vanessa
- Altmetrics:
- Abstract:
- Liver disease is associated with an imbalanced inflammatory response and accompanied by an increased risk for infections and sepsis, but the underlying molecular mechanisms are poorly understood. The ability of high-density lipoprotein (HDL) to promote reverse cholesterol transport from lipid laden macrophages and other cells in the artery wall to the liver is considered to be the a major function of HDL. Recent insights have added other important HDL-mediated activities which are considered to contribute to HDLs protective properties, including anti-oxidative and anti-inflammatory activities. Therefore, HDL is emerging as a relevant player in innate and adaptive immunity and as a major endogenous inhibitor of inflammatory responses. It recently became evident that inflammatory disease can alter HDL composition thereby rendering it dysfunctional. Functional impairment of HDL might contribute to the excess mortality experienced by patients with liver disease, but the effect of cirrhosis on HDL metabolism and function remains elusive. Therefore, we sought to determine whether cirrhosis has an impact on HDL metabolism, composition and function. To get an integrated measure of HDL quantity and quality, we assessed several metrics of HDL function using serum HDL (serum containing HDL but depleted of low-density lipoprotein (LDL) and very low–density lipoprotein (VLDL)) from patients with compensated cirrhosis, patients with acutely decompensated cirrhosis and healthy controls. We observed a significant decrease in HDL-cholesterol levels and profoundly altered activities of enzymes involved in HDL metabolism in patients with cirrhosis, including phospholipid transfer protein, cholesteryl-ester transfer protein and lecithin-cholesterol acyltransferase. Native gel electrophoresis revealed a shift towards the large, cholesteryl rich HDL2 subclass with a concurrent reduction in the amount of small HDL3 particles. Furthermore, we identified several HDL-associated proteins to be altered in patients with cirrhosis. Interestingly, the detected changes in HDL-cholesterol levels, HDL protein composition and HDL particle distribution were strongly associated with metrics of HDL function. HDL of cirrhotic patients showed a significantly reduced capacity to inhibit nuclear factor-¿B activation in lipopolysaccharide stimulated monocytes. This resulted in an increased production of the pro-inflammatory cytokines tumor necrosis factor-a and interleukin-6. Furthermore, the ability of HDL to stimulate the activation of the endothelial nitric oxide synthase, as well as paraoxonase activity and endothelial regenerative and barrier promoting activities were significantly suppressed in cirrhotic patients. Of particular interest, cholesterol efflux, which was significantly reduced in patients with cirrhosis, appeared to be strongly associated with liver disease mortality. In conclusion, HDL metabolism, composition and function are significantly altered in cirrhosis. Importantly, HDL cholesterol efflux capacity appeared to predict 1-year mortality independent of HDL-cholesterol levels. Our findings may be clinically relevant and improve our ability to identify cirrhotic patients at high risk.