Liver disease alters high-density lipoprotein composition, metabolism and function.
High-density lipoproteins (HDL) are important endogenous inhibitors of inflammatory responses. 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 remain elusive. To get an integrated measure of HDL quantity and quality, we assessed several metrics of HDL function using apolipoprotein (apo) B-depleted sera from patients with compensated cirrhosis, patients with acutely decompensated cirrhosis and healthy controls. We observed that sera of cirrhotic patients showed reduced levels of HDL-cholesterol and profoundly suppressed activities of several enzymes involved in HDL maturation and metabolism. Native gel electrophoresis analyses revealed that cirrhotic serum HDL shifts towards the larger HDL2 subclass. Proteomic assessment of isolated HDL identified several proteins, including apoA-I, apoC-III, apoE, paraoxonase 1 and acute phase serum amyloid A to be significantly altered in cirrhotic patients. With regard to function, these alterations in levels, composition and structure of HDL were strongly associated with metrics of function of apoB-depleted sera, including cholesterol efflux capability, paraoxonase activity, the ability to inhibit monocyte production of cytokines and endothelial regenerative activities. Of particular interest, cholesterol efflux capacity appeared to be strongly associated with liver disease mortality. Our findings may be clinically relevant and improve our ability to monitor cirrhotic patients at high risk.
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria.
Markus
M
Trieb
Division of Gastroenterology and Hepatology, Medical University of Graz, Austria.
Angela
A
Horvath
Research Unit of Functional Proteomics and Metabolic Pathways, Institute of Pathology, Medical University of Graz, Austria.
Ruth
R
Birner-Gruenberger
Division of Gastroenterology and Hepatology, Medical University of Graz, Austria.
Walter
W
Spindelboeck
Division of Gastroenterology and Hepatology, Medical University of Graz, Austria. Electronic address: vanessa.stadlbauer@medunigraz.at.
Vanessa
V
Stadlbauer
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria.
Ulrike
U
Taschler
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria.
Sanja
S
Curcic
Division of Gastroenterology and Hepatology, Medical University of Graz, Austria.
Rudolf E
RE
Stauber
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria.
Michael
M
Holzer
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria.
Lisa
L
Pasterk
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria.
Akos
A
Heinemann
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria. Electronic address: gunther.marsche@medunigraz.at.
Gunther
G
Marsche
D000368:Aged; D016632:Apolipoprotein A-I / Q000097:blood*; D053305:Apolipoprotein C-III / Q000097:blood*; D001055:Apolipoproteins B / Q000097:blood*; D001057:Apolipoproteins E / Q000097:blood; D043303:Aryldialkylphosphatase / Q000097:blood; D001663:Bilirubin / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood; D003404:Creatinine / Q000097:blood; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000097:blood* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D012709:Serum Albumin / Q000378:metabolism; D000685:Serum Amyloid A Protein; D016019:Survival Analysis; D014280:Triglycerides / Q000097:blood
C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D053305:Apolipoprotein C-III; D001055:Apolipoproteins B; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D016207:Cytokines; D012709:Serum Albumin; D000685:Serum Amyloid A Protein; D014280:Triglycerides; D003404:Creatinine; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D001663:Bilirubin
Cholesterol efflux; HDL-function; HDL-proteome; LCAT; Liver disease; Paraoxonase