Augmenter of liver regeneration (ALR) is a novel biomarker of hepatocellular stress/inflammation: in vitro, in vivo and in silico studies.
The liver is a central organ involved in inflammatory processes, including the elaboration of acute-phase proteins. Augmenter of liver regeneration (ALR) protein, expressed and secreted by hepatocytes, promotes liver regeneration and maintains viability of hepatocytes. ALR also stimulates secretion of inflammatory cytokines (tumor necrosis factor [TNF]-α and interleukin [IL]-6) and nitric oxide from Kupffer cells. We hypothesized that ALR may be involved in modulating inflammation induced by various stimuli. We found that hepatic ALR levels are elevated at 24 h, before or about the same time as an increase in the mRNA expression of TNF-α and IL-6, after portacaval shunt surgery in rats. Serum ALR also increased, but significantly only on d 4 when pathological changes in the liver become apparent. In rats, serum ALR was elevated after intraperitoneal administration of lipopolysaccharide alone and in a model of gram-negative sepsis. Serum ALR increased before alanine aminotransferase (ALT) in endotoxemia and in the same general time frame as TNF-α and IL-6 in the bacterial sepsis model. Furthermore, mathematical prediction of tissue damage correlated strongly with alterations in serum ALR in a mouse model of hemorrhagic shock. In vitro, monomethyl sulfonate, TNF-α, actinomycin D and lipopolysaccharide all caused increased release of ALR from rat hepatocytes, which preceded the loss of cell viability and/or inhibition of DNA synthesis. ALR may thus serve as a potential diagnostic marker of hepatocellular stress and/or acute inflammatory conditions.
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Yoram
Y
Vodovotz
John
J
Prelich
Claudio
C
Lagoa
Derek
D
Barclay
Ruben
R
Zamora
Noriko
N
Murase
Chandrashekhar R
CR
Gandhi
D000818:Animals; D015415:Biomarkers / Q000097:blood; D003198:Computer Simulation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D007249:Inflammation / Q000097:blood / Q000473:pathology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000097:blood / Q000150:complications / Q000235:genetics / Q000473:pathology; D012771:Shock, Hemorrhagic / Q000097:blood / Q000150:complications / Q000473:pathology; D013312:Stress, Physiological; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D050862:Oxidoreductases Acting on Sulfur Group Donors
D015415:Biomarkers; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011506:Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C088825:GFER protein, rat; D050862:Oxidoreductases Acting on Sulfur Group Donors