Increased heme oxygenase-1 and decreased delta-aminolevulinate synthase expression in the liver of patients with acute liver failure.
Acute liver failure (ALF) remains a serious problem in critical care with a high rate of mortality. Although the pathophysiology of ALF has not been fully elucidated, oxidative stress has been in part implicated in its pathogenesis. Heme oxygenase-1 (HO-1) is known to be induced not only by its substrate, heme, but also by various oxidative stresses, and thought to play an important role in the protection of the host from oxidative tissue injuries. In the present study, we examined expression of HO-1 as well as the non-specific delta-aminolevulinate synthase (ALAS-N, or ALAS1), the rate-limiting enzyme in heme catabolism and biosynthesis, respectively, in the livers of patients with ALF. Compared with livers from control subjects who had various disorders, but normal hepatic function, HO-1 in the liver of ALF patients was highly up-regulated at both transcriptional and protein levels. Immunohistochemical studies demonstrated that HO-1 expression occurred predominantly in hepatocytes, but not in non-parenchymal cells. In contrast to HO-1, ALAS1 gene expression was markedly down-regulated in ALF patients compared with controls. These findings suggest that, in the liver of ALF patients, there may be an increase in free heme concentration which up-regulates HO-1 gene expression, while down-regulating ALAS1 gene expression, resulting in markedly altered heme metabolism and liver function.
Fujii
Hiromi
H
Department of Anesthesiology and Resuscitology, Okayama University Medical School, Okayama 700-8558, Japan.
Takahashi
Toru
T
Matsumi
Masaki
M
Kaku
Ryuji
R
Shimizu
Hiroko
H
Yokoyama
Masataka
M
Ohmori
Emiko
E
Yagi
Takahito
T
Sadamori
Hiroshi
H
Tanaka
Noriaki
N
Akagi
Reiko
R
Morita
Kiyoshi
K
D000624:5-Aminolevulinate Synthetase / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D007150:Immunohistochemistry; D017114:Liver Failure, Acute / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D008565:Membrane Proteins; D012333:RNA, Messenger; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D000624:5-Aminolevulinate Synthetase