Inflammatory liver steatosis caused by IL-12 and IL-18.
Acute fatty degeneration in the liver is caused by various agents, such as aspirin, valproic acid, and ibuprofen, that directly inhibit mitochondrial beta-oxidation of fatty acid and oxidative phosphorylation. Endogenous molecules, such as cytokines and hormones, are also known to mediate microvesicular steatosis in liver failure. In this study, we examined how interleukin-12 (IL-12) and IL-18 cause steatosis in the liver. Administration of these cytokines in combination caused marked hepatosteatosis and weight loss in mice. There were marked increases in levels of interferon-gamma (IFN-gamma), nitrite (NO(2)/NO(3)), and fibrinogen in the circulation in these mice. On the other hand, the ATP concentration and blood flow in the liver were significantly reduced. These changes, except the production of IFN-gamma and NO, were partially inhibited by Z-VAD-fmk, a synthetic tripeptide inhibitor for NO-induced caspases. These results indicate that IL-12 and IL-18 may mediate inflammatory hepatosteatosis through impairment of the microcirculation, which leads to mitochondrial dysfunction in hepatocytes.
Kaneda
Masaya
M
Department of Gastroenterology, Hyogo College of Medicine, Nishinomiya, 663-8501, Japan.
Kashiwamura
Shin-Ichiro
S
Ueda
Haruyasu
H
Sawada
Koji
K
Sugihara
Ayako
A
Terada
Nobuyuki
N
Kimura-Shimmyo
Akiko
A
Fukuda
Yoshihiro
Y
Shimoyama
Takashi
T
Okamura
Haruki
H
D000255:Adenosine Triphosphate / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005234:Fatty Liver / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D018664:Interleukin-12 / Q000633:toxicity*; D020382:Interleukin-18 / Q000633:toxicity*; D017078:Laser-Doppler Flowmetry; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood / Q000378:metabolism; D010084:Oxidation-Reduction; D012039:Regional Blood Flow; D013997:Time Factors
D000590:Amino Acid Chloromethyl Ketones; D020382:Interleukin-18; D009573:Nitrites; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D005340:Fibrinogen; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse