Synthetic triglyceride containing an arachidonic acid branch (8A8) prevents lipopolysaccharide-induced liver injury.
OBJECTIVE
In this study, we investigated the effect of synthetic triglyceride containing an arachidonic acid branch (8A8) on lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-alpha and nitric oxide (NO) in macrophages, and LPS-induced liver injury in the rat.


METHODS
RAW264.7 macrophages were co-incubated with 8A8 and LPS (100ng/ml), and TNF-alpha mRNA/protein levels, nuclear factor (NF)-kappaB DNA binding activity, expression of inducible-type NO synthase (NOS2), and NO(2) production were measured. Male Wistar rats were given a single intraperitoneal injection of 8A8 prior to an intravenous injection of LPS (5mg/kg), and liver histology, apoptotic cell death, serum TNF-alpha levels, and hepatic TNF-alpha mRNA were then evaluated.


RESULTS
LPS-induced increases in TNF-alpha production in RAW264.7 macrophages were blunted by 8A8 in a dose-dependent manner, with 40% inhibition at 100ppm. Further, 8A8 dose-dependently prevented LPS-induced increases in TNF-alpha mRNA levels, as well as NF-kappaB DNA binding activities, in RAW264.7 macrophages. LPS-induction of NOS2 and NO(2) release from these cells was also decreased by 8A8 in a dose-dependent manner. In vivo, LPS-induced liver injury, including hepatocyte apoptosis, was largely prevented when 8A8 (100microl/kg) was given 30min prior to LPS. Indeed, 8A8 blunted increases in both serum TNF-alpha and hepatic TNF-alpha mRNA levels significantly.


CONCLUSIONS
LPS-induced liver injury was prevented by 8A8 most likely through the inhibition of TNF-alpha and NO production from hepatic macrophages, suggesting a potential usefulness of 8A8 as an immuno-modulating nutrient for prevention/treatment of endotoxin-related organ injuries including alcoholic liver disease and non-alcoholic steatohepatitis (NASH).
Piao
Nanzhe
N
Department of Gastroenterology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
Ikejima
Kenichi
K
Kon
Kazuyoshi
K
Aoyama
Tomonori
T
Osada
Taro
T
Takei
Yoshiyuki
Y
Sato
Nobuhiro
N
Watanabe
Sumio
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D063386:Cannabinoid Receptor Agonists; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006520:Hepatitis, Animal / Q000378:metabolism / Q000517:prevention & control*; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000637:Transaminases / Q000097:blood; D014280:Triglycerides / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism*
C539983:1,3-capryloyl-2-arachidonoyl glycerol; D063386:Cannabinoid Receptor Agonists; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D000637:Transaminases