Synthetic triglyceride containing an arachidonic acid branch (8A8) prevents lipopolysaccharide-induced liver injury

Abstract

Aims 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)-α and nitric oxide (NO) in macrophages, and LPS-induced liver injury in the rat. Main methods RAW264.7 macrophages were co-incubated with 8A8 and LPS (100 ng/ml), and TNF-α mRNA/protein levels, nuclear factor (NF)-κB 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 (5 mg/kg), and liver histology, apoptotic cell death, serum TNF-α levels, and hepatic TNF-α mRNA were then evaluated. Key findings LPS-induced increases in TNF-α production in RAW264.7 macrophages were blunted by 8A8 in a dose-dependent manner, with 40% inhibition at 100 ppm. Further, 8A8 dose-dependently prevented LPS-induced increases in TNF-α mRNA levels, as well as NF-κB 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 (100 µl/kg) was given 30 min prior to LPS. Indeed, 8A8 blunted increases in both serum TNF-α and hepatic TNF-α mRNA levels significantly. Significance LPS-induced liver injury was prevented by 8A8 most likely through the inhibition of TNF-α 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).