-The aim of this study was to determine whether nuclear factor-κB (NF-κB) inhibitors are efficient against hepatic ischemia/reperfusion (I/R) injury. We previously demonstrated that xanthine oxidase-derived reactive oxygen species activate NF-κB during ischemia. However, the role of NF-κB activation during ischemia in post-reperfusion injury remains unclear. Therefore, while we examined the effects of NF-κB inhibitors, sulfasalazine and pyrrolidinedithiocarbamate on hepatic I/R injury using a rat lobar hepatic I/R model, we estimated the relationship between NF-κB activation during ischemia and following hepatic damage caused by reperfusion. The portal vein and the hepatic artery were clamped for 1 hr followed by reperfusion for up to 24 hr. NF-κB activation was determined by Western blot analysis. NF-κB activation was observed in the ischemic lobe of the liver, and the activation was prevented by preadministration with NF-κB inhibitors. Although the serum ALT level, hepatic MPO activity and BSP clearance, as an index of hepatic injury, were increased after reperfusion, the increase was attenuated by pre-administration with NF-κB inhibitors. These findings suggest that NF-κB activation during ischemia is relevant to hepatic I/R injury. Moreover, we first showed that pre-administration with NF-κB inhibitors is effective against hepatic I/R injury.

Various pathological conditions can cause fatty liver in children. Nonalcoholic steatohepatitis (NASH) in children has been known since 1983. However, NASH diagnosed in childhood does not have a favorable outcome. The pathological characteristics of NASH are significantly different between children and adults. Nonalcoholic fatty liver disease (NAFLD)/NASH is accompanied by insulin resistance, which plays a pivotal role in its pathophysiology in both children and adults. In NASH, a "two-hit" model involving triglyceride accumulation (first hit) and liver damage (second hit) has been accepted. Insulin resistance was found to correlate with changes in fat levels; however, it did not correlate with fibrosis or NAFLD activity score in children. Therefore, insulin resistance may be important in the first hit. Because there is obvious familial clustering in NASH, genetic predisposition as well as environmental factors including diet might be the second hit of NAFLD/NASH.

Peroxisome proliferators (PxPs) are structurally diverse compounds, such as fibrates (hypolipidemic drugs), phthalate ester plasticizers, fatty acid analogues, cause induction of several proteins related to lipid metabolism, including peroxisomal b-oxidation (Px-ox), 1,2) accompanied by a hypolipidemic effect in rodents.3) Since the peroxisome proliferatoractivated receptors (PPARs), which are nuclear transcriptional receptors, 4) were found, they have been regarded as the wide lipid metabolism regulatory factors. Among the 3 subtypes of PPARs, a, b/d and g, PPARa is mainly involved in peroxisome proliferation, fatty acid b-oxidation, and plasma lipid metabolism, and is expressed predominantly in the livers and kidneys of rodents. 5) On hypolipidemic action, plasma triglyceride (TG) lowering effect of PxPs, which are PPARa ligands, are responses produced by PPARa-mediated transcriptional regulation. [6][7][8] However, in a contrasting line of studies, the TG lowering effect of PxPs was found to be exerted by a mechanism independent of PPARa.9-11) Thus, the mechanism of the hypolipidemic effect of PxPs has not been clearly established. Further, the implications of the two different and simultaneous responses by PxPs, which develop in a distant and distinct tissues, and their mechanisms, including physiological aims, and if it were, which is the initiator of another response, have not been elucidated.The plasma TG lowering effect of PxPs have been essentially ascribed to the induction of lipoprotein lipase (LPL) expression 12) and the inhibition of apolipoprotein C-III (apo C-III) gene transcription and activity. 13,14) The combined effects of PxPs toward LPL and apo C-III result in TG hydrolysis. On the other hand, fibrates induce fatty acid transporter protein in rat livers, 15) by which hepatic uptake of fatty acids is enhanced. A linear increasing correlation between Px-ox activity and cellular long chain fatty acid level by PxP was reported in rat cultured hepatocytes, 16) leading to hepatic TG accumulation when the TG synthesis process was completed, as well as a fibrate and a long chain fatty acid enhanced cellular TG level with a increase in Px-ox activity. 17) In in vivo experiments, PxPs including fatty acid analogues enhanced hepatic TG accumulation, 11,18,19) or in contrast, decrease it, [20][21][22] when the increase in Px-ox activity and the decrease in plasma TG were simultaneously observed. These discrepancy results could be due to the fact that physiological lipid metabolism is regulated by complicated, precise, and divers endogenous factors. Since the direct action of PxPs toward rat hepatocytes has been established, 23) we investigated the interrelationships among Px-ox activity, TG and apolipoprotein B (apo B) fluctuations in primary cultured rat hepatocytes in the present study, avoiding in vivo complex situations, especially hormonal modulations, organ-organ interrelation, moiety of blood components, physiological status and food intake. Cell Cultures and Treatments Rat parenchymal hepatocyte...