8). Although serum levels of 18:0- and 18:1-LPC were constitutively higher in ob/ob mice than those in wild-type mice, serum LPC levels were significantly decreased and serum levels of Selleckchem 3-deazaneplanocin A tauro-β-muricholate and taurocholate were markedly increased in GalN-injected ob/ob mice compared with saline-injected

ob/ob mice (Supporting Fig. 9A). The changes in the related gene expression corresponded to those in serum metabolites (Supporting Fig. 9B). Therefore, these results corroborate the view that decreased LPC and increased tauro-β-muricholate and taurocholate in serum were caused by enhancement of hepatic inflammatory signaling (Fig. 7). Serum metabolomic analysis in the present study revealed that 16:0-, 18:0-, and 18:1-LPC were significantly decreased and tauro-β-muricholate, taurocholate, and 12-HETE markedly increased in mice with PXD101 NASH induced by MCD diet treatment. The decreases in serum LPC resulted from hepatic up-regulation of Lpcat1-4, and the increases in serum bile acids were related to increased expression of Abcc1/4 and reduced expression of Slc10a1 and Slco1a1. Interestingly, these changes depended on steatohepatitis, but not dietary choline deficiency and the resultant steatosis. Furthermore, the mRNAs encoding Lpcat2/4 and Abcc1/4 were induced and those encoding Slc10a1 and Slco1a1 were suppressed

by TNF-α and/or TGF-β1 in primary hepatocytes, medchemexpress suggesting a direct contribution of proinflammatory cytokines to altered expression

of these genes. Finally, similar changes in serum metabolites and related gene expression were also detected in GalN-injected ob/ob mice showing steatohepatitis. These results demonstrate that phospholipid and bile acid metabolism is disrupted or significantly altered in NASH, likely because of enhancement of hepatic inflammation (Fig. 7). The decreases in serum LPC concentrations detected in mice with NASH were significantly correlated with hepatic up-regulation of Lpcat1-4, especially Lpcat1/2/4. Because the liver is known to be a major source of serum LPC,24, 25 it is plausible that serum LPC levels are strongly influenced by hepatic Lpcat expression. However, serum concentrations of 18:0- and 18:1-LPC were increased in ob/ob mice compared with wild-type mice regardless of unaltered Lpcat1-4 mRNA levels (Supporting Fig. 9), suggesting the presence of complex regulatory mechanisms of serum LPC concentrations. Lpcat1 expression was also significantly increased in both NASH models, but was not induced by exposure to TNF-α, TGF-β1, and H2O2 in primary hepatocytes. This is in agreement with a report that the activity and expression of Lpcat1 are independent of inflammatory stimuli in macrophages, in contrast to Lpcat2.26 At present, the precise mechanism of Lpcat1 regulation during these disease processes remains unclear.