Nonalcoholic steatohepatitis (NASH) is a progressive form of
nonalcoholic fatty liver disease that can develop into
cirrhosis, hepatic failure, and
hepatocellular carcinoma. Although several metabolic pathways are disrupted and endogenous metabolites may change in NASH, the alterations in serum metabolites during NASH development remain unclear. To gain insight into the disease mechanism, serum metabolite changes were assessed using metabolomics with ultraperformance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry and a conventional mouse NASH model induced by a
methionine- and
choline-deficient (MCD) diet. Significant decreases in serum palmitoyl-, stearoyl-, and oleoyl-
lysophosphatidylcholine (LPC) and marked increases in tauro-β-muricholate,
taurocholate and 12-hydroxyeicosatetraenoic
acid (12-HETE) were detected in mice with NASH. In agreement with these metabolite changes, hepatic mRNAs encoding
enzymes and
proteins involved in LPC degradation (
lysophosphatidylcholine acyltransferase [Lpcat] 1-4), basolateral
bile acid excretion (
ATP-binding cassette subfamily C member [Abcc] 1/4/5 and organic solute transporter β), and
12-HETE synthesis (arachidonate 12-lipoxygenase) were significantly up-regulated. In contrast, the expression of solute carrier family 10 member 1 (Slc10a1) and solute carrier
organic anion transporter family member (Slco) 1a1 and 1b2, responsible for transporting
bile acids into hepatocytes, were markedly suppressed. Supplementation of the MCD diet with
methionine revealed that the changes in serum metabolites and the related gene expression were derived from
steatohepatitis, but not dietary
choline deficiency or steatosis. Furthermore,
tumor necrosis factor-α and transforming growth factor-β1 induced the expression of Lpcat2/4 and Abcc1/4 and down-regulated Slc10a1 and Slco1a1 in primary hepatocytes, suggesting an association between the changes in serum LPC and
bile acids and proinflammatory
cytokines. Finally, induction of
hepatitis in ob/ob mice by D-
galactosamine injection led to similar changes in serum metabolites and related gene expression.
CONCLUSION: