Characterization of hepatic lipid profiles in a mouse model with nonalcoholic steatohepatitis and subsequent fibrosis.

Abstract

Nonalcoholic steatohepatitis (NASH) is a major health problem since it often leads to hepatocellular carcinoma. However, the underlying mechanisms of NASH development and subsequent fibrosis have yet to be clarified. We compared comprehensive lipidomic profiles between mice with high fat diet (HFD)-induced steatosis and STAM mice with NASH and subsequent fibrosis. The STAM mouse is a model that demonstrates NASH progression resembling the disease in humans: STAM mice manifest NASH at 8 weeks, which progresses to fibrosis at 12 weeks, and finally develop hepatocellular carcinoma. Overall, 250 lipid molecules were detected in the liver using liquid chromatography-mass spectrometry. We found that STAM mice with NASH presented a significantly higher abundance of sphingolipids and lower levels of triacylglycerols than the HFD-fed control mice. The abundance of certain fatty acids in phospholipid side chains was also significantly different between STAM and control mice, although global levels of phosphatidylcholines and phosphatidylethanolamines were comparable. Finally, increase in levels of acylcarnitines and some diacylglycerols was observed in STAM mice toward the fibrosis stage, but not in age-matched control mice. Our study provides insights into the lipid status of the steatotic, NASH, and fibrotic liver that would help elucidate the molecular pathophysiology of NASH progression.