Lipidomic signatures of NAFLD/NASH progression to HCC in a murine model with conditional hepatocyte-specific Pten deletion

Background: Nonalcoholic fatty liver disease (NAFLD) has become a major public health disease in the world, some of these patients will progress to decompensated liver cirrhosis or even liver cancer. To explore the systemic and dynamic lipid metabolic alterations during the pathological progression from NAFLD to spontaneous hepatocellular carcinoma (HCC) in an AlbCrePtenflox/flox mouse model. Methods: A multi-dimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) technology were used to quantify the main lipid classes in the liver and serum. Results: A total of 203 hepatic and 152 serum lipid species were detected. TAGs, PCs and phosphatidylinositol (PIs) contributed significantly to altered hepatic lipids from 10 weeks to 40 weeks in the Pten-null mutant mice. Enhanced levels of monounsaturated fatty acids (MUFAs) accompanied with reduced levels of polyunsaturated fatty acid (PUFAs) were detected in the liver tissue of the Pten-null mice. Reductions of PUFAs glycerophospholipids were also observed. In addition, alterations of 7, 16, 35 and 14 serum lipid species were observed in the Pten-null mutants from 10 to 60 weeks, correspondently (P < 0.05). A unique lipid signature with 8 TAG species in the liver and 1 particular PC (18:0-18:1) in the serum was consistently observed in the Pten-null mice with NASH. Conclusions: Collectively, the prominent and unique lipidomic signatures of NASH procession to HCC were identified in the Pten-null mice, which warranted for further validation as potential biomarkers for monitoring disease progression in patients with NASH. Keywords Nonalcoholic fatty liver disease; Hepatocellular carcinoma; Pten deficiency;Shotgun lipidomics