Metabolism dysregulation induces a specific lipid signature of nonalcoholic steatohepatitis in patients

Sci Rep. 2017 Apr 24;7:46658. doi: 10.1038/srep46658.

Abstract

Nonalcoholic steatohepatitis (NASH) is a condition which can progress to cirrhosis and hepatocellular carcinoma. Markers for NASH diagnosis are still lacking. We performed a comprehensive lipidomic analysis on human liver biopsies including normal liver, nonalcoholic fatty liver and NASH. Random forests-based machine learning approach allowed characterizing a signature of 32 lipids discriminating NASH with 100% sensitivity and specificity. Furthermore, we validated this signature in an independent group of NASH patients. Then, metabolism dysregulations were investigated in both patients and murine models. Alterations of elongase and desaturase activities were observed along the fatty acid synthesis pathway. The decreased activity of the desaturase FADS1 appeared as a bottleneck, leading upstream to an accumulation of fatty acids and downstream to a deficiency of long-chain fatty acids resulting to impaired phospholipid synthesis. In NASH, mass spectrometry imaging on tissue section revealed the spreading into the hepatic parenchyma of selectively accumulated fatty acids. Such lipids constituted a highly toxic mixture to human hepatocytes. In conclusion, this study characterized a specific and sensitive lipid signature of NASH and positioned FADS1 as a significant player in accumulating toxic lipids during NASH progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / metabolism
  • Adult
  • Animals
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cells, Cultured
  • Disease Progression
  • Fatty Acid Desaturases / metabolism
  • Fatty Acid Elongases
  • Fatty Acids / metabolism
  • Female
  • Hep G2 Cells
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Humans
  • Lipid Metabolism
  • Lipids / analysis
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Male
  • Metabolomics / methods
  • Mice, Inbred C57BL
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Non-alcoholic Fatty Liver Disease / pathology

Substances

  • Fatty Acids
  • Lipids
  • Fatty Acid Desaturases
  • delta-5 fatty acid desaturase
  • Acetyltransferases
  • Fatty Acid Elongases