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

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

Chiappini F1,2,3, Coilly A1,2,3,4, Kadar H5, Gual P6,7,8, Tran A6,7,8, Desterke C9,10, Samuel D1,2,3,4, Duclos-Vallée JC1,2,3,4, Touboul D5, Bertrand-Michel J11, Brunelle A5, Guettier C1,2,3,12, Le Naour F1,2,3,9,10.

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Inserm, Unité 1193, Villejuif, F-94800, France.
Univ Paris-Sud, UMR-S1193, Villejuif, F-94800, France.
DHU Hepatinov, Villejuif, F-94800, France.
AP-HP, Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, F-94800, France.
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Univ. Paris-Sud, Université Paris-Saclay, F-91198 Gif-Sur-Yvette, France.
Inserm, Unité 1065, Nice, F-06204, France.
University of Nice-Sophia-Antipolis, Nice, F-06204, France.
Centre Hospitalier Universitaire de Nice, Hôpital L'Archet, Nice Cedex 3, F-06202, France.
Inserm, US33, Villejuif, F-94800, France.
Univ Paris-Sud, US33, Villejuif, F-94800, France.
MetaToul-Lipidomic Facility, MetaboHUB, Inserm UMR1048, Toulouse, F-31432, France.
AP-HP, Hôpital du Kremlin-Bicêtre, Service d'Anatomopathologie, Le Kremlin-Bicêtre, F-94275, France.


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.

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