Metabolism dysregulation induces a specific lipid signature of nonalcoholic steatohepatitis in patients. Chiappini, F., Coilly, A., Kadar, H., Gual, P., Tran, A., Desterke, C., Samuel, D., Duclos-Vallée, J., Touboul, D., Bertrand-Michel, J., Brunelle, A., Guettier, C., & Le Naour, F. Scientific Reports, 7:46658, April, 2017. doi abstract bibtex 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.
@article{chiappini_metabolism_2017,
title = {Metabolism dysregulation induces a specific lipid signature of nonalcoholic steatohepatitis in patients},
volume = {7},
issn = {2045-2322},
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.},
language = {eng},
journal = {Scientific Reports},
author = {Chiappini, Franck and Coilly, Audrey and Kadar, Hanane and Gual, Philippe and Tran, Albert and Desterke, Christophe and Samuel, Didier and Duclos-Vallée, Jean-Charles and Touboul, David and Bertrand-Michel, Justine and Brunelle, Alain and Guettier, Catherine and Le Naour, François},
month = apr,
year = {2017},
pmid = {28436449},
pmcid = {PMC5402394},
pages = {46658},
}
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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.","language":"eng","journal":"Scientific Reports","author":[{"propositions":[],"lastnames":["Chiappini"],"firstnames":["Franck"],"suffixes":[]},{"propositions":[],"lastnames":["Coilly"],"firstnames":["Audrey"],"suffixes":[]},{"propositions":[],"lastnames":["Kadar"],"firstnames":["Hanane"],"suffixes":[]},{"propositions":[],"lastnames":["Gual"],"firstnames":["Philippe"],"suffixes":[]},{"propositions":[],"lastnames":["Tran"],"firstnames":["Albert"],"suffixes":[]},{"propositions":[],"lastnames":["Desterke"],"firstnames":["Christophe"],"suffixes":[]},{"propositions":[],"lastnames":["Samuel"],"firstnames":["Didier"],"suffixes":[]},{"propositions":[],"lastnames":["Duclos-Vallée"],"firstnames":["Jean-Charles"],"suffixes":[]},{"propositions":[],"lastnames":["Touboul"],"firstnames":["David"],"suffixes":[]},{"propositions":[],"lastnames":["Bertrand-Michel"],"firstnames":["Justine"],"suffixes":[]},{"propositions":[],"lastnames":["Brunelle"],"firstnames":["Alain"],"suffixes":[]},{"propositions":[],"lastnames":["Guettier"],"firstnames":["Catherine"],"suffixes":[]},{"propositions":[],"lastnames":["Le","Naour"],"firstnames":["François"],"suffixes":[]}],"month":"April","year":"2017","pmid":"28436449","pmcid":"PMC5402394","pages":"46658","bibtex":"@article{chiappini_metabolism_2017,\n\ttitle = {Metabolism dysregulation induces a specific lipid signature of nonalcoholic steatohepatitis in patients},\n\tvolume = {7},\n\tissn = {2045-2322},\n\tdoi = {10.1038/srep46658},\n\tabstract = {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. 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