title: Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease.
abstract: OBJECTIVE
  Recent data in mice have identified de novo ceramide synthesis as the key mediator of hepatic insulin resistance (IR) that in humans characterizes increases in liver fat due to IR ('Metabolic NAFLD' but not that due to the I148M gene variant in PNPLA3 ('PNPLA3 NAFLD'). We determined which bioactive lipids co-segregate with IR in the human liver.
  
  
  METHODS
  Liver lipidome was profiled in liver biopsies from 125 subjects that were divided into equally sized groups based on median HOMA-IR ('High and Low HOMA-IR', n=62 and n=63) or PNPLA3 genotype (PNPLA3(148MM/MI), n=61 vs. PNPLA3(148II), n=64). The subjects were also divided into 4 groups who had either IR, the I148M gene variant, both of the risk factors or neither.
  
  
  RESULTS
  Steatosis and NASH prevalence were similarly increased in 'High HOMA-IR' and PNPLA3(148MM/MI) groups compared to their respective control groups. The 'High HOMA-IR' but not the PNPLA3(148MM/MI) group had features of IR. The liver in 'High HOMA-IR' vs. 'Low HOMA-IR' was markedly enriched in saturated and monounsaturated triacylglycerols and free fatty acids, dihydroceramides (markers of de novo ceramide synthesis) and ceramides. Markers of other ceramide synthetic pathways were unchanged. In PNPLA3(148MM/MI)vs. PNPLA3(148II), the increase in liver fat was due to polyunsaturated triacylglycerols while other lipids were unchanged. Similar changes were observed when data were analyzed using the 4 subgroups.
  
  
  CONCLUSIONS
  Similar increases in liver fat and NASH are associated with a metabolically harmful saturated, ceramide-enriched liver lipidome in 'Metabolic NAFLD' but not in 'PNPLA3 NAFLD'. This difference may explain why metabolic but not PNPLA3 NAFLD increases the risk of type 2 diabetes and cardiovascular disease.
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Electronic address: panu.luukkonen@fimnet.fi.
authors.forename: Panu K
authors.initials: PK
authors.lastname: Luukkonen
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: You
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Sanja
authors.initials: S
authors.lastname: Sädevirta
authors.affiliation: Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Marja
authors.initials: M
authors.lastname: Leivonen
authors.affiliation: Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Arola
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Matej
authors.initials: M
authors.lastname: Orešič
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Tuulia
authors.initials: T
authors.lastname: Hyötyläinen
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Hannele
authors.initials: H
authors.lastname: Yki-Järvinen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001706:Biopsy; D002518:Ceramides / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology; D012307:Risk Factors; D055815:Young Adult
chemical_list: D002518:Ceramides
keywords: Ceramides; Dihydroceramides; Free fatty acids; Insulin resistance; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; PNPLA3; Patatin-like phospholipase domain containing protein 3