title: Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease.
abstract: Nonalcoholic fatty liver disease (NAFLD) can progress from simple steatosis (i.e., nonalcoholic fatty liver [NAFL]) to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Currently, the driver for this progression is not fully understood; in particular, it is not known how NAFLD and its early progression affects the distribution of lipids in the liver, producing lipotoxicity and inflammation. In this study, we used dietary and genetic mouse models of NAFL and NASH and translated the results to humans by correlating the spatial distribution of lipids in liver tissue with disease progression using advanced mass spectrometry imaging technology. We identified several lipids with distinct zonal distributions in control and NAFL samples and observed partial to complete loss of lipid zonation in NASH. In addition, we found increased hepatic expression of genes associated with remodeling the phospholipid membrane, release of arachidonic acid (AA) from the membrane, and production of eicosanoid species that promote inflammation and cell injury. The results of our immunohistochemistry analyses suggest that the zonal location of remodeling enzyme LPCAT2 plays a role in the change in spatial distribution for AA-containing lipids. This results in a cycle of AA-enrichment in pericentral hepatocytes, membrane release of AA, and generation of proinflammatory eicosanoids and may account for increased oxidative damage in pericentral regions in NASH.
  
  
  
  NAFLD is associated not only with lipid enrichment, but also with zonal changes of specific lipids and their associated metabolic pathways. This may play a role in the heterogeneous development of NAFLD. (Hepatology 2017;65:1165-1180).
authors.affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.|MRC Human Nutrition Research, Cambridge, United Kingdom.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Hall
authors.affiliation: MRC Human Nutrition Research, Cambridge, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Bond
authors.affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Ashmore
authors.affiliation: MRC Human Nutrition Research, Cambridge, United Kingdom.
authors.forename: Francis
authors.initials: F
authors.lastname: Sanders
authors.affiliation: MRC Human Nutrition Research, Cambridge, United Kingdom.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Ament
authors.affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Xinzhu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murray
authors.affiliation: Fondazione Mario Negri Sud, Santa Maria Imbaro, Chieti, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Bellafante
authors.affiliation: Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Sam
authors.initials: S
authors.lastname: Virtue
authors.affiliation: Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
authors.affiliation: Liver Unit, Department of Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Allison
authors.affiliation: Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Davies
authors.affiliation: MRC Human Nutrition Research, Cambridge, United Kingdom.
authors.forename: Albert
authors.identifier: 0000-0001-9998-051X
authors.initials: A
authors.lastname: Koulman
authors.affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.|MRC Human Nutrition Research, Cambridge, United Kingdom.|Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Michele
authors.initials: M
authors.lastname: Vacca
authors.affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.|MRC Human Nutrition Research, Cambridge, United Kingdom.
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D059305:Diet, High-Fat; D066273:Diet, Western; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology*; D010743:Phospholipids / Q000378:metabolism*; D011379:Prognosis; D011897:Random Allocation; D018570:Risk Assessment; D012720:Severity of Illness Index; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D015777:Eicosanoids; D010743:Phospholipids