title: Ketone body production is differentially altered in steatosis and non-alcoholic steatohepatitis in obese humans.
abstract: OBJECTIVE
  Levels of ketone bodies have been reported to be both increased and decreased in individuals with non-alcoholic fatty liver disease. We investigated whether the metabolism of ketone bodies is different in simple steatosis and in non-alcoholic steatohepatitis (NASH).
  
  
  METHODS
  Serum low molecular weight molecules including ketone bodies were measured using high-throughput proton (1H) nuclear magnetic resonance in 116 (76 categorized unequivocally to those with normal liver, simple steatosis or NASH) morbidly obese individuals [age 47.3 ± 8.7 (mean ± SD) years, body mass index 45.1 ± 6.1 kg/m(2) , 39 men and 77 women] with histological assessment of NASH and analysis of gene expression in the liver. Finally, we correlated β-hydroxybutyrate (β-OHB) levels with NASH predicting score in Metabolic Syndrome in Men Study (METSIM) population study (n = 8749 non-diabetic men).
  
  
  RESULTS
  Levels of ketone bodies were lower in individuals with NASH compared to individuals with simple steatosis (P = 0.004 and P = 0.018 for β-OHB and acetoacetate respectively). Lower levels of β-OHB were associated with the NASH predicting score in the METSIM study (P = 0.001). Liver inflammation correlated with mRNA expression of genes regulating ketolysis in the liver (Spearman correlation 0.379-0.388, P < 0.0006 for ACAT1, ACSS2 and BDH1).
  
  
  CONCLUSIONS
  Lower levels of ketone bodies in individuals with NASH compared to individuals with simple steatosis suggest a decrease in ketone body metabolism in NASH.
authors.affiliation: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Ville T
authors.initials: VT
authors.lastname: Männistö
authors.affiliation: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Simonen
authors.affiliation: Department of Medicine, University of Helsinki, Helsinki and Minerva Medical Research Institute, Helsinki, Finland.
authors.forename: Jenni
authors.initials: J
authors.lastname: Hyysalo
authors.affiliation: NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.|Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland.
authors.forename: Pasi
authors.initials: P
authors.lastname: Soininen
authors.affiliation: NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.|Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland.
authors.forename: Antti J
authors.initials: AJ
authors.lastname: Kangas
authors.affiliation: Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Kaminska
authors.affiliation: Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
authors.forename: Ananda K
authors.initials: AK
authors.lastname: Matte
authors.affiliation: Department of Surgery, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Sari
authors.initials: S
authors.lastname: Venesmaa
authors.affiliation: Department of Surgery, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Pirjo
authors.initials: P
authors.lastname: Käkelä
authors.affiliation: Department of Pathology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Vesa
authors.initials: V
authors.lastname: Kärjä
authors.affiliation: Department of Pathology, The Laboratory of Helsinki University Central Hospital, Helinski, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Arola
authors.affiliation: Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.|Department of Medicine, Division of Internal Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Helena
authors.initials: H
authors.lastname: Gylling
authors.affiliation: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Henna
authors.initials: H
authors.lastname: Cederberg
authors.affiliation: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
authors.affiliation: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.affiliation: Department of Medicine, University of Helsinki, Helsinki and Minerva Medical Research Institute, Helsinki, Finland.
authors.forename: Hannele
authors.initials: H
authors.lastname: Yki-Järvinen
authors.affiliation: NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.|Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland.|Computational Medicine, School of Social and Community Medicine & Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: Mika
authors.initials: M
authors.lastname: Ala-Korpela
authors.affiliation: Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.|Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Pihlajamäki
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000097:blood; D000106:Acetate-CoA Ligase / Q000235:genetics / Q000378:metabolism; D000101:Acetyl-CoA C-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005234:Fatty Liver / Q000097:blood* / Q000175:diagnosis / Q000209:etiology / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D057166:High-Throughput Screening Assays; D006801:Humans; D006884:Hydroxybutyrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D007657:Ketone Bodies / Q000097:blood*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood* / Q000175:diagnosis / Q000209:etiology / Q000235:genetics; D009767:Obesity, Morbid / Q000150:complications* / Q000175:diagnosis; D066244:Proton Magnetic Resonance Spectroscopy; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D015415:Biomarkers; D005230:Fatty Acids, Nonesterified; D007657:Ketone Bodies; D012333:RNA, Messenger; D006884:Hydroxybutyrate Dehydrogenase; C506639:ACAT1 protein, human; D000101:Acetyl-CoA C-Acetyltransferase; C000595379:ACSS2 protein, human; D000106:Acetate-CoA Ligase; D020155:3-Hydroxybutyric Acid
keywords: NASH; ketone bodies; lipid oxidation; serum NMR analysis; β-hydroxybutyrate