title: Metabolic profiling of fatty liver in young and middle-aged adults: Cross-sectional and prospective analyses of the Young Finns Study.
abstract: Nonalcoholic fatty liver is associated with obesity-related metabolic disturbances, but little is known about the metabolic perturbations preceding fatty liver disease. We performed comprehensive metabolic profiling to assess how circulating metabolites, such as lipoprotein lipids, fatty acids, amino acids, and glycolysis-related metabolites, reflect the presence of and future risk for fatty liver in young adults. Sixty-eight lipids and metabolites were quantified by nuclear magnetic resonance metabolomics in the population-based Young Finns Study from serum collected in 2001 (n = 1,575), 2007 (n = 1,509), and 2011 (n = 2,002). Fatty liver was diagnosed by ultrasound in 2011 when participants were aged 34-49 years (19% prevalence). Cross-sectional associations as well as 4-year and 10-year risks for fatty liver were assessed by logistic regression. Metabolites across multiple pathways were strongly associated with the presence of fatty liver (P < 0.0007 for 60 measures in age-adjusted and sex-adjusted cross-sectional analyses). The strongest direct associations were observed for extremely large very-low-density lipoprotein triglycerides (odds ratio [OR] = 4.86 per 1 standard deviation, 95% confidence interval 3.48-6.78), other very-low-density lipoprotein measures, and branched-chain amino acids (e.g., leucine OR = 2.94, 2.51-3.44). Strong inverse associations were observed for high-density lipoprotein measures, e.g., high-density lipoprotein size (OR = 0.36, 0.30-0.42) and several fatty acids including omega-6 (OR = 0.37, 0.32-0.42). The metabolic associations were attenuated but remained significant after adjusting for waist, physical activity, alcohol consumption, and smoking (P < 0.0007). Similar aberrations in the metabolic profile were observed already 10 years before fatty liver diagnosis.
  
  
  
  Circulating lipids, fatty acids, and amino acids reflect fatty liver independently of routine metabolic risk factors; these metabolic aberrations appear to precede the development of fatty liver in young adults. (Hepatology 2017;65:491-500).
authors: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.|Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
authors: Jari E
authors: JE
authors: Kaikkonen
authors: Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.
authors: Peter
authors: P
authors: Würtz
authors: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
authors: Emmi
authors: E
authors: Suomela
authors: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
authors: Miia
authors: M
authors: Lehtovirta
authors: Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.
authors: Antti J
authors: AJ
authors: Kangas
authors: National Institute for Health and Welfare, Turku, Finland.
authors: Antti
authors: A
authors: Jula
authors: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.|Division of Nutrition, Department of Food and Environmental Sciences, University of Helsinki, Helsinki, Finland.
authors: Vera
authors: V
authors: Mikkilä
authors: Department of Medicine, University of Turku and Division of Medicine, Turku University Hospital, Turku, Finland.
authors: Jorma S A
authors: JS
authors: Viikari
authors: Department of Medicine, University of Turku and Division of Medicine, Turku University Hospital, Turku, Finland.
authors: Markus
authors: M
authors: Juonala
authors: Department of Medicine, University of Turku and Division of Medicine, Turku University Hospital, Turku, Finland.
authors: Tapani
authors: T
authors: Rönnemaa
authors: Department of Pediatrics, Tampere University Hospital and University of Tampere, Tampere, Finland.
authors: Nina
authors: N
authors: Hutri-Kähönen
authors: Department of Clinical Physiology, Tampere University Hospital and University of Tampere, Tampere, Finland.
authors: Mika
authors: M
authors: Kähönen
authors: Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.
authors: Terho
authors: T
authors: Lehtimäki
authors: Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.|NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors: Pasi
authors: P
authors: Soininen
authors: Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.|NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.|School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.|Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
authors: Mika
authors: M
authors: Ala-Korpela
authors: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.|Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
authors: Olli T
authors: OT
authors: Raitakari
mesh_terms: D000328:Adult; D017677:Age Distribution; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000517:prevention & control; D003430:Cross-Sectional Studies; D005227:Fatty Acids / Q000097:blood; D005260:Female; D005387:Finland; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood*; D008079:Lipoproteins, VLDL / Q000097:blood*; D008297:Male; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood* / Q000000981:diagnostic imaging / Q000453:epidemiology*; D011237:Predictive Value of Tests; D015995:Prevalence; D011446:Prospective Studies; D018570:Risk Assessment; D017678:Sex Distribution; D018608:Ultrasonography, Doppler / Q000379:methods; D055815:Young Adult
chemical_list: D015415:Biomarkers; D005227:Fatty Acids; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL