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.