The
metabolic syndrome is associated with
nonalcoholic fatty liver disease (
NAFLD) as well as with
insulin resistance, inflammatory
adipokines, endothelial dysfunction, and higher plasma levels of
nonesterified fatty acids (
NEFA), all of which may also affect the development of
NAFLD. Therefore, we investigated to what extent the association between the
metabolic syndrome and
alanine aminotransferase (ALT, as a surrogate of
NAFLD) can be explained by different metabolic intermediates of the
metabolic syndrome. Cross-sectional analyses were performed in 434 subjects from the Cohort on Diabetes and
Atherosclerosis Maastricht study (264 men; mean age, 59.5 ± 7.1 years). We used multiple linear regression analyses to investigate the association between the
metabolic syndrome and ALT and the mediation role of potential mediators herein. The mediators considered were
insulin resistance (homeostasis model assessment), an inflammatory
adipokine score (based on
interleukin-6,
serum amyloid A,
intercellular adhesion molecule,
adiponectin, and
leptin), an endothelial dysfunction score (based on
E-selectin,
vascular cell adhesion molecule, and
von Willebrand factor), and plasma levels of
NEFA. All analyses were adjusted for age, sex, smoking, alcohol consumption, and use of medication. Subjects with the
metabolic syndrome (53.7%) had significantly higher levels of ALT (β = 0.67 SD [95% confidence interval, 0.49-0.85], P < .001). Adjustment for
insulin resistance attenuated this difference by 77.3% (to 0.15 SD [-0.04 to 0.35]). Attenuation by adipose tissue-associated
inflammation, endothelial dysfunction, and
NEFA was more modest (20.7%, 13.1%, and 9.5%, respectively). Part of the attenuation by
NEFA, but not of the other mediators, was additional to that of
insulin resistance.
Insulin resistance constitutes a key pathophysiological mechanism in the association between the
metabolic syndrome and
NAFLD (measured as ALT), which may operate through adipose tissue-associated
inflammation and endothelial dysfunction and to a lesser extent through
NEFA, which may have an independent role in the development of
NAFLD in subjects with the
metabolic syndrome.