Background: Obesity and liver fat are associated with decreased levels of sex hormone-binding globulin (SHBG). Previous laboratory studies have suggested that hepatic de novo lipogenesis (DNL) is involved in the downregulation of SHBG synthesis. The aim of the present study was to address the role of DNL on serum SHBG in humans.

Methods: This study consisted of two sub studies; 1) a cross-sectional study that examined the association between DNL, measured through stable isotopes, and serum SHBG in two combined cohorts (n=55), 2) a case-control study that compared serum SHBG in healthy individuals (n=14) with four monogenetic disorders affecting DNL and/or causing liver fat: glucokinase-maturity onset diabetes of the young (GCK-MODY; model of decreased DNL; n=11), glycogen storage disease type 1a (GSD1a; model of increased DNL; n=9), familial partial lipodystrophy (FPL, model of increased fatty acid flux; n=13) and abetalipoproteinemia (ABL, model of impaired VLDL secretion; n=2).

Results: DNL was inversely associated with serum SHBG in women (β: -0.015, 95%CI: -0.030;0.000), but not in men (0.007, 95%CI: -0.005;0.019) (p for interaction=0.068). This strength of association was hardly affected after correction for insulin in women (β: -0.013, 95%CI: -0.028;0.003). Serum SHBG levels were significantly lower in GSD1a patients when compared to controls (median: 13.0 nmol/L versus 43.0 nmol/L, p=0.003). Serum SHBG levels in GCK-MODY, FPL and ABL were not different from controls, despite a higher liver fat content in the latter two groups. Additional adjustment for serum insulin did not affect these outcomes.

Discussion: An inverse association between DNL and SHBG  may explain the decreased SHBG levels that are observed in obesity.