Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4α

Thyroid hormones increase hepatic sex hormone-binding globulin (SHBG) production, which is also regulated by hepatocyte nuclear factor-4 alpha (HNF-4 alpha) in response to changes in the metabolic state of the liver. Since the human SHBG promoter lacks a typical thyroid hormone response element, and because thyroid hormones influence metabolic state, we set out to determine whether thyroid hormones mediate SHBG expression indirectly via changes in HNF-4 alpha levels in HepG2 human hepatoblastoma cells, and in the livers of transgenic mice that express a 4.3 kb human SHBG transgene under the control of its own 0.8 kb promoter sequence. Thyroid hormones (triiodothyronine (T-3) and thyroxine (T-4)) increase SHBG accumulation in HepG2 cell culture medium over 5 days, and increase cellular SHBG mRNA levels. In addition, T-4 treatment of HepG2 cells for 5 days increased HNF-4 alpha mRNA and HNF-4 alpha levels in concert with decreased cellular palmitate levels. Plasma SHBG levels were also increased in mice expressing a human SHBG transgene after 5 days treatment with T-3 along with increased hepatic HNF-4 alpha levels. In HepG2 cells, the human SHBG promoter failed to respond acutely (within 24 h) to T-4 treatment, but a 4-day pre-treatment with T-4 resulted in a robust response that was prevented by co-treatment with HNF-4 alpha siRNA, or by blocking the beta-oxidation of palmitate through co-treatment with the carnitine palmitoyltransferase I inhibitor, etomoxir. These data lead us to conclude that thyroid hormones increase SHBG production indirectly by increasing HNF-4 alpha gene expression, and by reducing cellular palmitate levels that further contribute to increased HNF-4 alpha levels in hepatocytes.