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D Selva, Child & Family Research Institute, Vancouver, British Columbia, Canada
G Hammond, Child & Family Research Institute, Vancouver, British Columbia, V5Z 4H4, Canada

Correspondence: Geoffrey Hammond, Email: ghammond{at}cw.bc.ca

Abstract

Thyroid hormones increase hepatic sex hormone-binding globulin (SHBG) production, which is also regulated by hepatocyte nuclear factor-4 (HNF-4) 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 hepatic HNF-4 levels using the HepG2 human hepatoblastoma cell line, and in transgenic mice that express a 4.3 kb human SHBG transgene under the control of its own 0.8 kb promoter sequence. Thyroid hormones (T3 and T4) increase SHBG accumulation in HepG2 cell culture medium over 5 days, and increase cellular SHBG mRNA levels. In addition, T4 treatment of HepG2 cells for 5 days increased HNF-4 mRNA and HNF-4 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 T3 along with increased hepatic HNF-4 levels. In HepG2 cells, the human SHBG promoter failed to respond acutely (within 24 h) to T4 treatment, but a 4 day pre-treatment with T4 resulted in a robust response that was prevented by co-treatment with HNF-4 siRNA, or by blocking the beta-oxidation of palmitate through co-treatment with the carnitine palmitoyltransferase I inhibitor, etomoxir. These data have lead us to conclude that thyroid hormones increase SHBG production indirectly by increasing HNF-4 expression and by reducing cellular palmitate levels that further contribute to increased HNF-4 levels in hepatocytes.