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

Abstract

Thyroid hormones increase hepatic sex hormone-binding globulin (SHBG) production, which is also regulated by hepatocyte nuclear factor-4a (HNF-4a) 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-4a 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-4a mRNA and HNF-4a 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-4a 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-4a siRNA, or by blocking the b-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-4a gene expression, and by reducing cellular palmitate levels that further contribute to increased HNF-4a levels in hepatocytes.

Quality of life in patients with primary hypothyroidism related to BMI

“…SHBG is known to be a marker of hepatic TH state (17). In our study, a higher SHBG corresponded with a better QOL on various subscales.…”

“…In a study by Escobar-Morreale et al (16) in hypothyroid rats, no single dose of T 4 or T 3 could restore euthyroidism in all tissues at the same time, probably because of varying expression and function of TH transporters and deiodinases. Sex hormone binding globulin (SHBG) is known to be a marker of hepatic TH state (17) and could be a useful parameter of TH status at tissue level.…”

Inhibin B Levels in Hypothyroid Males

“…Thyroid hormone increases the production of plasma sex hormone binding globulin (SHBG) indirectly by increasing HNF-4a, but SHBG levels are low in hypothyroidism (13). As a result, total testosterone levels are low in hypothyroidism.…”

Sex hormone-binding globulin gene expression in the liver: Drugs and the metabolic syndrome

“…A c c e p t e d M a n u s c r i p t 5 Although another upstream HNF-4 binding site has little effect on basal transcription from the SHBG promoter, Selva and Hammond (2009b) have shown that this site also functions as a PPAR-response element (see below).…”

“…Surprisingly, Page 13 of 24 A c c e p t e d M a n u s c r i p t 13 treatment of HepG2 cells with rosiglitazone reduces SHBG production and SHBG promoter activity by 20-25%, whereas the PPARγ antagonist, GW9662, increased both by 2-3 fold (Selva and Hammond, 2009b). Moreover, these studies demonstrated that a common genetic variant of PPARγ-2 (Pro12 variant), which is transcriptionally more active than the PPARγ-2 Ala12 variant, is much more effective in repressing SHBG expression in HepG2 cells.…”