Transthyretin is up-regulated by sex hormones in mice liver

Abstract

Misfolding and aggregation of mutated and wild-type transthyretin (TTR) can cause familial amyloid polyneuropathy (FAP) and senile systemic amyloidosis (SSA), respectively. In some populations, FAP onset seems to occur on average 2-11 years earlier in men than in women, and SSA appears to be a disease of elderly men. Most (95-100%) SSA patients described in the literature are men, suggesting that amyloid deposition in these patients may be sex hormone related. On the basis of gender-related differences in FAP onset, and on the almost exclusivity of SSA in elder men, we hypothesize that, sex hormones may increase TTR synthesis by the liver, and therefore, may contribute to amyloid deposition. In order to test this hypothesis, castrated female and male mice were implanted with alzet mini-osmotic pumps, delivering 17beta-estradiol (E2) or 5alpha-dihydrotestosterone (DHT), or vehicle only, for 1 week. Sham operated animals were also included in the experiment. After hormonal stimulation, mice were euthanized under anaesthesia, and liver and sera were collected. The expression of TTR in liver, and the levels of TTR in sera in response to E2 and DHT were analysed by Real Time PCR and radioimmunoassay, respectively. Data analysis showed that, both hormones induced TTR transcription, which was concurrent with a consistent increase in the circulating levels of the protein. Taken together, all these data provide an indication that sex hormone stimulation may constitute a risk factor for SSA.