Nicotine increases hepatocyte transthyretin turnover: A possible mechanism for the protective effect of smoking on preeclampsia?

Abstract

Transthyretin is a thyroid hormone binding protein with a major role in the distribution of thyroid hormones to peripheral tissues. In preeclampsia, the failing placenta releases soluble endoglin into the maternal circulation causing systemic vascular dysfunction. Our group has previously shown that transthyretin binds to soluble endoglin and is taken up as a complex into hepatocytes. The risk of developing preeclampsia is greatly reduced by smoking cigarettes. The addictive component of cigarette smoke, nicotine, increases transthyretin expression in rodent brain and also stabilises binding between thyroxine and transthyretin.

The aim of this study was to determine the effects of nicotine on transthyretin expression, secretion and uptake by hepatocytes and if nicotine altered the uptake of transthyretin bound soluble endoglin. Nicotine treatment increased transthyretin mRNA and protein levels in cultured hepatocytes. Using live cell imaging, Alexa-transthyretin uptake was significantly increased in the presence of nicotine. Alexa-soluble endoglin uptake was also significantly increased by exposure to nicotine. The transthyretin-Alexa-soluble endoglin complex was taken up via the low-density lipoprotein receptor related protein-1 (LRP1). LRP1 protein levels were unaffected in nicotine treated hepatocytes.

Nicotine exposure increases hepatocyte synthesis, secretion and uptake of transthyretin as well as cell uptake of soluble endoglin. Nicotine may protect against preeclampsia by increasing serum TTR which can bind soluble endoglin and remove it from the circulation. Further research is required to better understand the role of transthyretin and nicotine in mitigating preeclampsia.