Diiodothyronines regulate metabolic homeostasis in primary human hepatocytes by modulating mTORC1 and mTORC2 activity

• Published in: Molecular and cellular endocrinology 2020-01, Vol.499, p.110604-110604, Article 110604
• Main Authors: Gnocchi, Davide, Ellis, Ewa C.S., Johansson, Helene, Eriksson, Mats, Bruscalupi, Giovannella, Steffensen, Knut R., Parini, Paolo
• Format: Article
• Language: English
• Subjects: Diiodothyronines; Human primary hepatocytes; Lipid and glucose metabolism; Medicin och hälsovetenskap; Metabolic homeostasis; mTORC1; mTORC2
• ISSN: 0303-7207; 1872-8057; 1872-8057
• DOI: 10.1016/j.mce.2019.110604

Until three decades, ago 3,5-diiodothyronine (3,5-T2) and 3,3′-diiodothyronine (3,3′-T2) were considered products of thyroid hormone catabolism without biological activity. Some metabolic effects have been described in rodents, but the physiological relevance in humans and the mechanisms of action are unknown. Aim of this work was to investigate the role and the mechanisms of action of 3,5-T2 and 3,3′-T2 in the regulation of metabolic homeostasis in human liver. We used primary human hepatocytes freshly isolated from donors and grown on Matrigel as the golden standard in vitro model to study human hepatic metabolism. Results show that diiodothyronines in the range of plasma physiological concentrations reduced hepatic lipid accumulation, by modulating the activity of the mTORC1/Raptor complex through an AMPK-mediated mechanism, and stimulated the mTORC2/Rictor complex-activated pathway, leading to the down regulation of the expression of key gluconeogenic genes. Hence, we propose that diiodothyronines act as key regulators of hepatic metabolic homeostasis in humans. [Display omitted] •Diiodothyronines regulate metabolic homeostasis in primary human hepatocytes.•Diiodothyronines exert their effect at plasma physiological concentrations.•Diiodothyronines modulate mTORC1 and mTORC2 activity.•mTORC2 is a key effector in transmitting DIDT signal.•Diiodothyronines regulate bile acid production.