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

Davide Gnocchi; Ewa C S Ellis; Helene Johansson; Mats Eriksson; Giovannella Bruscalupi; Knut R Steffensen; Paolo Parini

doi:10.1016/j.mce.2019.110604

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

Mol Cell Endocrinol. 2020 Jan 1:499:110604. doi: 10.1016/j.mce.2019.110604. Epub 2019 Sep 30.

Authors

Davide Gnocchi¹, Ewa C S Ellis², Helene Johansson², Mats Eriksson³, Giovannella Bruscalupi⁴, Knut R Steffensen¹, Paolo Parini⁵

Affiliations

¹ Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Stockholm, S-141 52, Sweden.
² Unit for Transplantation Surgery, Department of Clinical Science, Intervention and Technology, CLINTEC, Karolinska University Hospital Huddinge, Stockholm, S-141 86, Sweden.
³ Metabolism Unit, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, S-141 86, Sweden.
⁴ Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Rome, 00185, Italy.
⁵ Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Stockholm, S-141 52, Sweden; Metabolism Unit, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, S-141 86, Sweden; Patient Area Endocrinology and Nephrology, Inflammation and Infection Theme, Karolinska University Hospital, Stockholm, Sweden. Electronic address: paolo.parini@ki.se.

PMID: 31580898
DOI: 10.1016/j.mce.2019.110604

Abstract

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.

Keywords: Diiodothyronines; Human primary hepatocytes; Lipid and glucose metabolism; Metabolic homeostasis; mTORC1; mTORC2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Survival / drug effects
Cells, Cultured
Diiodothyronines / pharmacology*
Female
Gene Expression Regulation / drug effects
Hepatocytes / cytology*
Hepatocytes / drug effects
Hepatocytes / metabolism
Homeostasis / drug effects
Humans
Male
Mechanistic Target of Rapamycin Complex 1 / metabolism*
Mechanistic Target of Rapamycin Complex 2 / metabolism*
Primary Cell Culture
Signal Transduction / drug effects
Triglycerides / metabolism

Substances

Diiodothyronines
Triglycerides
3,5-diiodothyronine
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2