Influence of neonatal hypothyroidism on hepatic gene expression and lipid metabolism in adulthood

Ruymán Santana-Farré; Mercedes Mirecki-Garrido; Carlos Bocos; Luis A Henríquez-Hernández; Nusrat Kahlon; Emilio Herrera; Gunnar Norstedt; Paolo Parini; Amilcar Flores Morales; Leandro Fernández-Pérez

doi:10.1371/journal.pone.0037386

Influence of neonatal hypothyroidism on hepatic gene expression and lipid metabolism in adulthood

Ruymán Santana-Farré, Mercedes Mirecki-Garrido, Carlos Bocos, Luis A Henríquez-Hernández, Nusrat Kahlon, Emilio Herrera, Gunnar Norstedt, Paolo Parini, Amilcar Flores Morales, Leandro Fernández-Pérez

Novo Nordisk Foundation Center for Protein Research

14 Citations (Scopus)

Abstract

Thyroid hormones are required for normal growth and development in mammals. Congenital-neonatal hypothyroidism (CH) has a profound impact on physiology, but its specific influence in liver is less understood. Here, we studied how CH influences the liver gene expression program in adulthood. Pregnant rats were given the antithyroid drug methimazole (MMI) from GD12 until PND30 to induce CH in male offspring. Growth defects due to CH were evident as reductions in body weight and tail length from the second week of life. Once the MMI treatment was discontinued, the feed efficiency increased in CH, and this was accompanied by significant catch-up growth. On PND80, significant reductions in body mass, tail length, and circulating IGF-I levels remained in CH rats. Conversely, the mRNA levels of known GH target genes were significantly upregulated. The serum levels of thyroid hormones, cholesterol, and triglycerides showed no significant differences. In contrast, CH rats showed significant changes in the expression of hepatic genes involved in lipid metabolism, including an increased transcription of PPARα and a reduced expression of genes involved in fatty acid and cholesterol uptake, cellular sterol efflux, triglyceride assembly, bile acid synthesis, and lipogenesis. These changes were associated with a decrease of intrahepatic lipids. Finally, CH rats responded to the onset of hypothyroidism in adulthood with a reduction of serum fatty acids and hepatic cholesteryl esters and to T3 replacement with an enhanced activation of malic enzyme. In summary, we provide in vivo evidence that neonatal hypothyroidism influences the hepatic transcriptional program and tissue sensitivity to hormone treatment in adulthood. This highlights the critical role that a euthyroid state during development plays on normal liver physiology in adulthood.

Original language	English
Article number	e37386
Journal	PLOS ONE
Volume	7
Issue number	5
Pages (from-to)	e37386
DOIs	https://doi.org/10.1371/journal.pone.0037386
Publication status	Published - 16 May 2012

Access to Document

10.1371/journal.pone.0037386

Cite this

@article{1c4bdc0ce2a94e648db29a21b0d51dee,

title = "Influence of neonatal hypothyroidism on hepatic gene expression and lipid metabolism in adulthood",

abstract = "Thyroid hormones are required for normal growth and development in mammals. Congenital-neonatal hypothyroidism (CH) has a profound impact on physiology, but its specific influence in liver is less understood. Here, we studied how CH influences the liver gene expression program in adulthood. Pregnant rats were given the antithyroid drug methimazole (MMI) from GD12 until PND30 to induce CH in male offspring. Growth defects due to CH were evident as reductions in body weight and tail length from the second week of life. Once the MMI treatment was discontinued, the feed efficiency increased in CH, and this was accompanied by significant catch-up growth. On PND80, significant reductions in body mass, tail length, and circulating IGF-I levels remained in CH rats. Conversely, the mRNA levels of known GH target genes were significantly upregulated. The serum levels of thyroid hormones, cholesterol, and triglycerides showed no significant differences. In contrast, CH rats showed significant changes in the expression of hepatic genes involved in lipid metabolism, including an increased transcription of PPARα and a reduced expression of genes involved in fatty acid and cholesterol uptake, cellular sterol efflux, triglyceride assembly, bile acid synthesis, and lipogenesis. These changes were associated with a decrease of intrahepatic lipids. Finally, CH rats responded to the onset of hypothyroidism in adulthood with a reduction of serum fatty acids and hepatic cholesteryl esters and to T3 replacement with an enhanced activation of malic enzyme. In summary, we provide in vivo evidence that neonatal hypothyroidism influences the hepatic transcriptional program and tissue sensitivity to hormone treatment in adulthood. This highlights the critical role that a euthyroid state during development plays on normal liver physiology in adulthood.",

author = "Ruym{\'a}n Santana-Farr{\'e} and Mercedes Mirecki-Garrido and Carlos Bocos and Henr{\'i}quez-Hern{\'a}ndez, {Luis A} and Nusrat Kahlon and Emilio Herrera and Gunnar Norstedt and Paolo Parini and {Flores Morales}, Amilcar and Leandro Fern{\'a}ndez-P{\'e}rez",

year = "2012",

month = may,

day = "16",

doi = "10.1371/journal.pone.0037386",

language = "English",

volume = "7",

pages = "e37386",

journal = "PLoS Computational Biology",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "5",

}

TY - JOUR

T1 - Influence of neonatal hypothyroidism on hepatic gene expression and lipid metabolism in adulthood

AU - Santana-Farré, Ruymán

AU - Mirecki-Garrido, Mercedes

AU - Bocos, Carlos

AU - Henríquez-Hernández, Luis A

AU - Kahlon, Nusrat

AU - Herrera, Emilio

AU - Norstedt, Gunnar

AU - Parini, Paolo

AU - Flores Morales, Amilcar

AU - Fernández-Pérez, Leandro

PY - 2012/5/16

Y1 - 2012/5/16

N2 - Thyroid hormones are required for normal growth and development in mammals. Congenital-neonatal hypothyroidism (CH) has a profound impact on physiology, but its specific influence in liver is less understood. Here, we studied how CH influences the liver gene expression program in adulthood. Pregnant rats were given the antithyroid drug methimazole (MMI) from GD12 until PND30 to induce CH in male offspring. Growth defects due to CH were evident as reductions in body weight and tail length from the second week of life. Once the MMI treatment was discontinued, the feed efficiency increased in CH, and this was accompanied by significant catch-up growth. On PND80, significant reductions in body mass, tail length, and circulating IGF-I levels remained in CH rats. Conversely, the mRNA levels of known GH target genes were significantly upregulated. The serum levels of thyroid hormones, cholesterol, and triglycerides showed no significant differences. In contrast, CH rats showed significant changes in the expression of hepatic genes involved in lipid metabolism, including an increased transcription of PPARα and a reduced expression of genes involved in fatty acid and cholesterol uptake, cellular sterol efflux, triglyceride assembly, bile acid synthesis, and lipogenesis. These changes were associated with a decrease of intrahepatic lipids. Finally, CH rats responded to the onset of hypothyroidism in adulthood with a reduction of serum fatty acids and hepatic cholesteryl esters and to T3 replacement with an enhanced activation of malic enzyme. In summary, we provide in vivo evidence that neonatal hypothyroidism influences the hepatic transcriptional program and tissue sensitivity to hormone treatment in adulthood. This highlights the critical role that a euthyroid state during development plays on normal liver physiology in adulthood.

AB - Thyroid hormones are required for normal growth and development in mammals. Congenital-neonatal hypothyroidism (CH) has a profound impact on physiology, but its specific influence in liver is less understood. Here, we studied how CH influences the liver gene expression program in adulthood. Pregnant rats were given the antithyroid drug methimazole (MMI) from GD12 until PND30 to induce CH in male offspring. Growth defects due to CH were evident as reductions in body weight and tail length from the second week of life. Once the MMI treatment was discontinued, the feed efficiency increased in CH, and this was accompanied by significant catch-up growth. On PND80, significant reductions in body mass, tail length, and circulating IGF-I levels remained in CH rats. Conversely, the mRNA levels of known GH target genes were significantly upregulated. The serum levels of thyroid hormones, cholesterol, and triglycerides showed no significant differences. In contrast, CH rats showed significant changes in the expression of hepatic genes involved in lipid metabolism, including an increased transcription of PPARα and a reduced expression of genes involved in fatty acid and cholesterol uptake, cellular sterol efflux, triglyceride assembly, bile acid synthesis, and lipogenesis. These changes were associated with a decrease of intrahepatic lipids. Finally, CH rats responded to the onset of hypothyroidism in adulthood with a reduction of serum fatty acids and hepatic cholesteryl esters and to T3 replacement with an enhanced activation of malic enzyme. In summary, we provide in vivo evidence that neonatal hypothyroidism influences the hepatic transcriptional program and tissue sensitivity to hormone treatment in adulthood. This highlights the critical role that a euthyroid state during development plays on normal liver physiology in adulthood.

U2 - 10.1371/journal.pone.0037386

DO - 10.1371/journal.pone.0037386

M3 - Journal article

C2 - 22666351

SN - 1932-6203

VL - 7

SP - e37386

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 5

M1 - e37386

ER -

Influence of neonatal hypothyroidism on hepatic gene expression and lipid metabolism in adulthood

Abstract

Access to Document

Fingerprint

Cite this