Influence of neonatal hypothyroidism on hepatic gene expression and lipid metabolism in adulthood - PubMed (original) (raw)
Influence of neonatal hypothyroidism on hepatic gene expression and lipid metabolism in adulthood
Ruymán Santana-Farré et al. PLoS One. 2012.
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.
Conflict of interest statement
Competing Interests: The authors have read the journal's policy and have the following conflicts: AF-M is supported by the Novo Nordisk Foundation. This does not alter our adherence to all the PLoS ONE policies on sharing data and materials.
Figures
Figure 1. Effects of neonatal hypothyroidism on body growth development.
Percentages of body weight rate (A) or tail length rate (B) were measured at 7-d intervals as described in Material and Methods. Results are expressed as mean ± SD from six individual animals in each group. **, P<0.01, ***, P<0.001 for comparison with INTACT group.
Figure 2. Effects of neonatal hypothyroidism on mRNA expression levels of IGF-I and IGFBP genes in adult rat liver.
On PND80, the hepatic mRNA levels of IGF-I (A), IGFBP3 (B), and IGFBP2 (C) were measured by qPCR in rats exposed to neonatal hypothyroidism (CH), age-matched (INTACT) or weight-paired (WP) control groups. The mean mRNA expression level of each gene in the INTACT group is defined as 1, with all other expression values reported relative to this level. Bars represent mean ± SD from at least six individual animals. ***, P<0.001 for comparison with INTACT group. +++, P<0.001 for comparison with WP group.
Figure 3. Effects of neonatal hypothyroidism on mRNA expression levels of SOCS/CIS and male predominant genes in adult rat liver.
On PND80, the hepatic mRNA levels of SOCS2 (A), CIS (B), SOCS3 (C), PIAS3 (D), SOCS5 (E), CYP2C11 (F), CYP2C13 (G) and CYP2C7 (H) were measured by qPCR in rats exposed to neonatal hypothyroidism (CH), age-matched (INTACT) or weight-paired (WP) control groups. The mean mRNA expression level of each gene in the INTACT group is defined as 1, with all other expression values reported relative to this level. Bars represent mean ± SD from at least six individual animals. ***, P<0.001 for comparison with INTACT group. ++, P<0.01; +++, P<0.001 for comparison with WP group.
Figure 4. Effects of neonatal hypothyroidism on mRNA expression levels of genes related with lipid metabolism in adult rat liver.
On PND80, the hepatic mRNA levels of PPARα (A), CPT1 (B), ME (C), SREBP1c (D), ACC1 (E), FAS (F), CYP4FI (G), AOX (H), and L-FABP (I) were measured by qPCR in CH, age-matched INTACT, or weight-paired (WP) control groups. The mean mRNA expression level of each gene in the INTACT group is defined as 1, with all other expression values reported relative to this level. Bars represent mean ± SD from at least five individual animals. *, P<0.05; ***, P<0.001 for comparison with INTACT group. ++, P<0.01; +++, P<0.001 for comparison with WP group.
Figure 5. Effects of congenital hypothyroidism on mRNA expression levels of INSIG-1, SREBP2, LXR, and genes involved in lipid transport in adult rat liver.
On PND80, the hepatic mRNA levels of INSIG1 (A), SREBP2 (B), LDLR (C), CD36 (D), ABCA (E), LXR (F), HLipase (G), HMGCoAS (H), and HMHCoAR (I) were measured by qPCR in CH, age-matched INTACT or weight-paired (WP) control groups. The mean mRNA expression level of each gene in the INTACT group is defined as 1, with all other expression values reported relative to this level. Bars represent mean ± SD from at least five individual animals. *, P<0.05; ***, P<0.001 for comparison with INTACT group. +, P<0.05; ++, P<0.01; +++, P<0.001 for comparison with WP group.
Figure 6. Effects of congenital hypothyroidism on mRNA expression levels of genes involved in bile acid synthesis in adult rat liver.
On PND80, the hepatic mRNA levels of CYP7A1 (A), CYP27A1 (B), CYP8B1 (C), FXR (D), and SHP (E) were measured by qPCR in CH, age-matched INTACT or weight-paired (WP) control groups. The mean mRNA expression level of each gene in the INTACT group is defined as 1, with all other expression values reported relative to this level. Bars represent mean ± SD from at least five individual animals. **, P<0.01; ***, P<0.001 for comparison with INTACT group. +++, P<0.001 for comparison with WP group.
Figure 7. Effects of hormonal replacement on body weight and hepatic mRNA expression levels of IGF-I, ME, and FAS in adult hypothyroid rats without or with transient exposure to neonatal hypothyroidism.
Four groups were studied: 1) age-matched rats (INTACT); 2) adult rats with neonatal hypothyroidism (CH); 3) hypothyroid adult rats without CH (TX/−CH); and 4) hypothyroid adult rats with CH (TX/+CH). During the last week of life, TX/−CH and TX/+CH groups were treated with either T3 or GH daily. Control animals were injected with saline (VEH). Body weight (A and B) as well as hepatic mRNA levels of IGF-I (C), ME (D) and FAS (E) were measured. The hepatic mRNA levels of TRα (F) and TRβ (G) were also measured by qPCR in CH, age-matched INTACT or weight-paired (WP) control groups. The mean mRNA expression level of each gene in the INTACT group is defined as 1, with all other expression values reported relative to this level. Results represent mean ± SD from at least six individual rats *, P<0.05; **, P<0.01; ***, P<0.001 for comparison with INTACT group (panel A) and for comparison with CH group (panel B); +, P<0.05; ++, P<0.01; +++, P<0.001 for comparison with vehicle-treated TX group. ^̂̂, P<0.001 for comparison with WP group.
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