甲状腺激素受体β（THRβ1）是人类诱导多能干细胞衍生肝细胞中T3作用的主要调节因子。
Thyroid hormone receptor beta (THRβ1) is the major regulator of T3 action in human iPSC-derived hepatocytes.
作者信息
Soares De Oliveira Lorraine, Kaserman Joseph E, Van Der Spek Anne H, Lee Nora J, Undeutsch Hendrik J, Werder Rhiannon B, Wilson Andrew A, Hollenberg Anthony N
机构信息
Department of Medicine, Section of Endocrinology, Diabetes and Nutrition, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA 02118, USA; Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA.
Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA; Department of Medicine, Section of Pulmonary and Critical Care Medicine, Chobanian & Avedisian School of Medicine, Boston Medical Center, MA 02118, USA.
出版信息
Mol Metab. 2024 Dec;90:102057. doi: 10.1016/j.molmet.2024.102057. Epub 2024 Oct 29.
OBJECTIVE
Thyroid hormone (TH) action is mediated by thyroid hormone receptor (THR) isoforms. While THRβ1 is likely the main isoform expressed in liver, its role in human hepatocytes is not fully understood.
METHODS
To elucidate the role of THRβ1 action in human hepatocytes we used CRISPR/Cas9 editing to knock out THRβ1 in induced pluripotent stem cells (iPSC). Following directed differentiation to the hepatic lineage, iPSC-derived hepatocytes were then interrogated to determine the role of THRβ1 in ligand-independent and -dependent functions.
RESULTS
We found that the loss of THRβ1 promoted alterations in proliferation rate and metabolic pathways regulated by T3, including gluconeogenesis, lipid oxidation, fatty acid synthesis, and fatty acid uptake. We observed that key genes involved in liver metabolism are regulated through both T3 ligand-dependent and -independent THRβ1 signaling mechanisms. Finally, we demonstrate that following THRβ1 knockout, several key metabolic genes remain T3 responsive suggesting they are THRα targets.
CONCLUSIONS
These results highlight that iPSC-derived hepatocytes are an effective platform to study mechanisms regulating TH signaling in human hepatocytes.
目的
甲状腺激素（TH）的作用由甲状腺激素受体（THR）亚型介导。虽然THRβ1可能是肝脏中表达的主要亚型，但其在人肝细胞中的作用尚未完全明确。
方法
为了阐明THRβ1在人肝细胞中的作用，我们使用CRISPR/Cas9编辑技术在诱导多能干细胞（iPSC）中敲除THRβ1。在定向分化为肝系细胞后，对iPSC来源的肝细胞进行研究，以确定THRβ1在非配体依赖性和配体依赖性功能中的作用。
结果
我们发现THRβ1的缺失促进了由T3调节的增殖率和代谢途径的改变，包括糖异生、脂质氧化、脂肪酸合成和脂肪酸摄取。我们观察到参与肝脏代谢的关键基因通过T3配体依赖性和非依赖性THRβ1信号机制进行调节。最后，我们证明在敲除THRβ1后，几个关键代谢基因仍然对T3有反应，表明它们是THRα的靶点。
结论
这些结果突出表明，iPSC来源的肝细胞是研究人肝细胞中TH信号调节机制的有效平台。
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