Thrsp, also known as Thyroid hormone responsive spot 14, is a lipogenic nuclear protein. It is involved in regulating responses to thyroid hormones and is highly expressed in murine adipose tissue. It plays a role in de novo lipid synthesis and is associated with pathways like mitochondrial function, sphingolipid metabolism, and may regulate gene expression of rate-limiting enzymes in lipogenesis [2,5]. Genetic models, such as knockout mice, are valuable for studying its functions [7].

In hepatocellular carcinoma (HCC), decreased Thrsp expression was observed in tumor tissues compared to adjacent healthy tissues. Knockdown of Thrsp led to increased cell growth, migration, and invasion of HCC cells, suggesting it may act as a tumor suppressor by inhibiting epithelial-to-mesenchymal transition through the ERK/ZEB1 signaling pathway [3]. In the context of ADHD, the Thrsp gene could be a biomarker for the predominantly inattentive presentation (ADHD-PI), and THRSP OE mice may represent an animal model for studying this ADHD presentation. Proteomics in THRSP OE mice revealed an altered protein network involved in Wnt signaling, which affects hippocampal dentate gyrus cell proliferation and neural stem cell activity, contributing to behavioral impairment [1,6]. In dairy cows, a polymorphism in the Thrsp gene was associated with fatty acid composition in milk [4]. The Thrsp null mouse showed deficiencies in de novo lipogenesis in the lactating mammary gland, and its gene deletion affected body weight, glucose tolerance, and insulin sensitivity [7].

In conclusion, Thrsp is crucial for lipid-related metabolic processes, mitochondrial function, and sphingolipid metabolism. Model-based research, especially using Thrsp null mice, has provided insights into its role in diseases like HCC and ADHD, as well as in metabolic regulation such as in dairy cows. Understanding Thrsp's functions can potentially lead to new strategies for treating these diseases and managing related metabolic conditions.

References:

1. Custodio, Raly James Perez, Kim, Mikyung, Chung, Young-Chul, Kim, Hee Jin, Cheong, Jae Hoon. 2023. Thrsp Gene and the ADHD Predominantly Inattentive Presentation. In ACS chemical neuroscience, 14, 573-589. doi:10.1021/acschemneuro.2c00710. https://pubmed.ncbi.nlm.nih.gov/36716294/

2. Ahonen, Maria A, Höring, Marcus, Nguyen, Van Dien, Yki-Järvinen, Hannele, Olkkonen, Vesa M. 2022. Insulin-inducible THRSP maintains mitochondrial function and regulates sphingolipid metabolism in human adipocytes. In Molecular medicine (Cambridge, Mass.), 28, 68. doi:10.1186/s10020-022-00496-3. https://pubmed.ncbi.nlm.nih.gov/35715726/

3. Hu, Qiong, Ma, Xiaolu, Li, Chuner, Chen, Jiayao, Gu, Xuechun. 2021. Downregulation of THRSP Promotes Hepatocellular Carcinoma Progression by Triggering ZEB1 Transcription in an ERK-dependent Manner. In Journal of Cancer, 12, 4247-4256. doi:10.7150/jca.51657. https://pubmed.ncbi.nlm.nih.gov/34093825/

4. Polasik, Daniel, Golińczak, Jacek, Proskura, Witold, Terman, Arkadiusz, Dybus, Andrzej. 2021. Association between THRSP Gene Polymorphism and Fatty Acid Composition in Milk of Dairy Cows. In Animals : an open access journal from MDPI, 11, . doi:10.3390/ani11041144. https://pubmed.ncbi.nlm.nih.gov/33923760/

5. Zhan, Kai, Yang, Ning, Xu, Gui-Yun, Xu, Yue-Ying, Zhao, Rui-Hong. . [Progresses on thyroid hormone responsive spot 14 (THRSP) gene in chickens and ducks]. In Yi chuan = Hereditas, 31, 131-6. doi:. https://pubmed.ncbi.nlm.nih.gov/19273419/

6. Custodio, Raly James Perez, Kim, Hee Jin, Kim, Jiyeon, Yi, Eugene C, Cheong, Jae Hoon. 2023. Hippocampal dentate gyri proteomics reveals Wnt signaling involvement in the behavioral impairment in the THRSP-overexpressing ADHD mouse model. In Communications biology, 6, 55. doi:10.1038/s42003-022-04387-5. https://pubmed.ncbi.nlm.nih.gov/36646879/

7. Anderson, Grant W, Zhu, Qihong, Metkowski, Jennifer, Gopinath, Sunil, Mariash, Cary N. 2009. The Thrsp null mouse (Thrsp(tm1cnm)) and diet-induced obesity. In Molecular and cellular endocrinology, 302, 99-107. doi:10.1016/j.mce.2009.01.005. https://pubmed.ncbi.nlm.nih.gov/19356628/