Slc5a8-KO Mouse

Slc5a8, also known as SMCT1, is a gene encoding a transporter belonging to the Na(+)/glucose co-transporter gene family (SLC5) [6]. It mediates the Na(+)-coupled and electrogenic transport of various monocarboxylates, like short-chain fatty acids, lactate, and nicotinate, and might also transport iodide [6]. Functionally, it has a role in the active absorption of short-chain fatty acids, lactate, and nicotinate in the intestinal tract and kidney [6]. Butyrate, a substrate of Slc5a8, is a histone deacetylase inhibitor, and Slc5a8's ability to transport butyrate into colonic epithelial cells likely underlies its tumor-suppressive function [1,6,9].

In cervical cancer, overexpression of Slc5a8 in HeLa cells decreased cell proliferation by arresting cells in the G1 phase, inhibited cellular migration, and decreased tumor growth in xenograft transplants [3]. In addition, Slc5a8 over-expression in cervical cancer cells led to decreased proliferation activity, increased apoptosis, and inhibited activation of the Wnt signaling pathway, and the effects could be counteracted by the Wnt signaling pathway activator LiCl, indicating that Slc5a8 alleviates cervical cancer progression by regulating the Wnt signaling pathway [4]. In follicular thyroid cancer (FTC), the SLC5A8 methylation positive rate was higher in FTC patients compared to those with follicular thyroid adenoma (FTA), and patients with SLC5A8 methylation-positive had a higher recurrence rate at 5-year follow-ups, suggesting its potential role in FTC diagnosis and prognosis prediction [5]. In papillary thyroid carcinoma (PTC), the SLC5A8 level was significantly down-regulated, and its aberrant promoter hyper-methylation was related to aggressive PTC [7]. In cows with subacute ruminal acidosis (SARA), elevated concentrations of propionate and butyrate inhibited ruminal absorption of short-chain fatty acids (SCFA) via down-regulation of SLC5A8, and the expression of SLC5A8 played an important role in the etiology of SARA [8]. In rat thymocytes, the expression of Slc5a8 showed sex-related differences, and valproic acid (VPA) treatment altered its expression in a gender-and gonadal hormone-dependent manner [10]. Gamma-hydroxybutyric acid (GHB), a short-chain fatty acid, is a substrate for Slc5a8, and this transporter is a significant determinant of GHB's absorption, renal reabsorption, and brain and tissue uptake [2].

In summary, Slc5a8 is mainly involved in the transport of monocarboxylates, especially butyrate, which is related to its tumor-suppressive function in cancers such as colorectal, cervical, and thyroid cancers. Its role in other physiological and pathological conditions, like SARA in cows and the regulation of thymocyte function in rats, as well as its involvement in the pharmacokinetics of GHB, further demonstrates its diverse biological importance. The study of Slc5a8 in different in vivo models helps to understand its functions in specific biological processes and disease conditions.

References:

1. Gupta, Naren, Martin, Pamela M, Prasad, Puttur D, Ganapathy, Vadivel. 2005. SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter. In Life sciences, 78, 2419-25. doi:. https://pubmed.ncbi.nlm.nih.gov/16375929/

2. Felmlee, Melanie A, Morse, Bridget L, Morris, Marilyn E. 2021. γ-Hydroxybutyric Acid: Pharmacokinetics, Pharmacodynamics, and Toxicology. In The AAPS journal, 23, 22. doi:10.1208/s12248-020-00543-z. https://pubmed.ncbi.nlm.nih.gov/33417072/

3. Vargas-Sierra, Orlando, Hernández-Juárez, Jennifer, Uc-Uc, Perla Yaceli, Gariglio, Patricio, Díaz-Chávez, José. . Role of SLC5A8 as a Tumor Suppressor in Cervical Cancer. In Frontiers in bioscience (Landmark edition), 29, 16. doi:10.31083/j.fbl2901016. https://pubmed.ncbi.nlm.nih.gov/38287802/

4. Zhang, X-M, Meng, Q-H, Kong, F-F, Wang, K, Du, L-J. . SLC5A8 regulates the biological behaviors of cervical cancer cells through mediating the Wnt signaling pathway. In European review for medical and pharmacological sciences, 24, 4679-4686. doi:10.26355/eurrev_202005_21155. https://pubmed.ncbi.nlm.nih.gov/32432731/

5. Yang, Yan, Liao, Chenjin, Yang, Qian, Tang, Yunxiang, Xu, Bin. 2023. Role of hypermethylated SLC5A8 in follicular thyroid cancer diagnosis and prognosis prediction. In World journal of surgical oncology, 21, 367. doi:10.1186/s12957-023-03240-1. https://pubmed.ncbi.nlm.nih.gov/38007446/

6. Ganapathy, V, Gopal, E, Miyauchi, S, Prasad, P D. . Biological functions of SLC5A8, a candidate tumour suppressor. In Biochemical Society transactions, 33, 237-40. doi:. https://pubmed.ncbi.nlm.nih.gov/15667316/

7. Sheikholeslami, Sara, Azizi, Fereidoun, Ghasemi, Asghar, Hedayati, Mehdi, Teimoori-Toolabi, Ladan. . The Epigenetic Modification of SLC5A8 in Papillary Thyroid Carcinoma and its Effects on Clinic-Pathological Features. In Iranian journal of public health, 51, 634-642. doi:10.18502/ijph.v51i3.8940. https://pubmed.ncbi.nlm.nih.gov/35865047/

8. Zhao, Chenxu, Bobe, Gerd, Wang, Yazhou, Li, Xinwei, Liu, Guowen. 2020. Potential Role of SLC5A8 Expression in the Etiology of Subacute Ruminal Acidosis. In Frontiers in veterinary science, 7, 394. doi:10.3389/fvets.2020.00394. https://pubmed.ncbi.nlm.nih.gov/32850999/

9. Stilling, Roman M, van de Wouw, Marcel, Clarke, Gerard, Dinan, Timothy G, Cryan, John F. 2016. The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis? In Neurochemistry international, 99, 110-132. doi:10.1016/j.neuint.2016.06.011. https://pubmed.ncbi.nlm.nih.gov/27346602/

10. Juknevičienė, Milda, Balnytė, Ingrida, Valančiūtė, Angelija, Sužiedėlis, Kęstutis, Stakišaitis, Donatas. . The effect of valproic acid on SLC5A8 expression in gonad-intact and gonadectomized rat thymocytes. In International journal of immunopathology and pharmacology, 36, 20587384211051954. doi:10.1177/20587384211051954. https://pubmed.ncbi.nlm.nih.gov/35120418/