Slc47a1, also known as multidrug and toxin extrusion 1 (MATE1), is a lipid flippase. It plays a crucial role in lipid remodeling, with its function potentially linked to various cellular metabolic processes. It has been associated with pathways related to ferroptosis, a type of regulated necrosis, and is also involved in the pharmacokinetics and pharmacodynamics of metformin [1,2,3]. Genetic models, such as gene knockout mouse models, can be valuable in further elucidating its function.

In ferroptosis, the silencing of Slc47a1 in multiple cancer cells led to increased susceptibility to ferroptotic inducers like RSL3 or erastin. This was due to enhanced ACSL4-SOAT1-mediated production of polyunsaturated fatty acid cholesterol esters. The transcription factor PPARA transactivates Slc47a1, and depletion of either PPARA or Slc47a1 sensitized cells to ferroptosis. Blocking the PPARA-Slc47a1 pathway increased the anticancer activity of a ferroptosis inducer in mice [1]. In type 2 diabetes, the rs2289669 variant of Slc47a1 was associated with the glycemic response to metformin monotherapy, with the A carrier showing a different change in HbA1c levels compared to the GG genotype. Similar results were obtained in sensitivity analysis, and there were significant differences in HbA1c level changes between certain genotypes [2]. Additionally, in Chinese Han nationality newly diagnosed type 2 diabetic patients, SLC47A1 rs2289669 was correlated with the efficacy of metformin, especially in normal-weight patients where the AA and GG genotypes of this variant were associated with a greater reduction in fasting insulin and HOMA-IR [3]. In Egyptian type 2 diabetes patients on sulfonylurea and metformin combination therapy, SLC47A1 rs2289669 heterozygous and homozygous mutant genotypes (AA and AG) and mutant alleles were significantly related to increased response to combined therapy [4].

In conclusion, Slc47a1 is essential in lipid remodeling and significantly impacts ferroptosis regulation in cancer cells. In the context of type 2 diabetes, its genetic variants play a role in the response to metformin treatment. The use of gene knockout or other loss-of-function models in mice and human studies has provided valuable insights into its functions in these disease-related processes.

References:

1. Lin, Zhi, Liu, Jiao, Long, Fei, Tang, Daolin, Yang, Minghua. 2022. The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis. In Nature communications, 13, 7965. doi:10.1038/s41467-022-35707-2. https://pubmed.ncbi.nlm.nih.gov/36575162/

2. Kim, Hamin, Bae, Suhyun, Yoon, Ha Young, Yee, Jeong, Gwak, Hye Sun. . Association of the SLC47A1 Gene Variant With Responses to Metformin Monotherapy in Drug-naive Patients With Type 2 Diabetes. In The Journal of clinical endocrinology and metabolism, 107, 2684-2690. doi:10.1210/clinem/dgac333. https://pubmed.ncbi.nlm.nih.gov/35639991/

3. Chen, Peixian, Cao, Yumin, Chen, Shenren, Chen, Shiyi, Guo, Yali. 2022. Association of SLC22A1, SLC22A2, SLC47A1, and SLC47A2 Polymorphisms with Metformin Efficacy in Type 2 Diabetic Patients. In Biomedicines, 10, . doi:10.3390/biomedicines10102546. https://pubmed.ncbi.nlm.nih.gov/36289808/

4. Ahmed, Aya, Elsadek, Hany M, Shalaby, Sally M, Elnahas, Hanan M. 2023. Association of SLC22A1, SLC47A1, and KCNJ11 polymorphisms with efficacy and safety of metformin and sulfonylurea combination therapy in Egyptian patients with type 2 diabetes. In Research in pharmaceutical sciences, 18, 614-625. doi:10.4103/1735-5362.389949. https://pubmed.ncbi.nlm.nih.gov/39005567/