Slc22a5, also known as organic cation transporter novel family member 2 (OCTN2), is a crucial gene encoding a plasma membrane carnitine transporter. It plays an essential role in cell metabolism, especially in the process of fatty acid β -oxidation. It transports l -carnitine, which is used to shuttle acyl moieties to mitochondria in the carnitine shuttle. Its expression is regulated by transcription factors like peroxisome proliferator-activated receptors (PPARs) and estrogen receptor, and its transport activity is controlled by interactions with other proteins [1].

In the LCAD KO mouse model, introducing one defective Slc22a5 allele (Slc22a5 haploinsufficiency) decreased free carnitine levels in the liver, kidney, and heart, along with a similar decrease in long-chain acylcarnitines levels and an elevation in cardiac deoxycarnitine levels. However, major phenotypes of the LCAD KO mouse such as cardiac hypertrophy, fasting-induced hypoglycemia, and increased liver weight were not affected, suggesting that secondary carnitine deficiency may not play a major role in the pathophysiology of these phenotypes [3]. In macrophages, conditional knockout (CKO) of SIRPA transcriptionally downregulates Slc22a5 in lipopolysaccharide (LPS)-stimulated macrophages that efferocytose apoptotic neutrophils. Targeting Slc22a5 renders mitophagy inhibition of macrophages in response to LPS stimuli, improves survival, and deters the development of septic acute kidney injury [2].

In conclusion, Slc22a5 is essential for maintaining carnitine homeostasis and is crucial for cell metabolism through its role in fatty acid β -oxidation. The study of Slc22a5 using gene knockout models in mice has provided insights into its role in metabolic and immune-related disease conditions such as those associated with fatty acid oxidation disorders and septic acute kidney injury [2,3].

References:

1. Juraszek, Barbara, Nałęcz, Katarzyna A. 2019. SLC22A5 (OCTN2) Carnitine Transporter-Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer. In Molecules (Basel, Switzerland), 25, . doi:10.3390/molecules25010014. https://pubmed.ncbi.nlm.nih.gov/31861504/

2. Jia, Yu, Li, Jun-Hua, Hu, Bang-Chuan, Ye, Xiang-Ming, Mo, Shi-Jing. 2024. Targeting SLC22A5 fosters mitophagy inhibition-mediated macrophage immunity against septic acute kidney injury upon CD47-SIRPα axis blockade. In Heliyon, 10, e26791. doi:10.1016/j.heliyon.2024.e26791. https://pubmed.ncbi.nlm.nih.gov/38586373/

3. Ranea-Robles, Pablo, Yu, Chunli, van Vlies, Naomi, Vaz, Frédéric M, Houten, Sander M. 2019. Slc22a5 haploinsufficiency does not aggravate the phenotype of the long-chain acyl-CoA dehydrogenase KO mouse. In Journal of inherited metabolic disease, 43, 486-495. doi:10.1002/jimd.12204. https://pubmed.ncbi.nlm.nih.gov/31845336/