Fads3-KO Mouse

Fads3, a member of the Fatty Acid Desaturase (FADS) gene cluster, was initially suspected to code for a new mammalian membrane-bound fatty acid desaturase due to its high nucleotide sequence homology with FADS1 and FADS2 [1,4]. It is involved in multiple lipid-related metabolic pathways. In the biosynthesis of sphingolipids, Fads3 is responsible for introducing a cis double bond in 4,14-sphingadiene (sphingadiene; SPD), and shows substrate specificity towards sphingosine-containing ceramides (SPH-CERs) [2]. It also functions as a Δ14Z sphingoid base desaturase, contributing to gender differences in the human plasma sphingolipidome by forming Δ14Z double-bond-containing long-chain bases (LCBs) such as d18:2 and m18:1 [3].

In a Fads3 knockout (KO) mouse model, docosahexaenoic acid (DHA, 22:6n-3) levels in the brain of postnatal day 1 (P1) KO mice were lower than in wild-type (WT) mice, and the ratio of docosapentaenoic acid (DPA, 22:5n-3) to DHA in P1 KO liver was higher, suggesting lower desaturase activity. Concomitantly, changes in other fatty acid levels and related gene expressions were observed, indicating that Fads3 may enhance liver-mediated 22:6n-3 synthesis to support brain 22:6n-3 accretion before and during the brain growth spurt [5].

In conclusion, Fads3 has diverse functions in lipid metabolism, playing a role in sphingolipid biosynthesis and influencing fatty acid composition in the liver and brain. The Fads3 KO mouse model has provided insights into its role in supporting brain DHA accretion, and further research on Fads3 may offer a better understanding of lipid-related biological processes and potentially related disease mechanisms [5].

References:

1. Rioux, Vincent, Legrand, Philippe. 2019. Fatty Acid Desaturase 3 (FADS3) Is a Specific ∆13-Desaturase of Ruminant trans-Vaccenic Acid. In Lifestyle genomics, 12, 18-24. doi:10.1159/000502356. https://pubmed.ncbi.nlm.nih.gov/32911476/

2. Jojima, Keisuke, Kihara, Akio. 2023. Metabolism of sphingadiene and characterization of the sphingadiene-producing enzyme FADS3. In Biochimica et biophysica acta. Molecular and cell biology of lipids, 1868, 159335. doi:10.1016/j.bbalip.2023.159335. https://pubmed.ncbi.nlm.nih.gov/37209771/

3. Karsai, Gergely, Lone, Museer, Kutalik, Zoltán, von Eckardstein, Arnold, Hornemann, Thorsten. 2019. FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome. In The Journal of biological chemistry, 295, 1889-1897. doi:10.1074/jbc.AC119.011883. https://pubmed.ncbi.nlm.nih.gov/31862735/

4. Blanchard, H, Legrand, P, Pédrono, F. 2010. Fatty Acid Desaturase 3 (Fads3) is a singular member of the Fads cluster. In Biochimie, 93, 87-90. doi:10.1016/j.biochi.2010.03.002. https://pubmed.ncbi.nlm.nih.gov/20226833/

5. Zhang, Ji Yao, Qin, Xia, Liang, Allison, Kothapalli, Kumar S D, Brenna, J Thomas. 2017. Fads3 modulates docosahexaenoic acid in liver and brain. In Prostaglandins, leukotrienes, and essential fatty acids, 123, 25-32. doi:10.1016/j.plefa.2017.07.001. https://pubmed.ncbi.nlm.nih.gov/28838557/