FA2H, also known as fatty acid 2-hydroxylase, is an enzyme involved in the synthesis of many 2-hydroxylated sphingolipids, which are abundant in myelin and skin [6]. It plays a role in various biological processes and is associated with multiple diseases.

Mutations in FA2H can cause fatty acid hydroxylase-associated neurodegeneration (FAHN/SPG35), a neurodegenerative disorder with progressive motor and non-motor neurological symptoms [3]. In Drosophila, fa2h mutants show defects in cool temperature sensing, as the gene is required for cooling cells to respond to cool temperature, and its mutation leads to decreased 2-hydroxy sphingolipids in cell membranes and increased membrane fluidity [1]. In breast cancer, its role is controversial. Some studies suggest it suppresses cancer stemness by inhibiting the STAT3/IL6 axis and NFkB signaling, while others indicate it may stimulate breast cancer cell migration [2,5]. In gastric cancer, FA2H was found to be a target of miR-300, and FA2H-plasmid inhibited cell proliferation and induced apoptosis [4].

In conclusion, FA2H is crucial for the synthesis of 2-hydroxylated sphingolipids and is involved in temperature sensing in Drosophila. In human diseases, it has diverse roles, especially in neurodegenerative disorders like FAHN/SPG35 and in various cancers, as revealed through functional studies in different research models. The study of FA2H knockout or conditional knockout models, though not explicitly detailed in the provided references, would further enhance our understanding of its role in these biological processes and diseases.

References:

1. Li, Qiaoran, Chen, Limin, Yang, Libo, Zhang, Pumin. 2024. FA2H controls cool temperature sensing through modifying membrane sphingolipids in Drosophila. In Current biology : CB, 34, 997-1009.e6. doi:10.1016/j.cub.2024.01.058. https://pubmed.ncbi.nlm.nih.gov/38359821/

2. Dai, Xiaofeng, Zhang, Shuo, Cheng, Hongye, Chen, Xiao, Huang, Zhaohui. 2019. FA2H Exhibits Tumor Suppressive Roles on Breast Cancers via Cancer Stemness Control. In Frontiers in oncology, 9, 1089. doi:10.3389/fonc.2019.01089. https://pubmed.ncbi.nlm.nih.gov/31709178/

3. German, Alexander, Jukic, Jelena, Laner, Andreas, Abicht, Angela, Regensburger, Martin. 2023. Novel Homozygous FA2H Variant Causing the Full Spectrum of Fatty Acid Hydroxylase-Associated Neurodegeneration (SPG35). In Genes, 15, . doi:10.3390/genes15010014. https://pubmed.ncbi.nlm.nih.gov/38275596/

4. Hong, Bo, Li, Jie, Huang, Chunxiao, Zhang, Mengpei, Huang, Lijiang. 2020. miR-300/FA2H affects gastric cancer cell proliferation and apoptosis. In Open medicine (Warsaw, Poland), 15, 882-889. doi:10.1515/med-2020-0188. https://pubmed.ncbi.nlm.nih.gov/33344772/

5. Hirao-Suzuki, Masayo, Koga, Takayuki, Sakai, Genki, Ohara, Masahiro, Takeda, Shuso. 2020. Fatty acid 2-hydroxylase (FA2H) as a stimulatory molecule responsible for breast cancer cell migration. In Biochemical and biophysical research communications, 531, 215-222. doi:10.1016/j.bbrc.2020.07.043. https://pubmed.ncbi.nlm.nih.gov/32798015/

6. Eckhardt, Matthias. 2023. Fatty Acid 2-Hydroxylase and 2-Hydroxylated Sphingolipids: Metabolism and Function in Health and Diseases. In International journal of molecular sciences, 24, . doi:10.3390/ijms24054908. https://pubmed.ncbi.nlm.nih.gov/36902339/