Acer2, encoding alkaline ceramidase 2, is crucial in sphingolipid metabolism. It catalyzes the hydrolysis of ceramide to sphingosine, which is then converted to sphingosine-1-phosphate (S1P), thus influencing multiple cellular processes such as proliferation, apoptosis, inflammation, and tumor progression [2]. This process is part of the SphK/S1P pathway, which is vital in regulating various biological functions [2].

In diffuse large B-cell lymphoma (DLBCL), YTHDF2 binds to m6A sites on Acer2 mRNA, promoting its stability and expression. Enhanced Acer2 expression hydrolyzes ceramides, disrupting the ceramide-S1P balance, and activating the ERK and PI3K/AKT pathways, leading to tumorigenesis [1]. In adipose tissue, adipocyte hypoxia-inducible factor 2α (HIF-2α) upregulates Acer2, promoting ceramide catabolism and suppressing atherosclerosis [3]. Knockout of Acer2 in mice led to increased susceptibility to lithium-induced diabetes insipidus [4].

In summary, Acer2 is essential in sphingolipid metabolism, with its activity influencing diverse biological processes and disease states. Gene knockout models in mice have been instrumental in revealing its role in diseases like DLBCL, atherosclerosis, and lithium-induced diabetes insipidus, providing potential targets for therapeutic interventions in these areas.

References:

1. Chen, Xiaomin, Lu, Tiange, Ding, Mengfei, Zhou, Xiangxiang, Wang, Xin. 2023. Targeting YTHDF2 inhibits tumorigenesis of diffuse large B-cell lymphoma through ACER2-mediated ceramide catabolism. In Journal of advanced research, 63, 17-33. doi:10.1016/j.jare.2023.10.010. https://pubmed.ncbi.nlm.nih.gov/37865189/

2. Liu, Binggang, Zhou, Junfeng, Jiang, Biao, Liu, Ting, Lei, Pengcheng. 2024. The role of ACER2 in intestinal sphingolipid metabolism and gastrointestinal cancers. In Frontiers in immunology, 15, 1511283. doi:10.3389/fimmu.2024.1511283. https://pubmed.ncbi.nlm.nih.gov/39650647/

3. Zhang, Xingzhong, Zhang, Yangming, Wang, Pengcheng, Wang, Xian, Jiang, Changtao. 2019. Adipocyte Hypoxia-Inducible Factor 2α Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism. In Cell metabolism, 30, 937-951.e5. doi:10.1016/j.cmet.2019.09.016. https://pubmed.ncbi.nlm.nih.gov/31668872/

4. de Groot, Theun, Ebert, Lena K, Christensen, Birgitte Mønster, Deen, Peter M T, Korstanje, Ron. 2019. Identification of Acer2 as a First Susceptibility Gene for Lithium-Induced Nephrogenic Diabetes Insipidus in Mice. In Journal of the American Society of Nephrology : JASN, 30, 2322-2336. doi:10.1681/ASN.2018050549. https://pubmed.ncbi.nlm.nih.gov/31558682/