Cers2, encoding ceramide synthase 2, is responsible for the production of very long chain (VLC) ceramides in the sphingolipid metabolism pathway. Sphingolipids play crucial roles in cell signaling, membrane structure, and apoptosis, making Cers2 biologically significant. Genetic models, such as gene knockout mouse models, have been valuable for studying Cers2's functions [1,2,3].

In IL-10 deficiency, genetic deletion of Cers2 limited exacerbated inflammatory gene expression both in vitro and in vivo, indicating that saturated VLC ceramides produced by Cers2 are critical for heightened inflammation in this context [1]. In a mouse model of the rs267738 variant in Cers2, homozygous knock-in mice had reduced liver Cers2 activity, enhanced diet-induced glucose intolerance, and hepatic steatosis, suggesting that this SNP leads to a partial loss-of-function of Cers2 worsening metabolic parameters [2]. Also, CerS2 haploinsufficiency in mice led to compensatory increases in long-chain C16-ceramides and conferred susceptibility to diet-induced steatohepatitis and insulin resistance, likely due to impaired β-oxidation [3].

In conclusion, Cers2 is essential in sphingolipid metabolism, specifically in VLC ceramide production. Studies using gene knockout or knock-in mouse models have revealed its roles in inflammation, metabolic diseases such as glucose intolerance, hepatic steatosis, steatohepatitis, and insulin resistance. These findings contribute to understanding the underlying mechanisms of these disease conditions and may offer potential therapeutic targets.

References:

1. York, Autumn G, Skadow, Mathias H, Oh, Joonseok, Bensinger, Steven J, Flavell, Richard A. 2024. IL-10 constrains sphingolipid metabolism to limit inflammation. In Nature, 627, 628-635. doi:10.1038/s41586-024-07098-5. https://pubmed.ncbi.nlm.nih.gov/38383790/

2. Nicholson, Rebekah J, Poss, Annelise M, Maschek, J Alan, Holland, William L, Summers, Scott A. . Characterizing a Common CERS2 Polymorphism in a Mouse Model of Metabolic Disease and in Subjects from the Utah CAD Study. In The Journal of clinical endocrinology and metabolism, 106, e3098-e3109. doi:10.1210/clinem/dgab155. https://pubmed.ncbi.nlm.nih.gov/33705551/

3. Raichur, Suryaprakash, Wang, Siew Tein, Chan, Puck Wee, Futerman, Anthony H, Summers, Scott A. . CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. In Cell metabolism, 20, 687-95. doi:10.1016/j.cmet.2014.09.015. https://pubmed.ncbi.nlm.nih.gov/25295789/