Cers4, encoding ceramide synthase 4, is an important sphingolipid-metabolizing enzyme that catalyzes de novo ceramide synthesis [1]. Ceramide, a bioactive signaling sphingolipid, is involved in various biological processes, such as anti-inflammatory responses, apoptosis, and cell motility [3]. Sphingolipid metabolism, in which Cers4 plays a part, has been linked to tumor immunotherapy, obesity-related metabolic dysfunction, and other physiological and pathological processes. Genetic models, like gene knockout mice, are valuable for studying Cers4's functions.

In KO mouse models, global CerS4 knockout mice were highly sensitive to the toxic effect of azoxymethane/dextran sodium sulphate, leading to a high mortality rate. T-cell restricted knockout (CerS4 LCK/Cre) mice frequently suffered from pancolitis and developed more colon tumors, as CerS4-depleted CD8+ T-cells showed impaired proliferation and prolonged cytokine production. In contrast, intestinal epithelial-specific knockout (CerS4 Vil/Cre) mice had smaller tumors [2]. Downregulation of CerS4 in the liver of high-fat-diet (HFD)-fed mice reduced specific liver ceramides and acylcarnitine levels, promoted glycogen accumulation, enhanced insulin sensitivity, and mitigated HFD-induced hepatic insulin resistance [4].

In conclusion, Cers4 plays crucial roles in multiple biological processes. Its functions have been revealed through gene-knockout mouse models in areas such as colitis-associated cancer and hepatic insulin resistance. Understanding Cers4 provides insights into the mechanisms of these diseases and may offer potential therapeutic targets.

References:

1. Luo, Yuhong, Yang, Shoumei, Wu, Xuan, Liu, Weiwei, Gonzalez, Frank J. 2021. Intestinal MYC modulates obesity-related metabolic dysfunction. In Nature metabolism, 3, 923-939. doi:10.1038/s42255-021-00421-8. https://pubmed.ncbi.nlm.nih.gov/34211180/

2. El-Hindi, Khadija, Brachtendorf, Sebastian, Hartel, Jennifer Christina, Utermöhlen, Olaf, Grösch, Sabine. 2022. T-Cell-Specific CerS4 Depletion Prolonged Inflammation and Enhanced Tumor Burden in the AOM/DSS-Induced CAC Model. In International journal of molecular sciences, 23, . doi:10.3390/ijms23031866. https://pubmed.ncbi.nlm.nih.gov/35163788/

3. Hayama, Tamuro, Hama, Kotaro, Ozawa, Tsuyoshi, Misawa, Takeyuki, Fukagawa, Takeo. 2023. Ceramide synthase CERS4 gene downregulation is associated with KRAS mutation in colorectal cancer. In Scientific reports, 13, 16249. doi:10.1038/s41598-023-43557-1. https://pubmed.ncbi.nlm.nih.gov/37758931/

4. Roszczyc-Owsiejczuk, Kamila, Zabielski, Piotr, Imierska, Monika, Sadowska, Patrycja, Błachnio-Zabielska, Agnieszka. . Downregulation of CerS4 Instead of CerS2 in Liver Effectively Alleviates Hepatic Insulin Resistance in HFD Male Mice. In Endocrinology, 165, . doi:10.1210/endocr/bqae118. https://pubmed.ncbi.nlm.nih.gov/39233348/