Retinol saturase (RetSat) is an oxidoreductase. It was initially described to transform retinol to 13,14-dihydroretinol. It is expressed in metabolically active tissues and is involved in multiple biological processes, including adipocyte differentiation, hepatic glucose and lipid metabolism, macrophage function, vision, and the generation of reactive oxygen species (ROS) [4]. It also plays a role in pathways related to ferroptosis, replication stress response, and chromosome stability [2,1,3]. Genetic models such as knockout (KO) mouse models are valuable for studying its functions.

In pluripotent stem cells, RetSat deletion led to chromosome instability, up-regulation of cancer-associated gene pathways, and higher tumorigenic capacities in teratoma formation assay. Mechanistically, RetSat interacts with cohesin/condensin components, and its deletion impairs the chromosome loading dosage of related proteins, highlighting its role in chromosome condensation [3]. In pancreatic ductal adenocarcinoma (PDAC), high RetSat expression correlated with poor survival, and it promoted fork restarting under replication stress and maintained genomic stability by interacting with DDX39B to resolve R-loops, contributing to resistance to gemcitabine-based chemotherapy [1]. In cancer cells, RETSAT depletion protected cells from lipid peroxidation and ferroptosis, suggesting its role in promoting ferroptosis by transforming retinol to a relatively weak anti-ferroptosis regulator [2]. In metabolic studies, liver-specific depletion of RetSat in dietary obese mice lowered hepatic and circulating triglycerides and normalized hyperglycemia by reducing the activity of carbohydrate response element binding protein (ChREBP) [6]. Intestine-specific RetSat deletion in adult mice reduced weight gain and fat mass in high-fat diet (HFD)-fed mice and improved epithelial architecture in colitis [5]. Adipose-specific deletion of RetSat in mice impaired lipolysis in adipocytes and acute cold tolerance [7].

In summary, RetSat plays essential roles in multiple biological processes. Through KO/CKO mouse models, its functions in chromosome stability, cancer development and chemotherapy resistance, ferroptosis, and metabolic regulation have been revealed. These findings contribute to understanding related disease mechanisms, providing potential targets for treating diseases such as cancer, metabolic syndrome, and inflammatory bowel disease.

References:

1. Tu, Qiu, Liu, Xiuyun, Yao, Xiaoqing, Shi, Peng, Zhao, Bo. 2022. RETSAT associates with DDX39B to promote fork restarting and resistance to gemcitabine based chemotherapy in pancreatic ductal adenocarcinoma. In Journal of experimental & clinical cancer research : CR, 41, 274. doi:10.1186/s13046-022-02490-3. https://pubmed.ncbi.nlm.nih.gov/36109793/

2. Bi, Guoshu, Liang, Jiaqi, Shan, Guangyao, Gan, Boyi, Zhan, Cheng. . Retinol Saturase Mediates Retinoid Metabolism to Impair a Ferroptosis Defense System in Cancer Cells. In Cancer research, 83, 2387-2404. doi:10.1158/0008-5472.CAN-22-3977. https://pubmed.ncbi.nlm.nih.gov/37184371/

3. Cai, Wanzhi, Yao, Xiaoqing, Liu, Gaojing, Zhao, Bo, Shi, Peng. 2024. RetSat stabilizes mitotic chromosome segregation in pluripotent stem cells. In Cellular and molecular life sciences : CMLS, 81, 366. doi:10.1007/s00018-024-05413-x. https://pubmed.ncbi.nlm.nih.gov/39172275/

4. Weber, Pamela, Flores, Roberto E, Kiefer, Marie F, Schupp, Michael. 2020. Retinol Saturase: More than the Name Suggests. In Trends in pharmacological sciences, 41, 418-427. doi:10.1016/j.tips.2020.03.007. https://pubmed.ncbi.nlm.nih.gov/32345479/

5. Kiefer, Marie F, Meng, Yueming, Yang, Na, Sigal, Michael, Schupp, Michael. 2024. Intestinal retinol saturase is implicated in the development of obesity and epithelial homeostasis upon injury. In American journal of physiology. Endocrinology and metabolism, 327, E203-E216. doi:10.1152/ajpendo.00035.2024. https://pubmed.ncbi.nlm.nih.gov/38895981/

6. Heidenreich, Steffi, Witte, Nicole, Weber, Pamela, Muenzner, Matthias, Schupp, Michael. 2017. Retinol saturase coordinates liver metabolism by regulating ChREBP activity. In Nature communications, 8, 384. doi:10.1038/s41467-017-00430-w. https://pubmed.ncbi.nlm.nih.gov/28855500/

7. Li, Chen, Kiefer, Marie F, Dittrich, Sarah, Schulz, Tim J, Schupp, Michael. 2023. Adipose retinol saturase is regulated by β-adrenergic signaling and its deletion impairs lipolysis in adipocytes and acute cold tolerance in mice. In Molecular metabolism, 79, 101855. doi:10.1016/j.molmet.2023.101855. https://pubmed.ncbi.nlm.nih.gov/38128827/