Recently, the authoritative journal EMBO JOURNAL published the latest research results of Professor Hai-Ping Hao's team, Jing Xiong's group in the School of Pharmaceutical Sciences--SLC13A2 promotes hepatocyte metabolic remodeling and liver regeneration by enhancing de novo cholesterol biosynthesis. regeneration by enhancing de novo cholesterol biosynthesis, reporting a new target for regulating metabolic remodeling to promote liver regeneration. Li Shi, M.S. student, class of 2021, Hao Chen, Ph.D. student, class of 2024, and Yuxin Zhang, M.S. student, class of 2023, of the School of Pharmacy are the co-first authors of this article; Jing Xiong and Hai-Ping Hao are the co-corresponding authors of the School of Pharmacy; and the China Pharmaceutical University (CPU) is the sole corresponding author of this article.
The liver is continuously attacked by drug toxicants, viral infections, metabolic disorders, ischemia and hypoxia, and other pathogenic factors, resulting in different types of liver diseases that have become an important cause of death and disability worldwide. Despite the availability of targeted therapeutic drugs, the survival and recovery of patients with liver injury in most cases still depend on the strong regenerative capacity of the liver. Therefore, studies on the mechanisms of liver regeneration can greatly facilitate the development of novel therapeutic agents for liver disease.
The metabolic requirement for hepatocyte division is a prerequisite for regeneration after liver injury. Despite the large amount of data revealing the dynamic regulation of transcription during liver regeneration, its link to metabolic remodeling remains poorly understood. By integrating existing transcriptomic data, the research team identified the membrane transporter protein SLC13A2 as a key regulator of liver regeneration after major hepatectomy (PHx).The expression of SLC13A2 rapidly decreases after PHx and gradually increases to normal levels as liver weight and physiological functions are repaired. The research team demonstrated that SLC13A2 promotes liver regeneration induced by chronic injury caused by PHx surgery and prolonged feeding of HFD diet by constructing liver-specific overexpression or deletion mouse models. Mechanistic studies demonstrated that SLC13A2 transports citric acid, which is catalyzed by ACLY to release acetyl coenzyme A for cholesterol synthesis, and promotes SREBP2 activation and the expression of genes related to cholesterol metabolism (LDLR, HMGCR, etc.) The HMGCR inhibitor lovastatin counteracted the liver regeneration promoted by SLC13A2. In addition, the ACLY inhibitor inhibited cholesterol synthesis by suppressing SLC13A2-mediated citric acid cleavage, deterring hepatocyte proliferation and liver regeneration. The research team suggests that citric acid transported by SLC13A2 as an intermediate metabolite to restore the metabolic balance of liver regeneration could be a potential drug target to reduce liver injury and promote liver repair.
Jing Xiong's group is dedicated to the study of the molecular mechanism of metabolic remodeling and drug intervention in liver diseases, and recently published a paper on RNA binding motif protein 45-mediated phosphorylation enhances protein stability of ASCT2 to promote hepatocellular carcinoma in the leading journal of life sciences, Oncogene. ASCT2 to promote hepatocellular carcinoma progression, and Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma, in Acta Pharma Sin B, a leading journal in pharmacology. hepatocellular carcinoma in Acta Pharma Sin B, Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma in Acta Pharma Sin B, and published a series of papers in the top journals of medicine/pharmacy, such as Neoplasia, Frontiers in Immunology, and Chin J Nat Med.
This research work was supported by the National Natural Science Foundation of China (No. 82273982, 82070883), the Natural Science Foundation of Jiangsu Province (No. BK20221525), and the Research Program for High-level Introduced Talents of China Pharmaceutical University.
Link to the paper: https://www.embopress.org/doi/full/10.1038/s44318-025-00362-y
