PMID- 33771984 OWN - NLM STAT- MEDLINE DCOM- 20211013 LR - 20230130 IS - 2041-4889 (Electronic) VI - 12 IP - 4 DP - 2021 Mar 26 TI - Ceramides and sphingosine-1-phosphate mediate the distinct effects of M1/M2-macrophage infusion on liver recovery after hepatectomy. PG - 324 LID - 10.1038/s41419-021-03616-9 [doi] LID - 324 AB - Post-hepatectomy liver dysfunction is a life-threatening morbidity that lacks efficient therapy. Bioactive lipids involved in macrophage polarization crucially regulate tissue injury and regeneration. Herein, we investigate the key bioactive lipids that mediate the cytotherapeutic potential of polarized-macrophage for post-hepatectomy liver dysfunction. Untargeted lipidomics identified elevation of ceramide (CER) metabolites as signature lipid species relevant to M1/M2 polarization in mouse bone-marrow-derived-macrophages (BMDMs). M1 BMDMs expressed a CER-generation-metabolic pattern, leading to elevation of CER; M2 BMDMs expressed a CER-breakdown-metabolic pattern, resulting in upregulation of sphingosine-1-phosphate (S1P). After infusing M1- or M2-polarized BMDMs into the mouse liver after hepatectomy, we found that M1-BMDM infusion increased M1 polarization and CER accumulation, resulting in exaggeration of hepatocyte apoptosis and liver dysfunction. Conversely, M2-BMDM infusion enhanced M2 polarization and S1P generation, leading to alleviation of liver dysfunction with improved hepatocyte proliferation. Treatment of exogenous CER and S1P or inhibition CER and S1P synthesis by siRNA targeting relevant enzymes further revealed that CER induced apoptosis while S1P promoted proliferation in post-hepatectomy primary hepatocytes. In conclusion, CER and S1P are uncovered as critical lipid mediators for M1- and M2-polarized BMDMs to promote injury and regeneration in the liver after hepatectomy, respectively. Notably, the upregulation of hepatic S1P induced by M2-BMDM infusion may have therapeutic potential for post-hepatectomy liver dysfunction. FAU - Sun, Hang AU - Sun H AD - Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. FAU - Sun, Shibo AU - Sun S AD - Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. FAU - Chen, Gang AU - Chen G AD - Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. FAU - Xie, Haorong AU - Xie H AD - Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. AD - Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China. FAU - Yu, Sheng AU - Yu S AD - Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. FAU - Lin, Xinxin AU - Lin X AD - The First Clinical College, Southern Medical University, Guangzhou, Guangdong, China. FAU - Qian, Jianping AU - Qian J AD - Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. FAU - Mao, Cungui AU - Mao C AD - Department of Medicine and Cancer Center, The State University of New York at Stony Brook, Stony Brook, NY, USA. FAU - Peng, Hongxian AU - Peng H AD - Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. FAU - Chen, Hao AU - Chen H AD - Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. FAU - Chen, Xuefang AU - Chen X AD - Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. AD - Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China. FAU - Li, Yiyi AU - Li Y AD - Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. FAU - Liu, Cuiting AU - Liu C AD - Central Laboratory, Southern Medical University, Guangzhou, Guangdong, China. FAU - Shi, Junmin AU - Shi J AD - Central Laboratory, Southern Medical University, Guangzhou, Guangdong, China. FAU - Zhu, Bili AU - Zhu B AD - Huiqiao Department, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. FAU - Guo, Linghong AU - Guo L AD - Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. AD - Department of Colorectal Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi, China. FAU - Li, Qingping AU - Li Q AD - Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. FAU - Huang, Pengxiang AU - Huang P AD - Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. FAU - Wei, Yiran AU - Wei Y AD - The First Clinical College, Southern Medical University, Guangzhou, Guangdong, China. FAU - Huang, Xixin AU - Huang X AD - The First Clinical College, Southern Medical University, Guangzhou, Guangdong, China. FAU - Liu, Meiqi AU - Liu M AD - The First Clinical College, Southern Medical University, Guangzhou, Guangdong, China. FAU - Cui, Zhonglin AU - Cui Z AD - Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. FAU - Zhang, Qifan AU - Zhang Q AUID- ORCID: 0000-0002-1272-3156 AD - Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. zhangqifansmu@163.com. FAU - Zhou, Jie AU - Zhou J AUID- ORCID: 0000-0003-0376-0622 AD - Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. jacky@smu.edu.cn. FAU - Li, Chuanjiang AU - Li C AUID- ORCID: 0000-0002-3583-2881 AD - Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. licj@smu.edu.cn. FAU - Wang, Kai AU - Wang K AUID- ORCID: 0000-0001-5814-817X AD - Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. kaiwang@smu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210326 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Ceramides) RN - 0 (Lysophospholipids) RN - 26993-30-6 (sphingosine 1-phosphate) RN - NGZ37HRE42 (Sphingosine) SB - IM MH - Animals MH - Ceramides/*metabolism MH - Disease Models, Animal MH - Hepatectomy/*methods MH - Humans MH - Liver/*pathology/surgery MH - Lysophospholipids/*metabolism MH - Metabolomics/*methods MH - Mice MH - Sphingosine/*analogs & derivatives/metabolism MH - Transfection PMC - PMC7998020 COIS- The authors declare no competing interests. EDAT- 2021/03/28 06:00 MHDA- 2021/10/14 06:00 PMCR- 2021/03/26 CRDT- 2021/03/27 05:56 PHST- 2020/07/08 00:00 [received] PHST- 2021/03/11 00:00 [accepted] PHST- 2021/03/09 00:00 [revised] PHST- 2021/03/27 05:56 [entrez] PHST- 2021/03/28 06:00 [pubmed] PHST- 2021/10/14 06:00 [medline] PHST- 2021/03/26 00:00 [pmc-release] AID - 10.1038/s41419-021-03616-9 [pii] AID - 3616 [pii] AID - 10.1038/s41419-021-03616-9 [doi] PST - epublish SO - Cell Death Dis. 2021 Mar 26;12(4):324. doi: 10.1038/s41419-021-03616-9.