PMID- 35464270 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220429 IS - 2304-3881 (Print) IS - 2304-389X (Electronic) IS - 2304-3881 (Linking) VI - 11 IP - 2 DP - 2022 Apr TI - Myeloid peroxisome proliferator-activated receptor alpha deficiency accelerates liver regeneration via IL-6/STAT3 pathway after 2/3 partial hepatectomy in mice. PG - 199-211 LID - 10.21037/hbsn-20-688 [doi] AB - BACKGROUND: Liver regeneration is a fundamental process for sustained body homeostasis and liver function recovery after injury. Emerging evidence demonstrates that myeloid cells play a critical role in liver regeneration by secreting cytokines and growth factors. Peroxisome proliferator-activated receptor alpha (PPARalpha), the target of clinical lipid-lowering fibrate drugs, regulates cell metabolism, proliferation, and survival. However, the role of myeloid PPARalpha in partial hepatectomy (PHx)-induced liver regeneration remains unknown. METHODS: Myeloid-specific PPARa-deficient (Ppara (Mye-/-)) mice and the littermate controls (Ppara (fl/fl)) were subjected to sham or 2/3 PHx to induce liver regeneration. Hepatocyte proliferation and mitosis were assessed by immunohistochemical (IHC) staining for 5-bromo-2'-deoxyuridine (BrdU) and Ki67 as well as hematoxylin and eosin (H&E) staining. Macrophage and neutrophil infiltration into livers were reflected by IHC staining for galectin-3 and myeloperoxidase (MPO) as well as flow cytometry analysis. Macrophage migration ability was evaluated by transwell assay. The mRNA levels for cell cycle or inflammation-related genes were measured by quantitative real-time RT-PCR (qPCR). The protein levels of cell proliferation related protein and phosphorylated signal transducer and activator of transcription 3 (STAT3) were detected by Western blotting. RESULTS: Ppara (Mye-/-) mice showed enhanced hepatocyte proliferation and mitosis at 32 h after PHx compared with Ppara (fl/fl) mice, which was consistent with increased proliferating cell nuclear antigen (Pcna) mRNA and cyclinD1 (CYCD1) protein levels in Ppara (Mye-/-) mice at 32 h after PHx, indicating an accelerated liver regeneration in Ppara (Mye-/-) mice. IHC staining showed that macrophages and neutrophils were increased in Ppara (Mye-/-) liver at 32 h after PHx. Livers of Ppara (Mye-/-) mice also showed an enhanced infiltration of M1 macrophages at 32 h after PHx. In vitro, Ppara-deficient bone marrow-derived macrophages (BMDMs) exhibited markedly enhanced migratory capacity and upregulated M1 genes Il6 and Tnfa but downregulated M2 gene Arg1 expressions. Furthermore, the phosphorylation of STAT3, a key transcript factor mediating IL6-promoted hepatocyte survival and proliferation, was reinforced in the liver of Ppara (Mye-/-) mice after PHx. CONCLUSIONS: This study provides evidence that myeloid PPARalpha deficiency accelerates PHx-induced liver regeneration via macrophage polarization and consequent IL-6/STAT3 activation, thus providing a potential target for manipulating liver regeneration. CI - 2022 Hepatobiliary Surgery and Nutrition. All rights reserved. FAU - Xie, Guomin AU - Xie G AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. AD - Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China. FAU - Song, Yanting AU - Song Y AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. AD - Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China. FAU - Li, Na AU - Li N AD - Department of Endocrinology, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China. FAU - Zhang, Zhenzhen AU - Zhang Z AD - Department of Infectious Diseases, Peking University First Hospital, Beijing, China. FAU - Wang, Xia AU - Wang X AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. AD - Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China. FAU - Liu, Ye AU - Liu Y AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. AD - Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China. FAU - Jiao, Shiyu AU - Jiao S AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. AD - Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China. FAU - Wei, Ming AU - Wei M AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. AD - Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China. FAU - Yu, Baoqi AU - Yu B AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. AD - Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China. FAU - Wang, Yan AU - Wang Y AD - Department of Infectious Diseases, Peking University First Hospital, Beijing, China. FAU - Wang, Hua AU - Wang H AD - Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China. FAU - Qu, Aijuan AU - Qu A AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. AD - Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China. LA - eng PT - Journal Article PL - China (Republic : 1949- ) TA - Hepatobiliary Surg Nutr JT - Hepatobiliary surgery and nutrition JID - 101600750 PMC - PMC9023835 OTO - NOTNLM OT - Liver regeneration OT - interleukin 6 (IL-6) OT - myeloid cell OT - peroxisome proliferator-activated receptor alpha (PPARalpha) OT - signal transducer and activator of transcription 3 (STAT3) COIS- Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-20-688/coif). The authors have no conflicts of interest to declare. EDAT- 2022/04/26 06:00 MHDA- 2022/04/26 06:01 PMCR- 2022/04/01 CRDT- 2022/04/25 05:31 PHST- 2020/09/01 00:00 [received] PHST- 2021/01/19 00:00 [accepted] PHST- 2022/04/25 05:31 [entrez] PHST- 2022/04/26 06:00 [pubmed] PHST- 2022/04/26 06:01 [medline] PHST- 2022/04/01 00:00 [pmc-release] AID - hbsn-11-02-199 [pii] AID - 10.21037/hbsn-20-688 [doi] PST - ppublish SO - Hepatobiliary Surg Nutr. 2022 Apr;11(2):199-211. doi: 10.21037/hbsn-20-688.