Myeloid peroxisome proliferator-activated receptor alpha deficiency accelerates liver regeneration via IL-6/STAT3 pathway after 2/3 partial hepatectomy in mice

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 (PPAR alpha), the target of clinical lipid-lowering fibrate drugs, regulates cell metabolism, proliferation, and survival. However, the role of myeloid PPAR alpha in partial hepatectomy (PHx)-induced liver regeneration remains unknown. Methods: Mycloid-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 cytomctry 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 (Pena) 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 PPAR alpha deficiency accelerates PHx-induced liver regeneration via macrophage polarization and consequent IL-6/STAT3 activation, thus providing a potential target for manipulating liver regeneration.