FoxO3 restricts liver regeneration by suppressing the proliferation of hepatocytes

Abstract

Upon injury, the liver is capable of substantial regeneration from the original tissue until an appropriate functional size. The underlying mechanisms controlling the liver regeneration processes are not well elucidated. Previous studies have proposed that the transcription factor FoxO3 is involved in various liver diseases, but its exact role in the regulation of liver regeneration remains largely unclear. To directly test the detailed role of FoxO3 in liver regeneration, both a constitutive Albumin-Cre driver line and adeno-associated virus serotype 8 (AAV8)-Tbg-Cre (AAV-Cre)-injected adult FoxO3fl/fl mice were subjected to 70% partial hepatectomy (PH). Our data demonstrate that FoxO3 deletion accelerates liver regeneration primarily by limiting polyploidization and promoting the proliferation of hepatocytes during liver regeneration. RNA-seq analysis indicates that FoxO3 deficiency greatly alters the expression of gene sets associated with cell proliferation and apoptosis during liver regeneration. Chromatin immunoprecipitation-PCR (ChIP-PCR) and luciferase reporter assays reveal that FoxO3 promotes the expression of Nox4 but suppresses the expression of Nr4a1 in hepatocytes. AAV8 virus-mediated overexpression of Nox4 and knockdown of Nr4a1 significantly suppressed hepatocyte proliferation and liver regeneration in FoxO3-deficient mice. We demonstrate that FoxO3 negatively controls hepatocyte proliferation through Nox4 upregulation and Nr4a1 downregulation, thereby ensuring appropriate functional regeneration of the liver. Our findings provide novel mechanistic insight into the therapeutic mechanisms of FoxO3 in liver damage and repair.

Transcriptomics and metabolomics analysis reveal the dietary copper deficiency and supplementation effects of liver gene expression and metabolite change in grazing sheep

“…FOXO3 is associated with many age-related diseases, including cancer, cardiovascular disease, disc degeneration, and neurodegenerative diseases [ 29 ]. The research on the regulation of liver regeneration revealed that FOXO3 could limit liver regeneration by inhibiting hepatocyte proliferation [ 30 ]. Notably, FOXO3 was found to be enriched in the GO term of DNA damage response that exhibited significant enrichment in LCu.…”

Mitochondria-derived H2O2 triggers liver regeneration via FoxO3a signaling pathway after partial hepatectomy in mice

“…In a previous study, the deceased expression of FoxO3a is observed at the early stage of LR after PHx due to the direct transcriptional regulation by p53 and p73 [ 63 ]. A recent study reports that FoxO3a negatively controls hepatocyte proliferation and FoxO3a deletion accelerates LR [ 64 ]. Taken together, FoxO3a is a redox-sensitive transcription factor and a vital regulator of cell proliferation [ 21 , 23 ], making it the best candidate to bridge mitochondria-derived H 2 O 2 with LR after PHx.…”

Deep-Learning-Based Hepatic Ploidy Quantification Using H&E Histopathology Images

“…In contrast, our trained algorithm is an entirely automated, objective pipeline for the high-throughput processing of images. In addition to IF imaging, flow cytometry [ 14 , 21 , 27 , 28 , 29 ] and image cytometry [ 45 , 46 , 47 ] are frequently utilized in experimental research to accurately quantify ploidy. However, these methods have not seen widespread use in clinic because it is difficult to perfuse and obtain viable hepatocytes from biopsies.…”

“…Currently, the quantification of hepatic ploidy relies on two main technological approaches: flow cytometry and image-based analysis using immunofluorescence (IF) [ 12 , 15 , 16 , 17 , 18 , 19 , 25 , 26 ]. Flow cytometry [ 14 , 21 , 27 , 28 , 29 ] is the current gold standard for ploidy quantification. However, it requires fresh samples, which can be difficult to obtain in clinical settings.…”