YAP regulates the liver size during the fasting-refeeding transition in mice

Liver is the central hub regulating energy metabolism during feeding-fasting transition. Evidence suggests that fasting and refeeding induce dynamic changes in liver size, but the underlying mechanisms remain unclear. Yes-associated protein (YAP) is a key regulator of organ size. This study aims to explore the role of YAP in fasting- and refeeding-induced changes in liver size. Here, fasting significantly reduced liver size, which was recovered to the normal level after refeeding. Moreover, hepatocyte size was decreased and hepatocyte proliferation was inhibited after fasting. Conversely, refeeding promoted hepatocyte enlargement and proliferation compared to fasted state. Mechanistically, fasting or refeeding regulated the expression of YAP and its downstream targets, as well as the proliferation-related protein cyclin D1 (CCND1). Furthermore, fasting significantly reduced the liver size in AAV-control mice, which was mitigated in AAV Yap (5SA) mice. Yap overexpression also prevented the effect of fasting on hepatocyte size and proliferation. Besides, the recovery of liver size after refeeding was delayed in AAV Yap shRNA mice. Yap knockdown attenuated refeeding-induced hepatocyte enlargement and proliferation. In summary, this study demonstrated that YAP plays an important role in dynamic changes of liver size during fasting-refeeding transition, which provides new evidence for YAP in regulating liver size under energy stress.

Dynamic change of hepatocyte during PXR-induced liver enlargement / 药学学报

Pregnane X receptor (PXR), a member of nuclear receptor superfamily, plays an important role in xenobiotic and endogenous metabolism, endocrine balance, and cell proliferation, etc. Previous study has shown that pregnenolone 16α-carbonitrile (PCN), a mouse PXR agonist, could induce liver enlargement. And we found that the change in hepatocytes exhibits regional distribution characteristics: hepatocyte enlargement occurs around the central vein (CV) area, while hepatocyte proliferation occurs around the portal vein (PV) area. In this study, the dynamic changes of hepatocytes during PXR-induced liver enlargement were determined. Serum and liver samples from male C57BL/6 mice were collected for biochemical and pathological analysis after PCN treatment for 1, 2, 3, 5 days, respectively. The animal experiment was approved by the Animal Ethics Committee of Sun Yat-Sen University. The results showed that with the increase in the PCN treatment days, the feature of this regional change of hepatocyte around the CV and PV areas became more and more obvious. At the same time, the factors related to hepatocyte enlargement, such as the expression of PXR downstream genes and the hepatic content of triglyceride (TG), has gradually increased. The upregulation of proliferation-related proteins and downregulation of cyclin-dependent kinases inhibitor proteins were observed in the early stage of PCN treatment, suggesting that hepatocyte proliferation occurs earlier than hepatocyte enlargement during PXR-induced liver enlargement. This study reveals the dynamic change of hepatocytes during PXR-induced liver enlargement and provides a new insight in liver enlargement promoted via PXR activation.

Role of microRNAs in liver regeneration / 解剖学报

MicroRNAs (miRNAs) are a group of endogenous, small, noncoding RNA molecules which can regulate gene expression at posttranscriptional level by binding to the 3 ' untranslated regions (3' UTRs) of their target mRNAs. It has been reported that miRNAs regulated a variety of biological processes, including cell proliferation, differentiation, apoptosis, metabolic process, organ development, etc. Liver as one of the organs with extraordinary regenerative abilities, is considered to be an important material for the research of regeneration mechanism. This paper summarized the research advance of the role of microRNAs in liver regeneration.

Molecular mechanism and Chinese medicine intervention of liver regeneration / 中华肝胆外科杂志

Partial hepatectomy (PH) is an effective method for the treatment of various liver tumors,and liver regeneration dysfunction is one of the most serious complications.Therefore,liver regeneration (LR) after PH is particularly important.In this paper,we reviewed the molecular mechanisms of LR including cellular factors,growth factors,metabolism and related signaling pathways,and reviewed the research progresses of the traditional Chinese medicine (TCM) in promoting liver regeneration.The aim was to further clarify the mechanism of the occurrence and development of LR,and to provide valuable information for the development of drugs for treating liver regeneration disorders.

Effect of nodosin on accelerating hepatocyte regeneration after partial liver transplantation in rats / 器官移植

Objective To evaluate the effect of nodosin,as an effective element extracted from rabdosiae serrae, on hepatocyte regeneration after partial liver transplantation.Methods Wistar rats were used as donors and SD rats as recipients.Rat models with partial liver transplantation were established by modified two-cuff technique.Twenty-four recipient rats were randomly assigned into the nodosin and control groups.In the nodosin group,nodosin at a dosage of 1 00 μg/ml was administered via tail venous route after liver transplantation.Peripheral plasma and liver specimen were obtained at postoperative 3 and 7 d.The levels of alanine transaminase (ALT),aspartate aminotransferase (ALT)and albumin (ALB)in the peripheral plasma were measured by spectrophotometry.Hepatic histomorphological changes were observed under light microscope.The positive cell count of proliferating cell nuclear antigen (PCNA)antibody in the liver tissue was detected by immunohistochemistry. The expression levels of phosphorylated protein kinase (p-AKT ), phosphorylated mammalian target of rapamycin (p-mTOR),cyclin D1 and heme oxygenase (HO)-1 proteins were measured by western blot.The apoptosis of liver cells was detected by Annexin V method and TdT mediated-dUTP nick end labeling (TUNEL).Results Compared with the control group,the serum levels of ALT and AST were significantly lower at 3 d and 7 d after operation,whereas the ALB content was significantly higher in the nodosin group (all in P <0.05).And nodosin could alleviate the pathological injury of rat liver tissue after transplantation.The positive cell count of PCNA in the nodosin group was significantly higher than that in the control group (P <0.05).In the nodosin group,the expression levels of p-AKT,p-mTOR,cyclin D1 and HO-1 proteins were significantly higher than those in the control group (all in P <0.05).The quantity and percentage of apoptotic hepatocytes in the nodosin group were significantly lower than those in the control group (both in P <0.05).Conclusions Application of nodosin can decrease the quantity of apoptotic hepatocytes and accelerate hepatocyte proliferation after liver transplantation in rat models.

6 Paths of ERK5 signaling pathway regulate hepatocyte proliferation in rat liver regeneration.

Generally, extra-cellular-signal-regulated kinase 5 (ERK5) signaling pathway regulates many physiological activities, such as cell proliferation and cell differentiation. However, little is known about how ERK5 signaling pathway composed of 15 paths participates in regulating hepatocyte proliferation during liver regeneration (LR). In this study, to explore the influence ERK5 signaling pathway upon hepatocytes at gene transcription level, rat genome 230 2.0 array was used to detect expression changes of 75 related genes in isolated hepatocytes from rat regenerating liver. Bioinformatics and systems biology methods were applied to analyze the precise role of ERK5 signaling pathway in regulating hepatocyte proliferation during LR. Results showed that 62 genes were contained in the array and 22 genes were significantly changed. It was found that 6 paths were related to hepatocyte proliferation during rat LR. Among them, paths 3, 6 and 13 of ERK5 signaling pathway modulated cell cycle progression by decreasing the negative influence on ERK5 and paths 3, 4, 8 and 9 by reinforcing the positive influence on ERK5. In summary, the study shows that 22 genes and 6 paths of ERK5 signaling pathway participate in regulating proliferation of hepatocytes in rat LR.

THE PROLIFERATION OF HEPATOCYTES AND IMMUNOHISTOCHEMICAL STUDY OF ALPHAFETOPROTEIN AND ALBUMIN AFTER SUBTOTAL HEPATECTOMY AND DGALACTOSAMINE INDUCED HEPATIC INJURY / 解剖学报

Male Wistar rats were performed 70% partial hepatectomy (PH) or 1.5mg/g body weight D-galactosamine injection (Gal) intraperitoneally. From the 1st to the 7th day after treatment, the serum concentration of alpha-fetoprotein (AFP) and albumin (ALB) was measured and the liver sections were stained with routine and immunohistochemical methods and observed with light and electron microscopy. The mitotic index (MI) reached a maximum level (1.5%) on the 2nd day after PH, while the Gal group showed a lower (0.8%) and delayed (on the 3rd day) MI peak. On the 2nd and 3rd day after PH, AFP positive hepatocytes were predominantly observed in the periportal area and ALB positive cells mainly distributed around the central veins. In Gal group, AFP was detected both in hepatocytes near the necrotic areas and particularly in some special small cells which had not been seen in PH group. These small cells seemed to be able to transform into typical hepatocytes. Intracellular localization of AFP and ALB was observed in the perinuclear space, RER, and Golgi complex. Serum AFP and ALB levels in both groups presented reciprocal changes from the 1st to the 7th day after treatment.