Browsing by Author "Zou, Yuhong"

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    Keap1 modulates the redox cycle and hepatocyte cell cycle in regenerating liver
    (Taylor & Francis, 2014-08-01) Hu, Min; Zou, Yuhong; Nambiar, Shashank Manohar; Lee, Joonyong; Yang, Yan; Dai, Guoli; Department of Biology, School of Science
    Keap1 negatively controls the activity of transcription factor Nrf2. This Keap1/Nrf2 pathway plays a critical role in combating oxidative stress. We aimed at determining whether and how Keap1 modulates the cell cycle of replicating hepatocytes during liver regeneration. Two-thirds partial hepatectomy (PH) was performed on wild-type mice and Keap1+/- (Keap1 knockdown) mice. We found that, following PH, Keap1 knockdown resulted in a delay in S-phase entry, disruption of S-phase progression, and loss of mitotic rhythm of replicating hepatocytes. These events are associated with dysregulation of c-Met, EGFR, Akt1, p70S6K, Cyclin A2, and Cyclin B1 in regenerating livers. Astonishingly, normal regenerating livers exhibited the redox fluctuation coupled with hepatocyte cell cycle progression, while keeping Nrf2 quiescent. Keap1 knockdown caused severe disruption in both the redox cycle and the cell cycle of replicating hepatocytes. Thus, we demonstrate that Keap1 is a potent regulator of hepatic redox cycle and hepatocyte cell cycle during liver regeneration.
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    Maternal hepatic growth response to pregnancy in the mouse
    (SAGE, 2011-11) Dai, Guoli; Bustamante, Juan J.; Myronovych, Andriy; Zou, Yuhong; Bao, Qi; Kumar, Sudhanshu; Soares, Michael J.; Department of Biology, School of Science
    Pregnancy is characterized by physiological adjustments in the maternal compartment. In this investigation, the influence of pregnancy on maternal liver was examined in CD-1 mice. Dramatic changes were observed in the size of the maternal liver during pregnancy. Livers doubled in weight from the non-pregnant state to day 18 of pregnancy. The pregnancy-induced hepatomegaly was a physiological event of liver growth confirmed by DNA content increase and detection of hepatocyte hyperplasia and hypertrophy. Growth of the liver was initiated following implantation and peaked at parturition. The expression and/or activities of key genes known to regulate liver regeneration, a phenomenon of liver growth compensatory to liver mass loss, were investigated. The results showed that pregnancy-dependent liver growth was associated with interleukin (IL)-6, tumor necrosis factor α, c-Jun and IL-1β, but independent of hepatocyte growth factor, fibroblast growth factor 1, tumor necrosis factor receptor 1, constitutive androstane receptor and pregnane X receptor. Furthermore, maternal liver growth was associated with the activation of hepatic signal transducer and activator of transcription 3, β-catenin and epidermal growth factor receptor, but pregnancy did not activate hepatic c-Met. The findings suggest that the molecular mechanisms regulating pregnancy-induced liver growth and injury-induced liver regeneration exhibit overlapping features but are not identical. In summary, the liver of the mouse adapts to the demands of pregnancy via a dramatic growth response driven by hepatocyte proliferation and size increase.
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    Nrf2 Deficiency Augments the Activity of Hepatic Progenitor Cells during Cholestasis
    (Office of the Vice Chancellor for Research, 2013-04-05) Wang, Guo-Ying; Zou, Yuhong; Dai, Guoli
    Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a central regulator of cellular defense against oxidative stress and inflammation and is also involved in regulating liver regeneration. The aim of the study is to evaluate whether Nrf2 mediates hepatic repair response during cholestasis. Wild-type and Nrf2-null mice were subjected to bile duct ligation or sham operation. Various assessments were performed at 5, 10, 15, 25, and 40 days following surgery. Significant genotype-dependent differences in liver injury, cell proliferation, and collagen deposition were not seen over the time course of the study, in line with several reports. However, Nrf2-null mice exhibited a more prominent network of septual tissue containing laminin and α-fetal protein expressing cells at 15 days after injury, suggesting a stronger repair response, than their wild-type litter mates. In the livers of both genotypes of mice, cytokeratin 19 (CK19), a marker of bipotent liver epithelial progenitors and immature billiary epithelial cells, were expressed in the epithelial cells of newly formed bile ducts and a population of hepatocytic-appearing cells in parenchyma. Notably, Nrf2-null mice showed higher hepatic protein expression of CK19 at 5 days following BDL, indicating earlier onset of the activation of CK19+ progenitor cells, than wild-types. CD133, a marker of liver progenitors, were found to be expressed by newly generated bile duct epithelial cells and a population of hepatocytic-appearing parenchymal cells in the livers of the two genotypes of mice. Hepatic CD133 protein expression was gradually elevated, paralleling continuous increase in the number of CD133+ hepatocytic-appearing cells, as the cholestasis progressed. Remarkably, the lack of Nrf2 led to markedly higher magnitudes of the increases in hepatic CD133 protein level and in the number of CD133+ hepatocytic-appearing cells. Collectively, our data demonstrate that Nrf2 deficiency evokes higher activity of liver progenitor cells and thus stronger liver repair response. The findings indicate that Nrf2 is an important regulator of the activity of hepatic progenitor/stem cells during chronic liver injury.
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    Nrf2 is essential for timely M phase entry of replicating hepatocytes during liver regeneration
    (APS, 2015-02-15) Zou, Yuhong; Hu, Min; Lee, Joonyong; Nambiar, Shashank Manohar; Garcia, Veronica; Bao, Qi; Chan, Jefferson Y.; Dai, Guoli; Department of Biology, School of Science
    The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates various cellular activities, including redox balance, detoxification, metabolism, autophagy, proliferation, and apoptosis. Several studies have demonstrated that Nrf2 regulates hepatocyte proliferation during liver regeneration. The aim of this study was to investigate how Nrf2 modulates the cell cycle of replicating hepatocytes in regenerating livers. Wild-type and Nrf2 null mice were subjected to 2/3 partial hepatectomy (PH) and killed at multiple time points for various analyses. Nrf2 null mice exhibited delayed liver regrowth, although the lost liver mass was eventually restored 7 days after PH. Nrf2 deficiency did not affect the number of hepatocytes entering the cell cycle but did delay hepatocyte mitosis. Mechanistically, the lack of Nrf2 resulted in increased mRNA and protein levels of hepatic cyclin A2 when the remaining hepatocytes were replicating in response to PH. Moreover, Nrf2 deficiency in regenerating livers caused dysregulation of Wee1, Cdc2, and cyclin B1 mRNA and protein expression, leading to decreased Cdc2 activity. Thus, Nrf2 is required for timely M phase entry of replicating hepatocytes by ensuring proper regulation of cyclin A2 and the Wee1/Cdc2/cyclin B1 pathway during liver regeneration.
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    Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen
    (American Society for Pharmacology and Experimental Therapeutics, 2016-07) Rui, Wenjuan; Zou, Yuhong; Lee, Joonyong; Nambiar, Shashank Manohar; Lin, Jingmei; Zhang, Linjie; Yang, Yan; Dai, Guoli; Biology, School of Science
    Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates multiple biologic processes, including hepatic lipid metabolism. Estrogen exerts actions affecting energy homeostasis, including a liver fat-lowering effect. Increasing evidence indicates the crosstalk between these two molecules. The aim of this study was to evaluate whether Nrf2 modulates estrogen signaling in hepatic lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) was induced in wild-type and Nrf2-null mice fed a high-fat diet and the liver fat-lowering effect of exogenous estrogen was subsequently assessed. We found that exogenous estrogen eliminated 49% and 90% of hepatic triglycerides in wild-type and Nrf2-null mice with NAFLD, respectively. This observation demonstrates that Nrf2 signaling is antagonistic to estrogen signaling in hepatic fat metabolism; thus, Nrf2 absence results in striking amplification of the liver fat-lowering effect of estrogen. In addition, we found the association of trefoil factor 3 and fatty acid binding protein 5 with the liver fat-lowering effect of estrogen. In summary, we identified Nrf2 as a novel and potent inhibitor of estrogen signaling in hepatic lipid metabolism. Our finding may provide a potential strategy to treat NAFLD by dually targeting Nrf2 and estrogen signaling.
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    Proteomic analysis of immediate-early response plasma proteins after 70% and 90% partial hepatectomy
    (Wiley Blackwell (Blackwell Publishing), 2013-08) Kumar, Sudhanshu; Zou, Yuhong; Bao, Qi; Wang, Mu; Dai, Guoli; Department of Biology, School of Science
    AIM: Partial hepatectomy (PH) induces robust hepatic regenerative and metabolic responses that are considered to be triggered by humoral factors. The aim of the study was to identify plasma protein factors that potentially trigger or reflect the body's immediate-early responses to liver mass reduction. METHODS: Male C57BL/6 mice were subjected to sham operation, 70% PH or 90% PH. Blood was collected from the inferior vena cava at 20, 60 and 180 min after surgery. RESULTS: Using a label-free quantitative mass spectrometry-based proteomics approach, we identified 399 proteins exhibiting significant changes in plasma expression between any two groups. Of the 399 proteins, 167 proteins had multiple unique sequences and high peptide ID confidence (>90%) and were defined as priority 1 proteins. A group of plasma proteins largely associated with metabolism is enriched after 70% PH. Among the plasma proteins that respond to 90% PH are a dominant group of proteins that are also associated with metabolism and one known cytokine (platelet factor 4). Ninety percent PH and 70% PH induces similar changes in plasma protein profile. CONCLUSION: Our findings enable us to gain insight into the immediate-early response of plasma proteins to liver mass loss. Our data support the notion that increased metabolic demands of the body after massive liver mass loss may function as a sensor that calibrates hepatic regenerative response.