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Item Interleukin-6/ GP80-dependent pathways role in physiologic cachexia during liver regeneration after partial hepatectomy(Office of the Vice Chancellor for Research, 2015-04-17) Kronbergs, Andris; Zimmers, Teresa A.; Koniaris, Leonidas G.Liver has a unique capacity to regenerate its mass after tissue loss. Many of the cytokines and growth factors were shown to be critical in liver regeneration. Studies with interleukin-6 (IL-6) – deficient mice demonstrated that IL-6 plays central role in hepatocyte proliferation via activating signal transducer and activator of transcription 3 (STAT3). The biological activities of IL-6 are potentiated when it binds to an 80 kDa IL-6 (IL-6Ra) receptor located on target cells. IL-6 and Il-6Ra complex then associates with another glycoprotein, gp130, to initiate intracellular signaling. Another of many IL-6 functions is metabolic control of the body. Increased activation of IL6 and STAT3 due to acute body injury, such as partial hepatectomy, causes metabolic dysregulation associated with sustained muscle and adipose tissue loss, a condition called physiologic Cachexia. Two lines of trangenic mice with conditional knockout of gp 80 in the liver and conditional knockout of gp 80 in the muscle were generated to investigate the role of Il6 in liver regeneration and concomitant muscle wasting after partial hepatectomy. Here, we report that specific interruption of IL-6 pathway in the liver was presented with normal liver regeneration but associated with increased animal mortality after partial hepatectomy. Conversely, specific abrogation of IL-6 pathway in muscle lead to increased liver regeneration that did not increase muscle or adipose tissue wasting. These findings suggest that IL-6 pathway may play a central role in the liver regeneration and muscle wasting axis.Item 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, GuoliTranscription 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.Item 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 ScienceAIM: 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.Item The role of CFP1 in maintaining liver homeostasis in a murine model(2017-06-09) Chittajallu, Nandita; Skalnik, David G.CXXC finger protein 1 (CFP1) is an epigenetic regulator of H3K4 and cytosine methylation. Due to its role in establishing and maintaining methylation patterns, CFP1 determines whether DNA is found in its euchromatin or heterochromatin state and as such whether genes are transcriptionally active or inactive. In stem cells, deficiency of CFP1 results in inability to differentiate and in murine embryos it results in periimplantation death. Despite the demonstrated importance in developing tissue, the role of CFP1 in mature tissues, such as the liver, has yet to be elucidated. This study examined the role of CFP1 in maintaining liver homeostasis under conditions involving hepatocellular stress by examining liver regeneration, pregnancy-induced hepatomegaly, and non-alcoholic steatohepatitis (NASH) disease progression. The liver’s ability to recover was analyzed through liver:body mass ratios, blood serum analysis, liver histology, and qualitative observations. Deficiency of CFP1 in the livers of animals subjected to partial hepatectomies (PH) resulted in decreased liver regeneration capacity with liver mass restoration becoming significantly different starting at 48H post-PH and remaining so until 10D post-PH. This decreased regeneration appeared to be the result of reduced hepatocyte mitosis. Mouse dams lacking hepatic CFP1 mated with males expressing CFP1 displayed a proclivity for dystocia. Mice subjected to a fast food diet resulting in NASH while lacking hepatic CFP1 experienced decreased weight gain and hepatic lipid accumulation compared to their CFP1 expressing counterparts. Through these three studies, the critical role of CFP1 for the maintenance of liver homeostasis was demonstrated.