The overall goal of this proposal is to further our understanding of the molecular mechanisms governing hepatocyte proliferation in response to liver injury. Various insults including hepatotoxins, drug toxicity, and viral infection cause acute or chronic liver injury. However, the liver has an extraordinary ability to regenerate, replacing damaged tissue and restoring original structures and functions. Hepatocytes, as the main structural and functional cells in the liver, are extremely capable of replicating during liver tissue repair process. Remarkably, hepatocyte proliferation constitutes the fundamental process of liver regeneration. Timely and/or enhanced hepatocyte proliferation leads to recovery from liver injury and survival, whereas delayed and/or inhibited hepatocyte proliferation in pathological conditions results in liver failure and death. Therefore, understanding the regulation of hepatocyte proliferation is of particular importance in developing therapeutic means targeting liver tissue repair for prevention and treatment of liver injury. Forming a complex regulatory network, various growth factors and cytokines participate in modulating the proliferative process of hepatocytes. However, the precise molecular mechanisms that control hepatocyte proliferation in response to liver injury remain poorly defined. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is a transcription factor that plays a central role in regulating the transcription of genes encoding drug-detoxifying enzymes and antioxidant proteins. Our preliminary studies revealed that Nrf2 activation stimulates hepatocyte proliferation, which represents a novel function of this transcription factor. Furthermore, our preliminary studies demonstrated that Nrf2 is highly activated during partial hepatectomy (PH)-induced liver regeneration and lack of Nrf2 leads to severely suppressed liver growth after PH. These findings suggest that Nrf2 participates in modulating hepatocyte proliferation in response to liver mass loss. Therefore, our central hypothesis is that Nrf2 participates in regulating hepatocyte proliferation during liver regeneration. To test this hypothesis, two specific aims are proposed.
Specific Aim 1 : determine the molecular mechanisms by which Nrf2 regulates hepatocyte proliferation.
Specific Aim 2 : determine the effects of pharmacological activation of Nrf2 on hepatocyte proliferation and liver growth during liver regeneration. The proposed investigation will enable us to gain greater insight into the mechanisms governing hepatocyte proliferation during liver regeneration. Moreover, the proposed studies will establish the novel function of Nrf2 in regulating hepatocyte proliferation. Furthermore, our proposed studies will provide essential information to evaluate Nrf2 as a novel target for treatment of liver injury through a mechanism of enhancing liver repair.

Public Health Relevance

The proposed investigation will enable us to gain greater insight into the mechanisms governing hepatocyte proliferation during liver regeneration. Moreover, the proposed studies will establish the novel function of Nrf2 in regulating hepatocyte proliferation. Furthermore, our proposed studies will provide essential information to evaluate Nrf2 as a novel target for treatment of liver injury through a mechanism of enhancing liver repair.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK075968-05
Application #
8249102
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$264,138
Indirect Cost
$92,620
Name
Indiana University-Purdue University at Indianapolis
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Rui, Wenjuan; Zou, Yuhong; Lee, Joonyong et al. (2016) Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen. J Pharmacol Exp Ther 358:14-21
Zou, Yuhong; Hu, Min; Lee, Joonyong et al. (2015) Nrf2 is essential for timely M phase entry of replicating hepatocytes during liver regeneration. Am J Physiol Gastrointest Liver Physiol 308:G262-8
Zou, Yuhong; Lee, Joonyong; Nambiar, Shashank Manohar et al. (2014) Nrf2 is involved in maintaining hepatocyte identity during liver regeneration. PLoS One 9:e107423
Hu, Min; Zou, Yuhong; Nambiar, Shashank Manohar et al. (2014) Keap1 modulates the redox cycle and hepatocyte cell cycle in regenerating liver. Cell Cycle 13:2349-58
Kumar, Sudhanshu; Zou, Yuhong; Bao, Qi et al. (2013) Proteomic analysis of immediate-early response plasma proteins after 70% and 90% partial hepatectomy. Hepatol Res 43:876-89
Zou, Yuhong; Hu, Min; Bao, Qi et al. (2013) Nrf2 participates in regulating maternal hepatic adaptations to pregnancy. J Cell Sci 126:1618-25
Zou, Yuhong; Bao, Qi; Kumar, Sudhanshu et al. (2012) Four waves of hepatocyte proliferation linked with three waves of hepatic fat accumulation during partial hepatectomy-induced liver regeneration. PLoS One 7:e30675
Dai, Guoli; Bustamante, Juan J; Zou, Yuhong et al. (2011) Maternal hepatic growth response to pregnancy in the mouse. Exp Biol Med (Maywood) 236:1322-32