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NRF2 Activates Growth Factor Genes and Downstream AKT Signaling to Induce Mouse and Human Hepatomegaly

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NRF2 Activates Growth Factor Genes and Downstream AKT Signaling to Induce Mouse and Human Hepatomegaly

Hepatomegaly, or liver enlargement, is a nonspecific pathological reaction triggered by infections, liver cancer, metabolic disturbances, toxicant exposure, as well as alcohol abuse or drug-induced hepatitis [1x[1]Metze D, Cury VF, Gomez RS, Marco L, Robinson D, Melamed E, et al. Hepatomegaly. Encyclopedia of Molecular Mechanisms of Disease, Berlin, Heidelberg: Springer Berlin Heidelberg; 2009, p. 824–825.
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]. Congenital disorders, including hemolytic anemia, polycystic liver disease, sickle cell disease, hereditary fructose intolerance or carnitine palmitoyltransferase deficiency can also elicit hepatomegaly [2x[2]Ebert, E.C., Nagar, M., and Hagspiel, K.D. Gastrointestinal and Hepatic Complications of Sickle Cell Disease. Clinical Gastroenterology and Hepatology. 2010;
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]. In such cases, hepatomegaly has been attributed to hepatocyte glycogen accumulation driven by insulin-induced hepatic glycogenosis, especially in pediatric patients [8x[8]Chatila, R. and West, A.B. Hepatomegaly and abnormal liver tests due to glycogenosis in adults with diabetes. Medicine. 1996;
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]. By contrast, the mechanisms underlying hepatomegaly caused by other etiologies are poorly understood. Histopathological analysis suggests the involvement of vascular swelling and inflammation, as well as increased accumulation of iron, glycogen, fat or insoluble proteins within hepatocytes [1x[1]Metze D, Cury VF, Gomez RS, Marco L, Robinson D, Melamed E, et al. Hepatomegaly. Encyclopedia of Molecular Mechanisms of Disease, Berlin, Heidelberg: Springer Berlin Heidelberg; 2009, p. 824–825.
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]. Mimicking insulin overdosing, adenovirus-mediated hepatic overexpression of a constitutively active form of AKT, the key effector of insulin signaling [9x[9]Hay, N. Interplay between FOXO, TOR, and Akt. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research. 2011;
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Autophagy defects can also induce hepatomegaly. Indeed, both liver specific Atg5 (Atg5Δhep) and Atg7 (Atg7Δhep) knockout mice exhibit marked liver enlargement [11x[11]Ni, H.M., Chao, X., Yang, H., Deng, F., Wang, S., Bai, Q. et al. Dual Roles of Mammalian Target of Rapamycin in Regulating Liver Injury and Tumorigenesis in Autophagy-Defective Mouse Liver. Hepatology. 2019;
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]. Autophagy-deficient livers show accumulation of the autophagy substrate and signaling scaffold p62/SQSTM1 (hereafter referred to p62), which sequesters Kelch-like ECH-associated protein 1 (KEAP1) away from the oxidant-responsive transcription factor Nuclear factor erythroid 2-Related Factor 2 (NRF2), resulting in NRF2 nuclear accumulation and activation [13x[13]Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y. et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol. 2010;
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]. Nuclear NRF2 also accumulates in response to oxidative stress and KEAP1 inactivation [18x[18]Yamamoto, M., Kensler, T.W., and Motohashi, H. The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis. Physiological Reviews. 2018;
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]. Normally, NRF2 plays a critical role in t induction of genes that code for cytoprotective redox-active proteins and enzymes that detoxify reactive oxygen species (ROS) and xenobiotics [18x[18]Yamamoto, M., Kensler, T.W., and Motohashi, H. The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis. Physiological Reviews. 2018;
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]. But NRF2 can also undergo persistent activation in lung, liver and colon cancers due to gain-of-action mutations in the NFE2L2 gene that prevent binding to KEAP1 or loss-of-function mutations in the KEAP1 gene [20x[20]Shibata, T., Ohta, T., Tong, K.I., Kokubu, A., Odogawa, R., Tsuta, K. et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proceedings of the National Academy of Sciences. 2008;
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]. In addition to NRF2, several other factors may contribute to hepatomegaly in the autophagy-deficient liver, including YAP [24x[24]Lee, Y.A., Noon, L.A., Akat, K.M., Ybanez, M.D., Lee, T.F., Berres, M.L. et al. Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap. Nature Communications. 2018;
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], mTorc1 [11x[11]Ni, H.M., Chao, X., Yang, H., Deng, F., Wang, S., Bai, Q. et al. Dual Roles of Mammalian Target of Rapamycin in Regulating Liver Injury and Tumorigenesis in Autophagy-Defective Mouse Liver. Hepatology. 2019;
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], and FXR [25x[25]Khambu, B., Li, T., Yan, S., Yu, C., Chen, X., Goheen, M. et al. Hepatic Autophagy Deficiency Compromises Farnesoid X Receptor Functionality and Causes Cholestatic Injury. Hepatology. 2019;
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]. Thus, it is not clear whether NRF2 activation alone is sufficient for induction of hepatomegaly in oxidatively stressed or autophagy-deficient livers. Also, the relationship between the NRF2-induced protective response and hepatomegaly remains unknown.

NRF2 deficient mice are susceptible to a numerous electrophiles and oxidants [18x[18]Yamamoto, M., Kensler, T.W., and Motohashi, H. The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis. Physiological Reviews. 2018;
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], and also exhibit defective liver regeneration due to oxidative stress-mediated insulin/insulin-like growth factor (IGF) resistance [27x[27]Beyer, T.A., Xu, W., and Teupser, D. Auf Dem Keller U, Bugnon P, Hildt E, et al. Impaired liver regeneration in Nrf2 knockout mice: Role of ROS-mediated insulin/IGF-1 resistance. EMBO Journal. 2008;
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]. Conversely, NRF2 activation redirects glucose and glutamine into the anabolic pentose phosphate pathway when superimposed on persistently activated AKT in cancer cells that exhibit chronic upregulation of phosphatidylinositol 3-kinase (PI3K) signaling [28x[28]Mitsuishi, Y., Taguchi, K., Kawatani, Y., Shibata, T., Nukiwa, T., Aburatani, H. et al. Nrf2 Redirects Glucose and Glutamine into Anabolic Pathways in Metabolic Reprogramming. Cancer Cell. 2012;
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]. Although in cancer cells NRF2 activation confers survival and growth advantage [29x[29]Rojo de la Vega, M., Chapman, E., and Zhang, D.D. NRF2 and the Hallmarks of Cancer. Cancer Cell. 2018;
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, 31x[31]Chio, I.I.C., Jafarnejad, S.M., Ponz-Sarvise, M., Park, Y., Rivera, K., Palm, W. et al. NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer. Cell. 2016;
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, 32x[32]Umemura, A., He, F., Taniguchi, K., Nakagawa, H., Yamachika, S., Font-Burgada, J. et al. p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells. Cancer Cell. 2016;
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], in autophagy-defective livers NRF2 activation was reported to provoke hepatocyte death and liver injury [12x[12]Taguchi, K., Fujikawa, N., Komatsu, M., Ishii, T., Unno, M., Akaike, T. et al. Keap1 degradation by autophagy for the maintenance of redox homeostasis. Proceedings of the National Academy of Sciences of the United States of America. 2012;
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,13x[13]Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y. et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol. 2010;
12: 213–223
Crossref | PubMed | Scopus (1065)
| Google ScholarSee all References
,16x[16]Ni, H.M., Woolbright, B.L., Williams, J., Copple, B., Cui, W., Luyendyk, J.P. et al. Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy. Journal of Hepatology. 2014;
61: 617–625
Abstract | Full Text | Full Text PDF | PubMed | Scopus (94)
| Google ScholarSee all References
,25x[25]Khambu, B., Li, T., Yan, S., Yu, C., Chen, X., Goheen, M. et al. Hepatic Autophagy Deficiency Compromises Farnesoid X Receptor Functionality and Causes Cholestatic Injury. Hepatology. 2019;
69: 2196–2213
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,33x[33]Khambu, B., Huda, N., Chen, X., Antoine, D.J., Li, Y., Dai, G. et al. HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers. Journal of Clinical Investigation. 2018;
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]. How NRF2 activation promotes liver injury in the absence of autophagy is unknown. Moreover, persistent activation of NRF2 in an autophagy competent liver does not cause liver injury as shown by liver specific Keap1 knockout (Keap1Δhep) mice, which exhibit hepatomegaly without liver damage [12x[12]Taguchi, K., Fujikawa, N., Komatsu, M., Ishii, T., Unno, M., Akaike, T. et al. Keap1 degradation by autophagy for the maintenance of redox homeostasis. Proceedings of the National Academy of Sciences of the United States of America. 2012;
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]. Evidently, the effects of persistent NRF2 activation are highly context dependent.

We previously found that in the unstressed liver, p62 controls basal NRF2 activity [32x[32]Umemura, A., He, F., Taniguchi, K., Nakagawa, H., Yamachika, S., Font-Burgada, J. et al. p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells. Cancer Cell. 2016;
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Abstract | Full Text | Full Text PDF | PubMed | Scopus (130)
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] and that p62 accumulation due to autophagy disruption contributes to liver and pancreatic tumorigenesis by activating NRF2 [30x[30]Todoric, J., Antonucci, L., Di Caro, G., Li, N., Wu, X., Lytle, N.K.K. et al. Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas. Cancer Cell. 2017;
32: 824–839 e8
Abstract | Full Text | Full Text PDF | PubMed | Scopus (31)
| Google ScholarSee all References
,32x[32]Umemura, A., He, F., Taniguchi, K., Nakagawa, H., Yamachika, S., Font-Burgada, J. et al. p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells. Cancer Cell. 2016;
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,34x[34]Taniguchi, K., Yamachika, S., He, F., and Karin, M. p62/SQSTM1-Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer. FEBS Letters. 2016;
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]. To further understand the role of persistent NRF2 activation in hepatocytes and whether it is sufficient for hepatomegaly induction, we generated transgenic mice that express a KEAP1-resistant form of NRF2 in their hepatocytes (Nrf2Act-hep). We also used p62 adenovirus vectors to selectively overexpress p62 in hepatocytes. Here we describe that hepatocyte-specific activation of NRF2 by either method causes marked hepatomegaly, glycogenosis, hypoglycemia and hypertriglyceridemia. Unexpectedly, we found that persistent NRF2 activation leads to hepatomegaly via upregulation of AKT signaling and that the latter depends on autocrine EGF and PDGF signaling. The NRF2-AKT axis is also activated in human hepatomegaly.

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