- Email: [email protected]
mTORC1 pathway in acute liver failure
Medical Hypotheses 78 (2012) 58–59
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
A novel therapy of inducing hepatocyte hypertrophy by activating Akt/mTORC1 pathway in acute liver failure Tao Wei a, Ling Yu b, Yi Lv a,⇑ a b
Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an 710061, China Department of Neonatology, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an 710061, China
a r t i c l e
i n f o
Article history: Received 20 March 2011 Accepted 19 September 2011
a b s t r a c t As a severe clinical syndrome, acute liver failure (ALF) is associated with high morbidity and mortality and liver transplantation is the best treatment of choice in most critically-ill cases, which yet suffers from obvious drawbacks including lack of resources and unnecessary surgery for those who can recover spontaneously. In ALF, massive cell deaths occur whereas liver regeneration via hepatocyte proliferation is largely inhibited. The serine/threonine kinase Akt serves as a central role in regulating signaling of growth factors, cytokines and other cellular stimuli within cell and thus correlates with diverse cellular functions, including the pro-survival pathway by inducing hypertrophy. Physiologically, cellular hypertrophy is an adaption in response to increased functional demand or other stresses. It has been demonstrated recently that Akt/mTORC1-controlled switch of hyperplasia to hypertrophy in pregnancy restored the regenerative capacity of aged liver and pharmacological activation of this pathway is sufficient to induce cell growth in the liver of nonpregnant aged mice. We hypothesized, therefore, that pharmacological therapy targeting to induce hepatocyte hypertrophy by activating the Akt/mTORC1 pathway might be a novel and promising option in the early management of patients with ALF as an alternative way to impaired process of cell proliferation. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction Acute liver failure (ALF) is a clinical syndrome characterized by severe liver damage that is often accompanied with rapidly progressive multiple organ dysfunction and devastating complications such as hepatic encephalopathy and coagulopathy, and emergency liver transplantation is warranted in most critically-ill cases, which improve the survival of these patients substantially [1]. However, the liver transplantation is not always available immediately for every patient due to the lack of resources which is also associated with high early post-transplant mortality in the state of emergency. Even though the transplantation is successfully performed, recipients have to receive lifelong immunosuppressive therapy. Additionally, some patients can survive by spontaneous recovery without the need of transplantation but no well-defined approaches exist for the prediction of recovery. Providing the severity and high mortality of ALF, development of effective therapies other
⇑ Corresponding author. Address: Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, No. 277, West Yanta Road, Xi’an 710061, Shaanxi Province, China. Tel.: +86 29 85323204; fax: +86 29 85252580. E-mail address: [email protected] (Y. Lv). 0306-9877/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2011.09.040
than liver transplantation are of great value and always in urgent need.
Impaired process of hepatocyte proliferation in acute liver failure The mechanisms of ALF have been well established being defined as extensive hepatocyte death and inadequate capacity of liver regeneration. Normally, the mature hepatocyte possesses the ability to undergo mitotic division in response to partial hepatectomy or other types of liver injury [2]. In ALF, however, the proliferation of differentiated hepatocytes is inhibited after over 50% loss and the regenerative pattern involves the alternative way of replication and differentiation of hepatic progenitor cells [3]. It appeared, unfortunately, that patients who died or were transplanted after ALF had more hepatic progenitor cells activation and less mature hepatocyte proliferative activity comparing with those who survived, indicating that progenitor cells might inadequately perform the functions of mature cells [4]. Moreover, although circulating bone marrow-derived hematopoietic stem cells are recognized as a source to replenish the damaged hepatocytes, the process is far from efficient in this clinical scenario unless stem cell mobilization agents are used like granulocyte colony-stimulating factor [5].
T. Wei et al. / Medical Hypotheses 78 (2012) 58–59
Akt/mTORC1-mediated cellular hypertrophy reconstitute liver mass Hypertrophy is an adaptive response to changes in functional demand or specific extracellular stresses like hormonal stimulation featured by an increase in the size of individual cell in contrast to the increase of cell number in hyperplasia. Growth of cells enable them to synthesis more pertinent proteins and eventually achieve a balance between requirement and functional organ capacity. Most commonly, cellular hypertrophy is developed in myocytes of skeletal muscle and heart to various stimuli. In liver, similarly, hepatocyte hypertrophy is able to restore liver mass as an alternative mechanism when proliferation of quiescent hepatocyte and progenitor cell is blocked [6]. During pregnancy, hepatocytes also undergo adaptive process of hypertrophy which results in the hepatomegaly to accommodate the increased metabolic burden [7,8]. The serine/threonine kinase Akt directly controlled by upstream phosphatidylinositol 3-kinase (PI3K) and phosphoinositide-dependent protein kinase 1 (PDK1) serves as a central role in regulating signaling of growth factors, cytokines and other cellular stimuli within cell and thus is associated with diverse cellular functions, including the pro-survival pathway by inducing cellular hypertrophy [9]. It has been confirmed in liver that PI3K/PDK1/Akt-triggered cell growth have the ability to compensate for decreased hepatic volume and impaired function [10]. The mammalian target of rapamycin (mTOR) is the principal downstream target of Akt, which resides in two distinct forms, i.e. the rapamycin-sensitive mTOR complex 1 (mTORC1) and the rapamycin-insensitive mTOR complex 2 (mTORC2), and the activation of mTORC1 predominately contribute to the increase of cell mass [9]. It was recently demonstrated that the Akt/mTORC1-based switch of hepatocyte hyperplasia to hypertrophy during pregnancy restored the regenerative capacity of aged liver, of which normally the ability to regenerate after partial hepatectomy is gradually lost. Additionally, pharmacological activation of this pathway is sufficient to induce the hypertrophy of liver in nonpregnant aged mice [11]. On the other hand, pathological outcomes of hypertrophy may develop if a limit is reached or beyond, for example, hypertrophic heart caused by long-term hypertension eventually lead to heart failure. Gielchinsky et al. also proposed that hypertrophy is preferred over hyperplasia in transient situations like in pregnancy [11]. Therefore, cell growth is more like an expedient within a short period to compensate for increased functional demand. The hypothesis While extensive loss of normal cells develops in ALF, a small proportion of mature hepatocytes remains unaffected or mildly affected which yet have decreased potential activity of proliferation. We hypothesized that pharmacological therapy targeting to induce hypertrophy of remaining hepatocytes after ALF by activating the Akt/mTORC1 pathway might be a novel and promising treatment
59
option as an alternative way to impaired process of cell proliferation. Considering that hypertrophy compensates for a time-limited functional demand, this strategy is appropriate for temporary support of patients in the early management. Once the severely impaired liver recovers from the acute insult, withdrawn of pharmacological activator may allows the more efficient process of regeneration based on increase of cell number to undergo. Therefore, this therapy can be used as means either to ‘buy time’ for transplantation in the situations where the graft is not available immediately and avoid emergency surgery which commits patients with significant mortality or even assist in spontaneous recovery of patients who do not have fatal liver failure. Testing this hypothesis Animal experiments are the appropriate way to address this hypothesis and a variety of animal model of ALF which can be easily established have been widely adopted including intraperitoneal injection of D-galactosamine and carbon tetrachloride. Activation of Akt requires the generation of phosphatidylinositol-3,4,5-trisphosphate (PIP3) from phosphatidylinositol-4,5-bisphosphate (PIP2), which can be reversed by PIP3 phosphatase PTEN. Therefore, PTEN inhibitor is able to activate Akt/mTORC1 pathway and thus can be used as a pharmacological activator to test our hypothesis. Conflict of interest statement None declared. References [1] Bernal W, Auzinger G, Dhawan A, Wendon J. Acute liver failure. Lancet 2010;376(9736):190–201. [2] Michalopoulos GK. Liver regeneration. J Cell Physiol 2007;213(2):286–300. [3] Rutherford A, Chung RT. Acute liver failure: mechanisms of hepatocyte injury and regeneration. Semin Liver Dis 2008;28(2):167–74. [4] Katoonizadeh A, Nevens F, Verslype C, Pirenne J, Roskams T. Liver regeneration in acute severe liver impairment: a clinicopathological correlation study. Liver Int 2006;26(10):1225–33. [5] Mark AL, Sun Z, Warren DS, Lonze BE, Knabel MK, Melville Williams GM. Stem cell mobilization is life saving in an animal model of acute liver failure. Ann Surg 2010;252(4):591–6. [6] Nagy P, Teramoto T, Factor VM, Sanchez A, Schnur J, Paku S, et al. Reconstitution of liver mass via cellular hypertrophy in the rat. Hepatology 2001;33(2):339–45. [7] Hollister A, Okubara P, Watson JG, Chaykin S. Reproduction in mice: liver enlargement in mice during pregnancy and lactation. Life Sci 1987;40(1):11–8. [8] Milona A, Owen BM, van Mil S, Dormann D, Mataki C, Boudjelal M, et al. Am J Physiol Gastrointest Liver Physiol 2010;298(2):G151–8. [9] Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007;129(7):1261–74. [10] Haga S, Ozaki M, Inoue H, Okamoto Y, Ogawa W, Takeda K, et al. The survival pathways of phosphatidylinositol-3 kinase (PI3-K)/phosphoinositidedependent protein kinase 1 (PDK1)/Akt modulate liver regeneration through hepatocyte size rather than proliferation. Hepatology 2009;49(1):204–14. [11] Gielchinsky Y, Laufer N, Weitman E, Abramovitch R, Granot Z, Bergman Y, et al. Pregnancy restores the regenerative capacity of the aged liver via activation of an mTORC1-controlled hyperplasia/hypertrophy switch. Genes Dev 2010;24(6):543–8.
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
A novel therapy of inducing hepatocyte hypertrophy by activating Akt/mTORC1 pathway in acute liver failure Tao Wei a, Ling Yu b, Yi Lv a,⇑ a b
Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an 710061, China Department of Neonatology, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an 710061, China
a r t i c l e
i n f o
Article history: Received 20 March 2011 Accepted 19 September 2011
a b s t r a c t As a severe clinical syndrome, acute liver failure (ALF) is associated with high morbidity and mortality and liver transplantation is the best treatment of choice in most critically-ill cases, which yet suffers from obvious drawbacks including lack of resources and unnecessary surgery for those who can recover spontaneously. In ALF, massive cell deaths occur whereas liver regeneration via hepatocyte proliferation is largely inhibited. The serine/threonine kinase Akt serves as a central role in regulating signaling of growth factors, cytokines and other cellular stimuli within cell and thus correlates with diverse cellular functions, including the pro-survival pathway by inducing hypertrophy. Physiologically, cellular hypertrophy is an adaption in response to increased functional demand or other stresses. It has been demonstrated recently that Akt/mTORC1-controlled switch of hyperplasia to hypertrophy in pregnancy restored the regenerative capacity of aged liver and pharmacological activation of this pathway is sufficient to induce cell growth in the liver of nonpregnant aged mice. We hypothesized, therefore, that pharmacological therapy targeting to induce hepatocyte hypertrophy by activating the Akt/mTORC1 pathway might be a novel and promising option in the early management of patients with ALF as an alternative way to impaired process of cell proliferation. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction Acute liver failure (ALF) is a clinical syndrome characterized by severe liver damage that is often accompanied with rapidly progressive multiple organ dysfunction and devastating complications such as hepatic encephalopathy and coagulopathy, and emergency liver transplantation is warranted in most critically-ill cases, which improve the survival of these patients substantially [1]. However, the liver transplantation is not always available immediately for every patient due to the lack of resources which is also associated with high early post-transplant mortality in the state of emergency. Even though the transplantation is successfully performed, recipients have to receive lifelong immunosuppressive therapy. Additionally, some patients can survive by spontaneous recovery without the need of transplantation but no well-defined approaches exist for the prediction of recovery. Providing the severity and high mortality of ALF, development of effective therapies other
⇑ Corresponding author. Address: Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, No. 277, West Yanta Road, Xi’an 710061, Shaanxi Province, China. Tel.: +86 29 85323204; fax: +86 29 85252580. E-mail address: [email protected] (Y. Lv). 0306-9877/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2011.09.040
than liver transplantation are of great value and always in urgent need.
Impaired process of hepatocyte proliferation in acute liver failure The mechanisms of ALF have been well established being defined as extensive hepatocyte death and inadequate capacity of liver regeneration. Normally, the mature hepatocyte possesses the ability to undergo mitotic division in response to partial hepatectomy or other types of liver injury [2]. In ALF, however, the proliferation of differentiated hepatocytes is inhibited after over 50% loss and the regenerative pattern involves the alternative way of replication and differentiation of hepatic progenitor cells [3]. It appeared, unfortunately, that patients who died or were transplanted after ALF had more hepatic progenitor cells activation and less mature hepatocyte proliferative activity comparing with those who survived, indicating that progenitor cells might inadequately perform the functions of mature cells [4]. Moreover, although circulating bone marrow-derived hematopoietic stem cells are recognized as a source to replenish the damaged hepatocytes, the process is far from efficient in this clinical scenario unless stem cell mobilization agents are used like granulocyte colony-stimulating factor [5].
T. Wei et al. / Medical Hypotheses 78 (2012) 58–59
Akt/mTORC1-mediated cellular hypertrophy reconstitute liver mass Hypertrophy is an adaptive response to changes in functional demand or specific extracellular stresses like hormonal stimulation featured by an increase in the size of individual cell in contrast to the increase of cell number in hyperplasia. Growth of cells enable them to synthesis more pertinent proteins and eventually achieve a balance between requirement and functional organ capacity. Most commonly, cellular hypertrophy is developed in myocytes of skeletal muscle and heart to various stimuli. In liver, similarly, hepatocyte hypertrophy is able to restore liver mass as an alternative mechanism when proliferation of quiescent hepatocyte and progenitor cell is blocked [6]. During pregnancy, hepatocytes also undergo adaptive process of hypertrophy which results in the hepatomegaly to accommodate the increased metabolic burden [7,8]. The serine/threonine kinase Akt directly controlled by upstream phosphatidylinositol 3-kinase (PI3K) and phosphoinositide-dependent protein kinase 1 (PDK1) serves as a central role in regulating signaling of growth factors, cytokines and other cellular stimuli within cell and thus is associated with diverse cellular functions, including the pro-survival pathway by inducing cellular hypertrophy [9]. It has been confirmed in liver that PI3K/PDK1/Akt-triggered cell growth have the ability to compensate for decreased hepatic volume and impaired function [10]. The mammalian target of rapamycin (mTOR) is the principal downstream target of Akt, which resides in two distinct forms, i.e. the rapamycin-sensitive mTOR complex 1 (mTORC1) and the rapamycin-insensitive mTOR complex 2 (mTORC2), and the activation of mTORC1 predominately contribute to the increase of cell mass [9]. It was recently demonstrated that the Akt/mTORC1-based switch of hepatocyte hyperplasia to hypertrophy during pregnancy restored the regenerative capacity of aged liver, of which normally the ability to regenerate after partial hepatectomy is gradually lost. Additionally, pharmacological activation of this pathway is sufficient to induce the hypertrophy of liver in nonpregnant aged mice [11]. On the other hand, pathological outcomes of hypertrophy may develop if a limit is reached or beyond, for example, hypertrophic heart caused by long-term hypertension eventually lead to heart failure. Gielchinsky et al. also proposed that hypertrophy is preferred over hyperplasia in transient situations like in pregnancy [11]. Therefore, cell growth is more like an expedient within a short period to compensate for increased functional demand. The hypothesis While extensive loss of normal cells develops in ALF, a small proportion of mature hepatocytes remains unaffected or mildly affected which yet have decreased potential activity of proliferation. We hypothesized that pharmacological therapy targeting to induce hypertrophy of remaining hepatocytes after ALF by activating the Akt/mTORC1 pathway might be a novel and promising treatment
59
option as an alternative way to impaired process of cell proliferation. Considering that hypertrophy compensates for a time-limited functional demand, this strategy is appropriate for temporary support of patients in the early management. Once the severely impaired liver recovers from the acute insult, withdrawn of pharmacological activator may allows the more efficient process of regeneration based on increase of cell number to undergo. Therefore, this therapy can be used as means either to ‘buy time’ for transplantation in the situations where the graft is not available immediately and avoid emergency surgery which commits patients with significant mortality or even assist in spontaneous recovery of patients who do not have fatal liver failure. Testing this hypothesis Animal experiments are the appropriate way to address this hypothesis and a variety of animal model of ALF which can be easily established have been widely adopted including intraperitoneal injection of D-galactosamine and carbon tetrachloride. Activation of Akt requires the generation of phosphatidylinositol-3,4,5-trisphosphate (PIP3) from phosphatidylinositol-4,5-bisphosphate (PIP2), which can be reversed by PIP3 phosphatase PTEN. Therefore, PTEN inhibitor is able to activate Akt/mTORC1 pathway and thus can be used as a pharmacological activator to test our hypothesis. Conflict of interest statement None declared. References [1] Bernal W, Auzinger G, Dhawan A, Wendon J. Acute liver failure. Lancet 2010;376(9736):190–201. [2] Michalopoulos GK. Liver regeneration. J Cell Physiol 2007;213(2):286–300. [3] Rutherford A, Chung RT. Acute liver failure: mechanisms of hepatocyte injury and regeneration. Semin Liver Dis 2008;28(2):167–74. [4] Katoonizadeh A, Nevens F, Verslype C, Pirenne J, Roskams T. Liver regeneration in acute severe liver impairment: a clinicopathological correlation study. Liver Int 2006;26(10):1225–33. [5] Mark AL, Sun Z, Warren DS, Lonze BE, Knabel MK, Melville Williams GM. Stem cell mobilization is life saving in an animal model of acute liver failure. Ann Surg 2010;252(4):591–6. [6] Nagy P, Teramoto T, Factor VM, Sanchez A, Schnur J, Paku S, et al. Reconstitution of liver mass via cellular hypertrophy in the rat. Hepatology 2001;33(2):339–45. [7] Hollister A, Okubara P, Watson JG, Chaykin S. Reproduction in mice: liver enlargement in mice during pregnancy and lactation. Life Sci 1987;40(1):11–8. [8] Milona A, Owen BM, van Mil S, Dormann D, Mataki C, Boudjelal M, et al. Am J Physiol Gastrointest Liver Physiol 2010;298(2):G151–8. [9] Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007;129(7):1261–74. [10] Haga S, Ozaki M, Inoue H, Okamoto Y, Ogawa W, Takeda K, et al. The survival pathways of phosphatidylinositol-3 kinase (PI3-K)/phosphoinositidedependent protein kinase 1 (PDK1)/Akt modulate liver regeneration through hepatocyte size rather than proliferation. Hepatology 2009;49(1):204–14. [11] Gielchinsky Y, Laufer N, Weitman E, Abramovitch R, Granot Z, Bergman Y, et al. Pregnancy restores the regenerative capacity of the aged liver via activation of an mTORC1-controlled hyperplasia/hypertrophy switch. Genes Dev 2010;24(6):543–8.