Triiodothyronine stimulates hepatocyte proliferation in two models of impaired liver regeneration

Columbano, Amedeo; Simbula, Michela; Pibiri, Monica; Perra, Andrea; Deidda, Manuela; Locker, Joseph; Pisanu, Adolfo; Uccheddu, A; Ledda-Columbano, Giovanna M.

doi:10.1111/j.1365-2184.2008.00532.x

Cited by 36 publications

(24 citation statements)

References 24 publications

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“…The effect of T3 on liver regeneration has been examined in rats previously, and those results did show a regenerative advantage after partial hepatectomy, and a survival advantage in a 90% hepatectomy model, which is normally associated with high mortality 30 . Our results show significantly increased BrdU incorporation in hepatocytes 24 h after partial hepatectomy in mice that received T3- or GC-1-supplemented diet for 8 days prior to the surgery.…”

Section: Discussionmentioning

confidence: 99%

Thyroid Hormone Receptor β Agonist Induces β-Catenin-Dependent Hepatocyte Proliferation in Mice: Implications in Hepatic Regeneration

Alvarado

Puliga²,

Preziosi³

et al. 2016

gene expr

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Triiodothyronine (T3) induces hepatocyte proliferation in rodents. Recent work has shown molecular mechanism for T3’s mitogenic effect to be through activation of β-catenin signaling. Since systemic side effects of T3 may preclude its clinical use, and hepatocytes mostly express T3 hormone receptor β (TRβ), we investigated if selective TRβ agonists like GC-1 may also have β-catenin-dependent hepatocyte mitogenic effects. Here we studied the effect of GC-1 and T3 in conditional knockouts of various Wnt pathway components. We also assessed any regenerative advantage of T3 or GC-1 when given prior to partial hepatectomy in mice. Mice administered GC-1 showed increased pSer675-β-catenin, cyclin D1, BrdU incorporation, and PCNA. No abnormalities in liver function tests were noted. GC-1-injected liver-specific β-catenin knockouts (β-catenin LKO) showed decreased proliferation when compared to wild-type littermates. To address if Wnt signaling was required for T3- or GC-1-mediated hepatocyte proliferation, we used LRP5-6-LKO, which lacks the two redundant Wnt coreceptors. Surprisingly, decreased hepatocyte proliferation was also evident in LRP5-6-LKO in response to T3 and GC-1, despite increased pSer675-β-catenin. Further, increased levels of active β-catenin (hypophosphorylated at Ser33, Ser37, and Thr41) were evident after T3 and GC-1 treatment. Finally, mice pretreated with T3 or GC-1 for 7 days followed by partial hepatectomy showed a significant increase in hepatocyte proliferation both at the time (T0) and 24 h after surgery. In conclusion, like T3, TRβ-selective agonists induce hepatocyte proliferation through β-catenin activation via both PKA- and Wnt-dependent mechanisms and confer a regenerative advantage following surgical resection. Hence, these agents may be useful regenerative therapies in liver transplantation or other surgical settings.

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Section: Discussionmentioning

confidence: 99%

Thyroid Hormone Receptor β Agonist Induces β-Catenin-Dependent Hepatocyte Proliferation in Mice: Implications in Hepatic Regeneration

Alvarado

Puliga²,

Preziosi³

et al. 2016

gene expr

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“…Triiodothyronine or T3 has been shown to induce hepatocyte proliferation in rats and mice, although the mechanism remains unclear (76). Since T3 induces cyclin-D1 expression, we investigated if β-catenin may be involved in the process (77).…”

Section: β-Catenin Signaling In Liver Regenerationmentioning

confidence: 99%

Role and Regulation of β-Catenin Signaling During Physiological Liver Growth

Monga

2014

gene expr

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Wnt/β-catenin signaling plays key roles not only during development but also in adult tissue homeostasis. This is also evident in liver biology where many temporal roles of β-catenin have been identified during hepatic development, where, in hepatic progenitors or hepatoblasts, it is a key determinant of proliferation and eventually differentiation to mature hepatocytes, while also playing an important role in bile duct homeostasis. β-Catenin signaling cascade is mostly quiescent in hepatocytes in an adult liver except in the centrizonal region of a hepatic lobule. This small rim of hepatocytes around the central vein show constitutive β-catenin activation that in turn regulates expression of genes whose products play an important role in ammonia and xenobiotic metabolism. Intriguingly, β-catenin can also undergo activation in hepatocytes after acute liver loss secondary to surgical or toxicant insult. Such activation of this progrowth protein is observed as nuclear translocation of β-catenin and formation of its complex with the T-cell factor (TCF) family of transcription factors. Expression of cyclin-D1, a key inducer of transition from the G1 to S phase of cell cycle is regulated by β-catenin-TCF complex. Thus β-catenin activation is absolutely critical in the normal regeneration process of the liver as shown by studies in several models across various species. In the current review, the temporal role and regulation of β-catenin in liver development, metabolic zonation in a basal adult liver, and during the liver regeneration process, will be discussed. In addition, the probability of therapeutically regulating β-catenin activity as a possible future treatment strategy for liver insufficiency will also be discussed.

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“…A variety of strategies have been developed to enhance liver regeneration after liver transplantation including the injection of growth factors like HGF [102] andhormones like T 3 [103,104,105]. However, these strategies have only been applied to rats and whether interspecies differences (rats vs. humans) will prevent the application of these approaches on humans will require further experimentation.…”

Section: Factors Affecting Liver Regeneration After Transplantationmentioning

confidence: 99%

Liver Regeneration after Liver Transplantation

Taki-Eldin

Zhou²,

Xie³

et al. 2012

Eur Surg Res

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Background/Purpose: The liver has a remarkable capacity to regenerate after injury or resection. The aim of this review is to outline the mechanisms and factors affecting liver regeneration after liver transplantation. Methods: Relevant studies were reviewed using Medline, PubMed and Springer databases. Results: A variety of cytokines (such as interleukin-6 and tumor necrosis factor-α), growth factors (like hepatocyte growth factor and transforming growth factor-α) and cells are involved in liver regeneration. Several factors affect liver regeneration after transplantation such as ischemic injury, graft size, immunosuppression, steatosis, donor age and viral hepatitis. Conclusion: Liver regeneration has been studied for many years. However, further research is essential to reveal the complex processes affecting liver regeneration, which may provide novel strategies in the management of liver transplantation recipients and donors.

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Triiodothyronine stimulates hepatocyte proliferation in two models of impaired liver regeneration

Abstract: These findings show in principle that mitogen-induced hyperplasia could be applied to human therapy in patients with reduced regenerative capacity or massive loss of hepatocytes.

Cited by 36 publications

References 24 publications

Thyroid Hormone Receptor β Agonist Induces β-Catenin-Dependent Hepatocyte Proliferation in Mice: Implications in Hepatic Regeneration

Thyroid Hormone Receptor β Agonist Induces β-Catenin-Dependent Hepatocyte Proliferation in Mice: Implications in Hepatic Regeneration

Role and Regulation of β-Catenin Signaling During Physiological Liver Growth

Liver Regeneration after Liver Transplantation

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