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1
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Marino L, Kim A, Ni B, Celi FS. Thyroid hormone action and liver disease, a complex interplay. Hepatology 2025; 81:651-669. [PMID: 37535802 PMCID: PMC11737129 DOI: 10.1097/hep.0000000000000551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 07/05/2023] [Indexed: 08/05/2023]
Abstract
Thyroid hormone action is involved in virtually all physiological processes. It is well known that the liver and thyroid are intimately linked, with thyroid hormone playing important roles in de novo lipogenesis, beta-oxidation (fatty acid oxidation), cholesterol metabolism, and carbohydrate metabolism. Clinical and mechanistic research studies have shown that thyroid hormone can be involved in chronic liver diseases, including alcohol-associated or NAFLD and HCC. Thyroid hormone action and synthetic thyroid hormone analogs can exert beneficial actions in terms of lowering lipids, preventing chronic liver disease and as liver anticancer agents. More recently, preclinical and clinical studies have indicated that some analogs of thyroid hormone could also play a role in the treatment of liver disease. These synthetic molecules, thyromimetics, can modulate lipid metabolism, particularly in NAFLD/NASH. In this review, we first summarize the thyroid hormone signaling axis in the context of liver biology, then we describe the changes in thyroid hormone signaling in liver disease and how liver diseases affect the thyroid hormone homeostasis, and finally we discuss the use of thyroid hormone-analog for the treatment of liver disease.
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Affiliation(s)
- Luigi Marino
- Department of Medicine, UConn Health, University of Connecticut, Farmington, Connecticut, USA
| | - Adam Kim
- Division of Gastroenterology and Hepatology, Department of Medicine, UConn Health, University of Connecticut, Farmington, Connecticut, USA
| | - Bin Ni
- Alliance Pharma, Philadelphia, Pennsylvania, USA
| | - Francesco S. Celi
- Department of Medicine, UConn Health, University of Connecticut, Farmington, Connecticut, USA
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2
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Qian Y, Shang Z, Gao Y, Wu H, Kong X. Liver Regeneration in Chronic Liver Injuries: Basic and Clinical Applications Focusing on Macrophages and Natural Killer Cells. Cell Mol Gastroenterol Hepatol 2022; 14:971-981. [PMID: 35738473 PMCID: PMC9489753 DOI: 10.1016/j.jcmgh.2022.05.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 04/28/2022] [Accepted: 07/27/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND & AIMS Liver regeneration is a necessary but complex process involving multiple cell types besides hepatocytes. Mechanisms underlying liver regeneration after partial hepatectomy and acute liver injury have been well-described. However, in patients with chronic and severe liver injury, the remnant liver cannot completely restore the liver mass and function, thereby involving liver progenitor-like cells (LPLCs) and various immune cells. RESULTS Macrophages are beneficial to LPLCs proliferation and the differentiation of LPLCs to hepatocytes. Also, cells expressing natural killer (NK) cell markers have been studied in promoting both liver injury and liver regeneration. NK cells can promote LPLC-induced liver regeneration, but the excessive activation of hepatic NK cells may lead to high serum levels of interferon-γ, thus inhibiting liver regeneration. CONCLUSIONS This review summarizes the recent research on 2 important innate immune cells, macrophages and NK cells, in LPLC-induced liver regeneration and the mechanisms of liver regeneration during chronic liver injury, as well as the latest macrophage- and NK cell-based therapies for chronic liver injury. These novel findings can further help identify new treatments for chronic liver injury, saving patients from the pain of liver transplantations.
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Affiliation(s)
- Yihan Qian
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhi Shang
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yueqiu Gao
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hailong Wu
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China.
| | - Xiaoni Kong
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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3
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Tang Q, Zeng M, Chen L, Fu N. Targeting Thyroid Hormone/Thyroid Hormone Receptor Axis: An Attractive Therapy Strategy in Liver Diseases. Front Pharmacol 2022; 13:871100. [PMID: 35721201 PMCID: PMC9201453 DOI: 10.3389/fphar.2022.871100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 04/19/2022] [Indexed: 12/24/2022] Open
Abstract
Thyroid hormone/thyroid hormone receptor (TH/TR) axis is characterized by TH with the assistance of plasma membrane transporters to combine with TR and mediate biological activities. Growing evidence suggests that TH/TR participates in plenty of hepatic metabolism. Thus, this review focuses on the role of the TH/TR axis in the liver diseases. To be specific, the TH/TR axis may improve metabolic-associated fatty liver disease, hepatitis, liver fibrosis, and liver injury while exacerbating the progression of acute liver failure and alcoholic liver disease. Also, the TH/TR axis has paradoxical roles in hepatocellular carcinoma. The TH/TR axis may be a prospecting target to cure hepatic diseases.
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Affiliation(s)
- Qianyu Tang
- Department of Gastroenterology, The Affiliated Nanhua Hospital, Hunan Provincial Clinical Research Center of Metabolic Associated Fatty Liver Disease, Hengyang Medical School, University of South China, Hengyang, China
| | - Min Zeng
- Department of Gastroenterology, Liuyang Hospital of Chinese Medicine, Changsha, China
| | - Linxi Chen
- Department of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Basic Medical Science, Hengyang Medical School, University of South China, Hengyang, China
| | - Nian Fu
- Department of Gastroenterology, The Affiliated Nanhua Hospital, Hunan Provincial Clinical Research Center of Metabolic Associated Fatty Liver Disease, Hengyang Medical School, University of South China, Hengyang, China
- The Affiliated Nanhua Hospital, Laboratory of Liver Disease, Institute of Clinical Research, Hengyang Medical School, University of South China, Hengyang, China
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4
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Hadjittofi C, Feretis M, Martin J, Harper S, Huguet E. Liver regeneration biology: Implications for liver tumour therapies. World J Clin Oncol 2021; 12:1101-1156. [PMID: 35070734 PMCID: PMC8716989 DOI: 10.5306/wjco.v12.i12.1101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
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Affiliation(s)
- Christopher Hadjittofi
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Michael Feretis
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jack Martin
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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5
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Effects of Thyroid Hormone on Tissue Hypoxia: Relevance to Sepsis Therapy. J Clin Med 2021; 10:jcm10245855. [PMID: 34945151 PMCID: PMC8703810 DOI: 10.3390/jcm10245855] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 11/29/2021] [Accepted: 12/10/2021] [Indexed: 01/14/2023] Open
Abstract
Tissue hypoxia occurs in various conditions such as myocardial or brain ischemia and infarction, sepsis, and trauma, and induces cellular damage and tissue remodeling with recapitulation of fetal-like reprogramming, which eventually results in organ failure. Analogies seem to exist between the damaged hypoxic and developing organs, indicating that a regulatory network which drives embryonic organ development may control aspects of heart (or tissue) repair. In this context, thyroid hormone (TH), which is a critical regulator of organ maturation, physiologic angiogenesis, and mitochondrial biogenesis during fetal development, may be of important physiological relevance upon stress (hypoxia)-induced fetal reprogramming. TH signaling has been implicated in hypoxic tissue remodeling after myocardial infarction and T3 prevents remodeling of the postinfarcted heart. Similarly, preliminary experimental evidence suggests that T3 can prevent early tissue hypoxia during sepsis with important physiological consequences. Thus, based on common pathways between different paradigms, we propose a possible role of TH in tissue hypoxia after sepsis with the potential to reduce secondary organ failure.
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Abu Rmilah AA, Zhou W, Nyberg SL. Hormonal Contribution to Liver Regeneration. Mayo Clin Proc Innov Qual Outcomes 2020; 4:315-338. [PMID: 32542223 PMCID: PMC7283948 DOI: 10.1016/j.mayocpiqo.2020.02.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 02/01/2020] [Accepted: 02/07/2020] [Indexed: 02/07/2023] Open
Abstract
An understanding of the molecular basis of liver regeneration will open new horizons for the development of novel therapies for chronic liver failure. Such therapies would solve the drawbacks associated with liver transplant, including the shortage of donor organs, long waitlist time, high medical costs, and lifelong use of immunosuppressive agents. Regeneration after partial hepatectomy has been studied in animal models, particularly fumarylacetoacetate hydrolase-deficient (FAH -/-) mice and pigs. The process of regeneration is distinctive, complex, and well coordinated, and it depends on the interplay among several signaling pathways (eg, nuclear factor κβ, Notch, Hippo), cytokines (eg, tumor necrosis factor α, interleukin 6), and growth factors (eg, hepatocyte growth factor, epidermal growth factor, vascular endothelial growth factor), and other components. Furthermore, endocrinal hormones (eg, norepinephrine, growth hormone, insulin, thyroid hormones) also can influence the aforementioned pathways and factors. We believe that these endocrinal hormones are important hepatic mitogens that strongly induce and accelerate hepatocyte proliferation (regeneration) by directly and indirectly triggering the activity of the involved signaling pathways, cytokines, growth factors, and transcription factors. The subsequent induction of cyclins and associated cyclin-dependent kinase complexes allow hepatocytes to enter the cell cycle. In this review article, we comprehensively summarize the current knowledge regarding the roles and mechanisms of these hormones in liver regeneration. Articles used for this review were identified by searching MEDLINE and EMBASE databases from inception through June 1, 2019.
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Key Words
- CDK, cyclin-dependent kinase
- EGF, epidermal growth factor
- EGFR, EGF receptor
- ERK, extracellular signal-regulated kinase
- FAH, fumarylacetoacetate hydrolase
- GH, growth hormone
- Ghr-/-, growth hormone receptor gene knockout
- HGF, hepatocyte growth factor
- HNF, hepatocyte nuclear factor
- HPC, hepatic progenitor cell
- IGF, insulinlike growth factor
- IL, interleukin
- IR, insulin receptor
- InsP3, inositol 1,4,5-trisphosphate
- JNK, JUN N-terminal kinase
- LDLT, living donor liver transplant
- LRP, low-density lipoprotein-related protein
- MAPK, mitogen-activated protein kinase
- NF-κβ, nuclear factor κβ
- NOS, nitric oxide synthase
- NTBC, 2-nitro-4-trifluoro-methyl-benzoyl-1,3-cyclohexanedione
- PCNA, proliferating cell nuclear antigen
- PCR, polymerase chain reaction
- PH, partial hepatectomy
- PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase
- PKB, protein kinase B
- PTU, 6-n-propyl-2-thiouracil
- ROS, reactive oxygen species
- STAT, signal transducer and activator of transcription
- T3, triiodothyronine
- TGF, transforming growth factor
- TNF, tumor necrosis factor
- TR, thyroid receptor
- hESC, human embryonic stem cell
- hiPSC, human induced pluripotent stem cells
- mRNA, messenger RNA
- mTOR, mammalian target of rapamycin
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Affiliation(s)
| | - Wei Zhou
- Division of Transplantation Surgery, Mayo Clinic, Rochester, MN.,First Affiliated Hospital of China, Medical University, Department of Hepatobiliary Surgery, Shenyang, China
| | - Scott L Nyberg
- Division of Transplantation Surgery, Mayo Clinic, Rochester, MN
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7
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Perra A, Kowalik MA, Cabras L, Runfola M, Sestito S, Migliore C, Giordano S, Chiellini G, Rapposelli S, Columbano A. Potential role of two novel agonists of thyroid hormone receptor-β on liver regeneration. Cell Prolif 2020; 53:e12808. [PMID: 32347601 PMCID: PMC7260063 DOI: 10.1111/cpr.12808] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 03/11/2020] [Accepted: 03/23/2020] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVES Although the hepatomitogenic activity of triiodothyronine (T3) is well established, the wide range of harmful effects exerted by this hormone precludes its use in liver regenerative therapy. Selective agonists of the beta isoform of thyroid hormone receptor (TRβ) do not exhibit T3-induced cardiotoxicity and show a good safety profile in patients with NASH. The aim of this study was to investigate whether two novel TRβ agonists, the prodrug TG68 and the active compound IS25 could stimulate hepatocyte proliferation without T3/TRα-dependent side effects. METHODS Rats were treated with three different doses (12.5, 25 and 50 μg/100 g body weight) for one week. Hepatocyte proliferation, liver injury and serum biochemical parameters were measured by immunohistochemistry, qRT-PCR and Western blot. RESULTS Both drugs increased hepatocyte proliferation as assessed by bromodeoxyuridine incorporation (from 14% to 28% vs 5% of controls) and mitotic activity. Enhanced proliferation occurred in the absence of significant signs of liver injury as shown by lack of increased serum transaminase levels or of apoptosis. No cardiac or renal hypertrophy typically associated with treatment with T3 was observed. Importantly, no proliferation of pancreatic acinar cells, such as that seen after administration of T3 or the TRβ agonist GC1 was detected following either TG68 or IS25, demonstrating the hepato-specificity of these novel TRβ agonists. CONCLUSIONS The present study shows that TG68 and IS25 induce massive hepatocyte proliferation without overt toxicity. Hence, these agents may have a significant clinical application for regenerative therapies in liver transplantation or other surgical settings.
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Affiliation(s)
- Andrea Perra
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Marta Anna Kowalik
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Lavinia Cabras
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | | | - Simona Sestito
- Department of Pathology, University of Pisa, Pisa, Italy
| | - Cristina Migliore
- Department of Oncology, University of Turin, Turin, Italy.,Institute-FPO, IRCCS, Italy
| | - Silvia Giordano
- Department of Oncology, University of Turin, Turin, Italy.,Institute-FPO, IRCCS, Italy
| | | | | | - Amedeo Columbano
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
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8
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Malagola E, Chen R, Bombardo M, Saponara E, Dentice M, Salvatore D, Reding T, Myers S, Hills AP, Graf R, Sonda S. Local hyperthyroidism promotes pancreatic acinar cell proliferation during acute pancreatitis. J Pathol 2019; 248:217-229. [PMID: 30714146 DOI: 10.1002/path.5247] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 12/17/2018] [Accepted: 01/08/2019] [Indexed: 01/01/2023]
Abstract
Proliferation of pancreatic acinar cells is a critical process in the pathophysiology of pancreatic diseases, because limited or defective proliferation is associated with organ dysfunction and patient morbidity. In this context, elucidating the signalling pathways that trigger and sustain acinar proliferation is pivotal to develop therapeutic interventions promoting the regenerative process of the organ. In this study we used genetic and pharmacological approaches to manipulate both local and systemic levels of thyroid hormones to elucidate their role in acinar proliferation following caerulein-mediated acute pancreatitis in mice. In addition, molecular mechanisms mediating the effects of thyroid hormones were identified by genetic and pharmacological inactivation of selected signalling pathways.In this study we demonstrated that levels of the thyroid hormone 3,3',5-triiodo-l-thyronine (T3) transiently increased in the pancreas during acute pancreatitis. Moreover, by using genetic and pharmacological approaches to manipulate both local and systemic levels of thyroid hormones, we showed that T3 was required to promote proliferation of pancreatic acinar cells, without affecting the extent of tissue damage or inflammatory infiltration.Finally, upon genetic and pharmacological inactivation of selected signalling pathways, we demonstrated that T3 exerted its mitogenic effect on acinar cells via a tightly controlled action on different molecular effectors, including histone deacetylase, AKT, and TGFβ signalling.In conclusion, our data suggest that local availability of T3 in the pancreas is required to promote acinar cell proliferation and provide the rationale to exploit thyroid hormone signalling to enhance pancreatic regeneration. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Ermanno Malagola
- Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland
| | - Rong Chen
- Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland
| | - Marta Bombardo
- Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland
| | - Enrica Saponara
- Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland
| | - Monica Dentice
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Domenico Salvatore
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Theresia Reding
- Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland
| | - Stephen Myers
- School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Australia
| | - Andrew P Hills
- School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Australia
| | - Rolf Graf
- Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland.,Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
| | - Sabrina Sonda
- Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland.,School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Australia.,Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
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9
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Kowalik MA, Columbano A, Perra A. Thyroid Hormones, Thyromimetics and Their Metabolites in the Treatment of Liver Disease. Front Endocrinol (Lausanne) 2018; 9:382. [PMID: 30042736 PMCID: PMC6048875 DOI: 10.3389/fendo.2018.00382] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 06/22/2018] [Indexed: 12/13/2022] Open
Abstract
The signaling pathways activated by thyroid hormone receptors (THR) are of fundamental importance for organogenesis, growth and differentiation, and significantly influence energy metabolism, lipid utilization and glucose homeostasis. Pharmacological control of these pathways would likely impact the treatment of several human diseases characterized by altered metabolism, growth or differentiation. Not surprisingly, biomedical research has been trying for the past decades to pharmacologically target the 3,5,3'-triiodothyronine (T3)/THR axis. In vitro and in vivo studies have provided evidence of the potential utility of the activation of the T3-dependent pathways in metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), and in the treatment of hepatocellular carcinoma (HCC). Unfortunately, supra-physiological doses of the THR agonist T3 cause severe thyrotoxicosis thus hampering its therapeutic use. However, the observation that most of the desired beneficial effects of T3 are mediated by the activation of the beta isoform of THR (THRβ) in metabolically active organs has led to the synthesis of a number of THRβ-selective thyromimetics. Among these drugs, GC-1, GC-24, KB141, KB2115, and MB07344 displayed a promising therapeutic strategy for liver diseases. However, although these drugs exhibited encouraging results when tested in the treatment of experimentally-induced obesity, dyslipidemia, and HCC, significant adverse effects limited their use in clinical trials. More recently, evidence has been provided that some metabolites of thyroid hormones (TH), mono and diiodothyronines, could also play a role in the treatment of liver disease. These molecules, for a long time considered inactive byproducts of the metabolism of thyroid hormones, have now been proposed to be able to modulate and control lipid and cell energy metabolism. In this review, we will summarize the current knowledge regarding T3, its metabolites and analogs with reference to their possible clinical application in the treatment of liver disease. In particular, we will focus our attention on NAFLD, non-alcoholic steatohepatitis (NASH) and HCC. In addition, the possible therapeutic use of mono- and diiodothyronines in metabolic and/or neoplastic liver disease will be discussed.
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10
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Columbano A, Chiellini G, Kowalik MA. GC-1: A Thyromimetic With Multiple Therapeutic Applications in Liver Disease. Gene Expr 2017; 17:265-275. [PMID: 28635586 PMCID: PMC5885148 DOI: 10.3727/105221617x14968563796227] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Thyroid hormones (THs), namely, 3,5,3'-triiodo-l-thyronine (T3) and 3,5,3',5'-tetraiodo-l-thyronine (thyroxine or T4), influence a variety of physiological processes that have important implications in fetal development, metabolism, cell growth, and proliferation. While THs elicit several beneficial effects on lipid metabolism and improve myocardial contractility, these therapeutically desirable effects are associated to a thyrotoxic state that severely limits the possible use of THs as therapeutic agents. Therefore, several efforts have been made to develop T3 analogs that could retain the beneficial actions (triglyceride, cholesterol, obesity, and body mass lowering) without the adverse TH-dependent side effects. This goal was achieved by the synthesis of TRβ-selective agonists. In this review, we summarize the current knowledge on the effects of one of the best characterized TH analogs, the TRβ1-selective thyromimetic, GC-1. In particular, we review some of the effects of GC-1 on different liver disorders, with reference to its possible clinical application. A brief comment on the possible therapeutic use of GC-1 in extrahepatic disorders is also included.
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Affiliation(s)
- Amedeo Columbano
- *Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Grazia Chiellini
- †Department of Surgical, Medical and Molecular Pathology, University of Pisa, Pisa, Italy
| | - Marta Anna Kowalik
- *Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
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11
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Goemann IM, Romitti M, Meyer ELS, Wajner SM, Maia AL. Role of thyroid hormones in the neoplastic process: an overview. Endocr Relat Cancer 2017; 24:R367-R385. [PMID: 28928142 DOI: 10.1530/erc-17-0192] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 08/24/2017] [Indexed: 12/13/2022]
Abstract
Thyroid hormones (TH) are critical regulators of several physiological processes, which include development, differentiation and growth in virtually all tissues. In past decades, several studies have shown that changes in TH levels caused by thyroid dysfunction, disruption of deiodinases and/or thyroid hormone receptor (TR) expression in tumor cells, influence cell proliferation, differentiation, survival and invasion in a variety of neoplasms in a cell type-specific manner. The function of THs and TRs in neoplastic cell proliferation involves complex mechanisms that seem to be cell specific, exerting effects via genomic and nongenomic pathways, repressing or stimulating transcription factors, influencing angiogenesis and promoting invasiveness. Taken together, these observations indicate an important role of TH status in the pathogenesis and/or development of human neoplasia. Here, we aim to present an updated and comprehensive picture of the accumulated knowledge and the current understanding of the potential role of TH status on the different hallmarks of the neoplastic process.
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Affiliation(s)
- Iuri Martin Goemann
- Thyroid SectionEndocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Mirian Romitti
- Thyroid SectionEndocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Erika L Souza Meyer
- Department of Internal MedicineUniversidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
| | - Simone Magagnin Wajner
- Thyroid SectionEndocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Ana Luiza Maia
- Thyroid SectionEndocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
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12
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Szydlowska M, Pibiri M, Perra A, Puliga E, Mattu S, Ledda-Columbano GM, Columbano A, Leoni VP. The Thyromimetic KB2115 (Eprotirome) Induces Rat Hepatocyte Proliferation. Gene Expr 2017; 17:207-218. [PMID: 28409553 PMCID: PMC5896737 DOI: 10.3727/105221617x695438] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Although the hepatomitogenic activity of T3 is well established, the wide range of harmful effects exerted by this hormone precludes its use in regenerative therapy. The aim of this study was to investigate whether an agonist of TRβ, KB2115 (Eprotirome), could exert a mitogenic effect in the liver, without most of the adverse T3/TRα-dependent side effects. F-344 rats treated with KB2115 for 1 week displayed a massive increase in bromodeoxyuridine incorporation (from 20% to 40% vs. 5% of controls), which was associated with increased mitotic activity in the absence of significant signs of liver toxicity. Noteworthy, while cardiac hypertrophy typical of T3 was not observed, beneficial effects, such as lowering blood cholesterol levels, were associated to KB2115 administration. Following a single dose of KB2115, hepatocyte proliferation was evident as early as 18 h, demonstrating its direct mitogenic effect. No increase in serum transaminase levels or apoptosis was observed prior to or concomitantly with the S phase. While KB2115-induced mitogenesis was not associated to enhance expression of c-fos, c-jun, and c-myc, cyclin D1 levels rapidly increased. In conclusion, KB2115 induces hepatocyte proliferation without overt toxicity. Hence, this agent may be useful for regenerative therapies in liver transplantation or other surgical settings.
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Affiliation(s)
- Marta Szydlowska
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Monica Pibiri
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Andrea Perra
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Elisabetta Puliga
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Sandra Mattu
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Giovanna M. Ledda-Columbano
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Amedeo Columbano
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Vera P. Leoni
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
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Perra A, Plateroti M, Columbano A. T3/TRs axis in hepatocellular carcinoma: new concepts for an old pair. Endocr Relat Cancer 2016; 23:R353-69. [PMID: 27353037 DOI: 10.1530/erc-16-0152] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 06/27/2016] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and its burden is expected to further increase in the next years. Chronic inflammation, induced by multiple viruses or metabolic alterations, and epigenetic and genetic modifications, cooperate in cancer development via a combination of common and distinct aetiology-specific pathways. In spite of the advances of classical therapies, the prognosis of this neoplasm has not considerably improved over the past few years. The advent of targeted therapies and the approval of the systemic treatment of advanced HCC with the kinase inhibitor sorafenib have provided some hope for the future. However, the benefits obtained from this treatment are still disappointing, as it extends the median life expectancy of patients by only few months. It is thus mandatory to find alternative effective treatments. Although the role played by thyroid hormones (THs) and their nuclear receptors (TRs) in human cancer is still unclear, mounting evidence indicates that they behave as oncosuppressors in HCC. However, the molecular mechanisms by which they exert this effect and the consequence of their activation following ligand binding on HCC progression remain elusive. In this review, we re-evaluate the existing evidence of the role of TH/TRs in HCC development; we will also discuss how TR alterations could affect fundamental biological processes, such as hepatocyte proliferation and differentiation, and consequently HCC progression. Finally, we will discuss if and how TRs can be foreseen as therapeutic targets in HCC and whether selective TR modulation by TH analogues may hold promise for HCC treatment.
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Affiliation(s)
- Andrea Perra
- Department of Biomedical SciencesUniversity of Cagliari, Cagliari, Italy
| | - Michelina Plateroti
- Cancer Research Center of Lyon INSERM U1052CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard, Département de la Recherche, Lyon, France
| | - Amedeo Columbano
- Department of Biomedical SciencesUniversity of Cagliari, Cagliari, Italy
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Rebolledo RA, Van Erp AC, Ottens PJ, Wiersema-Buist J, Leuvenink HGD, Romanque P. Anti-Apoptotic Effects of 3,3',5-Triiodo-L-Thyronine in the Liver of Brain-Dead Rats. PLoS One 2015; 10:e0138749. [PMID: 26437380 PMCID: PMC4593580 DOI: 10.1371/journal.pone.0138749] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 09/03/2015] [Indexed: 12/31/2022] Open
Abstract
Background Thyroid hormone treatment in brain-dead organ donors has been extensively studied and applied in the clinical setting. However, its clinical applicability remains controversial due to a varying degree of success and a lack of mechanistic understanding about the therapeutic effects of 3,3’,5-Triiodo-L-thyronine (T3). T3 pre-conditioning leads to anti-apoptotic and pro-mitotic effects in liver tissue following ischemia/reperfusion injury. Therefore, we aimed to study the effects of T3 pre-conditioning in the liver of brain-dead rats. Methods Brain death (BD) was induced in mechanically ventilated rats by inflation of a Fogarty catheter in the epidural space. T3 (0.1 mg/kg) or vehicle was administered intraperitoneally 2 h prior to BD induction. After 4 h of BD, serum and liver tissue were collected. RT-qPCR, routine biochemistry, and immunohistochemistry were performed. Results Brain-dead animals treated with T3 had lower plasma levels of AST and ALT, reduced Bax gene expression, and less hepatic cleaved Caspase-3 activation compared to brain-dead animals treated with vehicle. Interestingly, no differences in the expression of inflammatory genes (IL-6, MCP-1, IL-1β) or the presence of pro-mitotic markers (Cyclin-D and Ki-67) were found in brain-dead animals treated with T3 compared to vehicle-treated animals. Conclusion T3 pre-conditioning leads to beneficial effects in the liver of brain-dead rats as seen by lower cellular injury and reduced apoptosis, and supports the suggested role of T3 hormone therapy in the management of brain-dead donors.
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Affiliation(s)
- Rolando A. Rebolledo
- Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
- Physiopathology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Anne C. Van Erp
- Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
| | - Petra J. Ottens
- Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Henri G. D. Leuvenink
- Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
- * E-mail:
| | - Pamela Romanque
- Physiopathology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
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Best J, Manka P, Syn WK, Dollé L, van Grunsven LA, Canbay A. Role of liver progenitors in liver regeneration. Hepatobiliary Surg Nutr 2015; 4:48-58. [PMID: 25713804 DOI: 10.3978/j.issn.2304-3881.2015.01.16] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 01/20/2015] [Indexed: 12/16/2022]
Abstract
During massive liver injury and hepatocyte loss, the intrinsic regenerative capacity of the liver by replication of resident hepatocytes is overwhelmed. Treatment of this condition depends on the cause of liver injury, though in many cases liver transplantation (LT) remains the only curative option. LT for end stage chronic and acute liver diseases is hampered by shortage of donor organs and requires immunosuppression. Hepatocyte transplantation is limited by yet unresolved technical difficulties. Since currently no treatment is available to facilitate liver regeneration directly, therapies involving the use of resident liver stem or progenitor cells (LPCs) or non-liver stem cells are coming to fore. LPCs are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. Non-liver stem cells include embryonic stem cells (ES cells) and mesenchymal stem cells (MSCs). In the first section, we aim to provide an overview of the role of putative cytokines, growth factors, mitogens and hormones in regulating LPC response and briefly discuss the prognostic value of the LPC response in clinical practice. In the latter section, we will highlight the role of other (non-liver) stem cells in transplantation and discuss advantages and disadvantages of ES cells, induced pluripotent stem cells (iPS), as well as MSCs.
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Affiliation(s)
- Jan Best
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Paul Manka
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Wing-Kin Syn
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Laurent Dollé
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Leo A van Grunsven
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Ali Canbay
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
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16
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Gebhardt R. Speeding up hepatocyte proliferation: how triiodothyronine and β-catenin join forces. Hepatology 2014; 59:2074-6. [PMID: 24919451 DOI: 10.1002/hep.26984] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 12/15/2013] [Indexed: 01/20/2023]
Affiliation(s)
- Rolf Gebhardt
- Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany
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17
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Vasilopoulou E, Loubière LS, Lash GE, Ohizua O, McCabe CJ, Franklyn JA, Kilby MD, Chan SY. Triiodothyronine regulates angiogenic growth factor and cytokine secretion by isolated human decidual cells in a cell-type specific and gestational age-dependent manner. Hum Reprod 2014; 29:1161-72. [PMID: 24626803 PMCID: PMC4017942 DOI: 10.1093/humrep/deu046] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
STUDY QUESTION Does triiodothyronine (T3) regulate the secretion of angiogenic growth factors and cytokines by human decidual cells isolated from early pregnancy? SUMMARY ANSWER T3 modulates the secretion of specific angiogenic growth factors and cytokines, with different regulatory patterns observed amongst various isolated subpopulations of human decidual cells and with a distinct change between the first and second trimesters of pregnancy. WHAT IS KNOWN ALREADY Maternal thyroid dysfunction during early pregnancy is associated with complications of malplacentation including miscarriage and pre-eclampsia. T3 regulates the proliferation and apoptosis of fetal-derived trophoblasts, as well as promotes the invasive capability of extravillous trophoblasts (EVT). We hypothesize that T3 may also have a direct impact on human maternal-derived decidual cells, which are known to exert paracrine regulation upon trophoblast behaviour and vascular development at the uteroplacental interface. STUDY DESIGN, SIZE, DURATION This laboratory-based study used human decidua from first (8–11 weeks; n = 18) and second (12–16 weeks; n = 12) trimester surgical terminations of apparently uncomplicated pregnancies. PARTICIPANTS/MATERIALS, SETTING, METHODS Primary cultures of total decidual cells, and immunomagnetic bead-isolated populations of stromal-enriched (CD10+) and stromal-depleted (CD10−) cells, uterine natural killer cells (uNK cells; CD56+) and macrophages (CD14+) were assessed for thyroid hormone receptors and transporters by immunocytochemistry. Each cell population was treated with T3 (0, 1, 10, 100 nM) and assessments were made of cell viability (MTT assay) and angiogenic growth factor and cytokine secretion (immunomediated assay). The effect of decidual cell-conditioned media on EVT invasion through Matrigel® was evaluated. MAIN RESULTS AND THE ROLE OF CHANCE Immunocytochemistry showed the expression of thyroid hormone transporters (MCT8, MCT10) and receptors (TRα1, TRβ1) required for thyroid hormone-responsiveness in uNK cells and macrophages from the first trimester. The viability of total decidual cells and the different cell isolates were unaffected by T3 so changes in cell numbers could not account for any observed effects. In the first trimester, T3 decreased VEGF-A secretion by total decidual cells (P < 0.05) and increased angiopoietin-2 secretion by stromal-depleted cells (P < 0.05) but in the second trimester total decidual cells showed only increased angiogenin secretion (P < 0.05). In the first trimester, T3 reduced IL-10 secretion by total decidual cells (P < 0.05), and reduced granulocyte macrophage colony stimulating factor (P < 0.01), IL-8 (P < 0.05), IL-10 (P < 0.01), IL-1β (P < 0.05) and monocyte chemotactic protein -1 (P < 0.001) secretion by macrophages, but increased tumour necrosis factor-α secretion by stromal-depleted cells (P < 0.05) and increased IL-6 by uNK cells (P < 0.05). In contrast, in the second trimester T3 increased IL-10 secretion by total decidual cells (P < 0.01) but did not affect cytokine secretion by uNK cells and macrophages. Conditioned media from first trimester T3-treated total decidual cells and macrophages did not alter EVT invasion compared with untreated controls. Thus, treatment of decidual cells with T3 resulted in changes in both angiogenic growth factor and cytokine secretion in a cell type-specific and gestational age-dependent manner, with first trimester decidual macrophages being the most responsive to T3 treatment, but these changes in decidual cell secretome did not affect EVT invasion in vitro. LIMITATIONS, REASONS FOR CAUTION Our results are based on in vitro findings and we cannot be certain if a similar response occurs in human pregnancy in vivo. WIDER IMPLICATIONS OF THE FINDINGS Optimal maternal thyroid hormone concentrations could play a critical role in maintaining a balanced inflammatory response in early pregnancy to prevent fetal immune rejection and promote normal placental development through the regulation of the secretion of critical cytokines and angiogenic growth factors by human decidual cells. Our data suggest that there is an ontogenically determined regulatory ‘switch’ in T3 responsiveness between the first and second trimesters, and support the notion that the timely and early correction of maternal thyroid dysfunction is critical in influencing pregnancy outcomes. STUDY FUNDING/COMPETING INTEREST(S) This study is funded by Wellbeing of Women (RG/1082/09 to S.Y.C., M.D.K., J.A.F., L.S.L., G.E.L.) and Action Medical Research – Henry Smith Charity (SP4335 to M.D.K., S.Y.C., L.S.L., J.A.F.). The authors have no conflicts of interest to disclose.
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Affiliation(s)
- E Vasilopoulou
- School of Clinical and Experimental Medicine and the Centre for Women's and Children Health, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
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Best J, Dollé L, Manka P, Coombes J, van Grunsven LA, Syn WK. Role of liver progenitors in acute liver injury. Front Physiol 2013; 4:258. [PMID: 24133449 PMCID: PMC3783932 DOI: 10.3389/fphys.2013.00258] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Accepted: 09/03/2013] [Indexed: 12/13/2022] Open
Abstract
Acute liver failure (ALF) results from the acute and rapid loss of hepatocyte function and frequently exhibits a fulminant course, characterized by high mortality in the absence of immediate state-of-the-art intensive care and/or emergency liver transplantation (ELT). The role of hepatocyte-mediated liver regeneration during acute and chronic liver injury has been extensively investigated, and recent studies suggest that hepatocytes are not exclusively responsible for the regeneration of the injured liver during fulminant liver injury. Liver progenitor cells (LPC) (or resident liver stem cells) are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. This review aims to provide an overview of the role of the LPC population during ALF, and the role of putative cytokines, growth factors, mitogens, and hormones in the LPC response. We will highlight the potential interaction among cellular compartments during ALF, and discuss the possible prognostic value of the LPC response on ALF outcomes.
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Affiliation(s)
- Jan Best
- Department of Gastroenterology and Hepatology, University Hospital Essen Essen, Germany ; Liver Cell Biology Lab (LIVR), Department of Cell Biology (CYTO), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel Brussels, Belgium
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19
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The role of thyroid hormone signaling in the prevention of digestive system cancers. Int J Mol Sci 2013; 14:16240-57. [PMID: 23924944 PMCID: PMC3759909 DOI: 10.3390/ijms140816240] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Revised: 07/25/2013] [Accepted: 07/30/2013] [Indexed: 11/17/2022] Open
Abstract
Thyroid hormones play a critical role in the growth and development of the alimentary tract in vertebrates. Their effects are mediated by nuclear receptors as well as the cell surface receptor integrin αVβ3. Systemic thyroid hormone levels are controlled via activation and deactivation by iodothyronine deiodinases in the liver and other tissues. Given that thyroid hormone signaling has been characterized as a major effector of digestive system growth and homeostasis, numerous investigations have examined its role in the occurrence and progression of cancers in various tissues of this organ system. The present review summarizes current findings regarding the effects of thyroid hormone signaling on cancers of the esophagus, stomach, liver, pancreas, and colon. Particular attention is given to the roles of different thyroid hormone receptor isoforms, the novel integrin αVβ3 receptor, and thyroid hormone-related nutrients as possible protective agents and therapeutic targets. Future investigations geared towards a better understanding of thyroid hormone signaling in digestive system cancers may provide preventive or therapeutic strategies to diminish risk, improve outcome and avert recurrence in afflicted individuals.
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20
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Triiodothyronine attenuates hepatic ischemia/reperfusion injury in a partial hepatectomy model through inhibition of proinflammatory cytokines, transcription factors, and adhesion molecules. J Surg Res 2012; 178:646-56. [DOI: 10.1016/j.jss.2012.05.069] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2012] [Revised: 04/25/2012] [Accepted: 05/23/2012] [Indexed: 02/04/2023]
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Karaman K, Bostanci EB, Dincer N, Ulas M, Ozer I, Dalgic T, Ercin U, Bilgihan A, Ginis Z, Akoglu M. Effects of thyroid hormone supplementation on anastomotic healing after segmental colonic resection. J Surg Res 2011; 176:460-7. [PMID: 22316672 DOI: 10.1016/j.jss.2011.11.1015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2011] [Revised: 10/23/2011] [Accepted: 11/18/2011] [Indexed: 12/12/2022]
Abstract
BACKGROUND Alterations of thyroid hormones in colorectal surgery were previously studied. The aim of the present study was to determine the effects of triiodothyronine (T3) supplementation on anastomotic healing after segmental colectomy. MATERIAL AND METHODS Thirty male Wistar albino rats were divided into sham (n = 6), control (n = 12), and experimental (n = 12) groups. Sham group rats were immediately sacrificed after segmental colonic resection. Control and experimental group rats underwent resection and anastomosis. Experimental group rats received a single dose of T3 (400 μg/100 g) in postoperative day 1. Half of both control and experimental group rats were sacrificed on postoperative d 3 and the remaining half were sacrificed on postoperative d 7. Hydroxiproline (HP), myeloperoxidase (MPO), thyroid stimulating hormone (TSH), free T3 (FT3), and free thyroxine (FT4) levels, bursting pressure, and histologic analyses of the anastomotic segments were compared. RESULTS FT3 levels significantly decreased in control groups rats compared with the sham group (P < 0.01). However, T3 hormone given rats had no decline in FT3 levels. Anastomotic bursting pressure was significantly higher in the experimental group rats on postoperative d 7 (P = 0.015). Histopathologic analyses of the anastomotic segments determined significantly more severe edema and necrosis in control group rats (P < 0.05). Collagen deposition in the anastomotic tissue was significantly higher in experimental group rats on postoperative d 7 (P = 0.015). CONCLUSION Anastomosis after colon resection is associated with decreased FT3 level. T3 supplementation ameliorates the reduction in FT3 and seems to provide constructive therapeutic effects on anastomotic healing.
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Affiliation(s)
- Kerem Karaman
- Department of Gastroenterological Surgery, Turkiye Yuksek Ihtisas Teaching and Research Hospital, Ankara, Turkey.
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22
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Taki-Eldin A, Zhou L, Xie HY, Chen KJ, Zhou WH, Zhang W, Xing CY, Yang Z, Zhang K, Zheng SS. Tri-iodothyronine enhances liver regeneration after living donor liver transplantation in rats. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2011; 18:806-14. [PMID: 21584707 DOI: 10.1007/s00534-011-0397-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Ahmed Taki-Eldin
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Lin Zhou
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Hai-Yang Xie
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Kang-jie Chen
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Wu-hua Zhou
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Wu Zhang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Chun-Yang Xing
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Zhe Yang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Kai Zhang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Shu-Sen Zheng
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
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Davis PJ, Davis FB, Mousa SA. Thyroid hormone-induced angiogenesis. Curr Cardiol Rev 2009; 5:12-6. [PMID: 20066142 PMCID: PMC2803282 DOI: 10.2174/157340309787048158] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2008] [Revised: 07/24/2008] [Accepted: 07/24/2008] [Indexed: 11/22/2022] Open
Abstract
A series of reports in the past decade have ascribed pro-angiogenic activity to several thyroid hormone analogues, including L-thyroxine (T(4)), 3,5,3-triiodo-L-thyronine (T(3)) and diiodothyropropionic acid (DITPA). Model systems of angiogenesis have demonstrated that thyroid hormone-induced neovascularization is initiated at a cell surface receptor for the hormone on an integrin. The hormone signal is transduced within the cell by extracellular regulated kinase 1/2 (ERK1/2) into secretion of basic fibroblast growth factor (bFGF) and other vascular growth factors and consequent angiogenesis. Intact animal studies have shown that endogenous thyroid hormone supports blood vessel density in heart and brain and that thyroid hormone administration can induce angiogenesis in ischemic limbs.
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Affiliation(s)
- Paul J Davis
- Address for correspondence to this author at the Signal Transduction Laboratory, Ordway Research Institute, Inc., 150 New Scotland Avenue, Albany, NY 12208 USA; Tel: 518 641 6410; Fax: 518 641 6303; E-mail:
| | | | - Shaker A Mousa
- Pharmaceutical Research Institute, Albany College of Pharmacy, Albany, NY, USAOrdway Research Institute, Inc., Albany, New York
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Erythropoietin Treatment Improves Liver Regeneration and Survival in Rat Models of Extended Liver Resection and Living Donor Liver Transplantation. Transplantation 2008; 86:1578-85. [DOI: 10.1097/tp.0b013e31818b22b4] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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25
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Kress E, Rezza A, Nadjar J, Samarut J, Plateroti M. The frizzled-related sFRP2 gene is a target of thyroid hormone receptor alpha1 and activates beta-catenin signaling in mouse intestine. J Biol Chem 2008; 284:1234-41. [PMID: 19001373 DOI: 10.1074/jbc.m806548200] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The thyroid hormone receptor TRalpha1 regulates intestinal development and homeostasis by controlling epithelial proliferation in the crypts. This involves positive control of the Wnt/beta-catenin pathway. To further investigate the effect of thyroid hormone-TRalpha1 signaling on the intestinal epithelium proliferating compartment, we performed a comparative transcription profile analysis on laser microdissected crypt cells recovered from wild type animals with normal or perturbed hormonal status, as well as from TR knock-out mice. Statistical analysis and an in silico approach allowed us to identify 179 differentially regulated genes and to group them into organized functional networks. We focused on the "cell cycle/cell proliferation" network and, in particular, on the Frizzled-related protein sFRP2, whose expression was greatly increased in response to thyroid hormones. In vitro and in vivo analyses showed that the expression of sFRP2 is directly regulated by TRalpha1 and that it activates beta-catenin signaling via Frizzled receptors. Indeed, sFRP2 stabilizes beta-catenin, activates its target genes, and enhances cell proliferation. In conclusion, these new data, in conjunction with our previous results, indicate a complex interplay between TRalpha1 and components of the Wnt/beta-catenin pathway. Moreover, we describe in this study a novel mechanism of action of sFRP2, responsible for the activation of beta-catenin signaling.
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Affiliation(s)
- Elsa Kress
- Université de Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, INRA, CNRS, Institut de Génomique Fonctionnelle de Lyon, 69364 Lyon, France
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The use of the Papworth cocktail is detrimental to steatotic livers after ischemia-reperfusion injury. Transplantation 2008; 86:286-92. [PMID: 18645492 DOI: 10.1097/tp.0b013e31817b900f] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Hormonal resuscitation, specifically administration of levothyroxine (T4) and methylprednisolone (steroid, i.e., the "T4 Protocol") in organ transplant donors, is becoming increasingly used. Previous studies have shown that this maximizes the number of usable organs by reducing metabolic disturbances post-brain death. However, anecdotal evidence has shown that steatotic livers are adversely affected by this protocol. Therefore, we sought to investigate the hypothesis that the use of T4 and steroid is detrimental to steatotic livers in a model of total hepatic warm ischemia-reperfusion (I/R). METHODS We subjected 8- to -10-week-old male C57BL/6 and ob/ob mice to injections of T4 and steroid 48 hr before 15 min of total hepatic ischemia, followed by 24 hr of reperfusion. RESULTS We saw a significant decrease in survival in ob/ob animals given T4 and steroid as compared with single-treated or vehicle-treated animals. This decrease in survival was accompanied by a dramatic increase in liver necrosis (as measured on a scale from 0 to 3) in these animals as compared with controls. Previous work in our lab has shown that uncoupling protein-2 is a major mediator of I/R in steatotic animals, as it upsets normal energy homeostasis. Following with this hypothesis, we see a dramatic increase in uncoupling protein-2 levels in the combination treated animals, which is accompanied by a concomitant decrease in ATP levels after reperfusion. CONCLUSIONS The T4 protocol is detrimental to steatotic livers subjected to I/R, likely because of a decreased ability to recover after reperfusion caused by decreased ability to form ATP.
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Davis PJ. Fibroblast growth factor actions and thyroid hormone. Curr Opin Endocrinol Diabetes Obes 2007; 14:382. [PMID: 17940467 DOI: 10.1097/med.0b013e3282eee941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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