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Molecular Functions and Clinical Impact of Thyroid Hormone-Triggered Autophagy in Liver-Related Diseases

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Molecular Functions and Clinical Impact of Thyroid Hormone-Triggered Autophagy in Liver-Related Diseases Chi et al. Journal of Biomedical Science (2019) 26:24 https://doi.org/10.1186/s12929-019-0517-x REVIEW Open Access Molecular functions and clinical impact of thyroid hormone-triggered autophagy in liver-related diseases Hsiang-Cheng Chi1†, Chung-Ying Tsai2†, Ming-Ming Tsai3,4,7, Chau-Ting Yeh5 and Kwang-Huei Lin5,6,7* Abstract The liver is controlled by several metabolic hormones, including thyroid hormone, and characteristically displays high lysosomal activity as well as metabolic stress-triggered autophagy, which is stringently regulated by the levels of hormones and metabolites. Hepatic autophagy provides energy through catabolism of glucose, amino acids and free fatty acids for starved cells, facilitating the generation of new macromolecules and maintenance of the quantity and quality of cellular organelles, such as mitochondria. Dysregulation of autophagy and defective mitochondrial homeostasis contribute to hepatocyte injury and liver-related diseases, such as non-alcoholic fatty liver disease (NAFLD) and liver cancer. Thyroid hormones (TH) mediate several critical physiological processes including organ development, cell differentiation, metabolism and cell growth and maintenance. Accumulating evidence has revealed dysregulation of cellular TH activity as the underlying cause of several liver-related diseases, including alcoholic or non-alcoholic fatty liver disease and liver cancer. Data from epidemiologic, animal and clinical studies collectively support preventive functions of THs in liver-related diseases, highlighting the therapeutic potential of TH analogs. Elucidation of the molecular mechanisms and downstream targets of TH should thus facilitate the development of therapeutic strategies for a number of major public health issues. Here, we have reviewed recent studies focusing on the involvement of THs in hepatic homeostasis through induction of autophagy and their implications in liver-related diseases. Additionally, the potential underlying molecular pathways and therapeutic applications of THs in NAFLD and HCC are discussed. Keywords: Thyroid hormone, Thyroid hormone receptor, Autophagy, non-alcoholic fatty liver disease, hepatocellular carcinoma Background body is associated with multiple chronic diseases, inclu- Thyroid hormones (TH) serve as potent regulators of cel- ding diabetes mellitus [3, 4], cardiovascular disease [5, 6] lular development, growth and metabolism in mammals and liver-related disorders [7]. Liver is one of the most [1] and control several metabolic activities related to ana- important target organs whereby THs regulate compo- bolism or catabolism of macromolecules, including carbo- nents involved in cellular metabolism, such as fatty acids, hydrates, proteins, lipids and damaged organelles within supporting the possibility that disruption of TH action in cells to maintain homeostasis under different physiological liver contributes to development of non-alcoholic fatty conditions [2]. In addition to their critical regulatory roles liver disease (NAFLD). Indeed, recent studies have re- in cellular homeostasis, imbalance of TH levels in the ported associations between alterations in cellular TH sig- naling and several liver-related diseases, including * Correspondence: [email protected] NAFLD and hepatocellular carcinoma (HCC). Earl- † Hsiang-Cheng Chi and Chung-Ying Tsai contributed equally to this work. ier epidemiological findings suggest that long-term 5Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan333 6Department of Biochemistry, College of Medicine, Chang-Gung University, 259 Wen-Hwa 1 Road, Taoyuan 333, Taiwan, Republic of China Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chi et al. Journal of Biomedical Science (2019) 26:24 Page 2 of 15 hypothyroidism is positively associated with high binding affinity of T4 is considerably lower (10-fold less) risk of NAFLD and HCC incidence, independent of than that for T3. The conversion of T4 to T3 is regulated other risk factors [8, 9]. Moreover, treatment with T3 or its via iodothyronine deiodinases (DIO1, DIO2, and DIO3) analogs has been shown to prevent a spectrum of liver- in extrathyroidal tissue. Type I and type II iodothyronine related diseases ranging from hepatic steatosis to deiodinases (DIO1, DIO2) deiodinate circulating T4 to HCC in rodents subjected to high-fat diet (HFD) or produce biologically active T3. Conversely, type III deio- carcinogens [10–17]. These collective findings support dinase (DIO3) suppresses intracellular thyroid activity by the potential utility of TH analogs as therapeutic converting T4 and T3 to the comparatively inactive drugs to prevent liver disease progression. Analysis of forms, reverse T3 (rT3) and T2. Recently, T2 was shown the downstream signals of TH in liver may further to possess thyromimetic activity and mimic some of the shed light on the underlying TH pathways that induce effects of T3 on liver metabolism [28, 29], implying that therapeutic effects against liver-related diseases. T2 or rT3 may not just be inert metabolites as originally Autophagy is a self-digestion process primarily involving suggested. Expression levels and activities of DIO1, recycling of cellular fuel stores in lysosomes to generate DIO2 and DIO3 vary among different tissues, causing a amino acids, glucose and fatty acids [18]. Catabolism of tissue-specific increase or decrease in circulating TH lipids through autophagy is termed lipophagy [19]. In levels or availability of active hormones for THR binding addition to metabolic functions, autophagy presents a [7, 30]. To exert genomic effects, cytoplasmic T3 enters cellular surveillance mechanism to suppress accumulation the nucleus, most likely through passive diffusion, and of toxic protein aggregates and impairment of organelles, binds THRs associated with thyroid hormone response thus facilitating maintenance of organelle integrity and elements (TRE) within the promoter regions of down- cellular homeostasis [20].Thespecificregulatoryfunc- stream genes of TH/THR [31–33]. Typical TREs within tions of autophagy in hepatic homeostasis have been promoter regions of downstream genes contain two increasingly explored in recent years. Dysregulation of half-site sequences (A/G)GGT(C/A/G)A in a palindromic, the autophagic process is reported to cause an imbalance direct repeat or inverted repeat arrangement that are in energy metabolism in the liver and consequently affect recognized by THR [1]. – hepatic physiology and trigger disease [21 24]. Several THRs are T3-inducible transcription factors belonging research groups, including ours, have shown that hepatic to the nuclear receptor superfamily that are encoded by lipid turnover is stimulated by THs through lipophagy, two tissue-specific genes, THRA (TRα) and THRB preventing hepatosteatosis, both in vitro and in vivo (TRβ). The THRA gene encodes one active T3-binding [25, 26]. Additionally, TH stimulates the metabolic receptor, TRα1, and two dominant-negative spliced rate accompanied by increased mitochondrial turnover variants, TRΔα1 and TRΔα2[34]. that lack T3 binding through mitophagy, leading to elimination of mitochon- ability [35]. TRα1 is the predominant subtype highly drial dysfunction induced by hepatic carcinogens or hepa- expressed in brain, cardiac and skeletal muscle [36]. titis B virus HBx protein [16, 17, 27]. The finding that THRB encodes two functional T3-binding TRβ isoforms THs and Thyroid hormone receptors (THRs) prevent (TRβ1andTRβ2) and another dominant-negative iso- hepatic damage, hepatosteatosis and hepatocarcinogenesis form, TRβ4[34]. TRβ1 is predominately expressed in via autophagy stimulation supports their therapeutic brain, liver and kidney whereas TRβ2 is limited to the potential in clinical applications. In the current report, hypothalamus, retina and pituitary. THRs exert transcrip- we have reviewed studies published by our research tional effects via formation of homodimers or hetero- group and other investigators on the involvement of dimers with other nuclear receptors, such as retinoid X TH-induced autophagy in liver-related diseases, parti- receptor (RXR), Vitamin D receptors (VDR) and other cularly NAFLD and HCC. Elucidation of the network of retinoic acid receptor subtypes. RXR generally functions molecular mechanisms underlying the effects of TH/THR as a partner of several nuclear receptors to regulate target on hepatic metabolism may aid in the design of effective genes [47]. THRs form heterodimers with RXR on TREs therapeutic strategies for a range of liver-related diseases. within the promoter regions of target genes. In addition, recent ChIP-Seq studies have shown that THRs bind to specific response element motifs with Molecular actions of thyroid hormones and receptors non-conserved sequences and in non-promoter regions Genomic actions of TH [37–39], implying that interactions with other tran- T3 (triiodothyronine) and
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