Molecular Functions of Thyroid Hormones and Their Clinical Significance in Liver-Related Diseases

Thyroid hormones (THs) are potent mediators of several physiological processes, including embryonic development, cellular differentiation, metabolism, and cell growth. Triiodothyronine (T3) is the most biologically active TH form. Thyroid hormone receptors (TRs) belong to the nuclear receptor superfamily and mediate the biological functions of T3via transcriptional regulation. TRs generally form heterodimers with the retinoid X receptor (RXR) and regulate target genes upon T3stimulation. Research over the past few decades has revealed that disruption of cellular TH signaling triggers chronic liver diseases, including alcoholic or nonalcoholic fatty liver disease and hepatocellular carcinoma (HCC). Animal model experiments and epidemiologic studies to date imply close associations between high TH levels and prevention of liver disease. Moreover, several investigations spanning four decades have reported the therapeutic potential of T3analogs in lowering lipids, preventing chronic liver disease, and as anticancer agents. Thus, elucidating downstream genes/signaling pathways and molecular mechanisms of TH actions is critical for the treatment of significant public health issues. Here, we have reviewed recent studies focusing on the roles of THs and TRs in several disorders, in particular, liver diseases. We also discuss the potential therapeutic applications of THs and underlying molecular mechanisms.

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LncRNAs Act as a Link between Chronic Liver Disease and Hepatocellular Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms21082883 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2883

Author(s):

Young-Ah Kim ◽

Kwan-Kyu Park ◽

Sun-Jae Lee

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Disease ◽

Chronic Liver Disease ◽

Hepatic Fibrosis ◽

Liver Diseases ◽

Molecular Mechanisms ◽

Chronic Liver ◽

Chronic Liver Diseases ◽

Nonalcoholic Fatty Liver ◽

Underlying Mechanisms

Long non-coding RNAs (lncRNAs) are emerging as important contributors to the biological processes underlying the pathophysiology of various human diseases, including hepatocellular carcinoma (HCC). However, the involvement of these molecules in chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD) and viral hepatitis, has only recently been considered in scientific research. While extensive studies on the pathogenesis of the development of HCC from hepatic fibrosis have been conducted, their regulatory molecular mechanisms are still only partially understood. The underlying mechanisms related to lncRNAs leading to HCC from chronic liver diseases and cirrhosis have not yet been entirely elucidated. Therefore, elucidating the functional roles of lncRNAs in chronic liver disease and HCC can contribute to a better understanding of the molecular mechanisms, and may help in developing novel diagnostic biomarkers and therapeutic targets for HCC, as well as in preventing the progression of chronic liver disease to HCC. Here, we comprehensively review and briefly summarize some lncRNAs that participate in both hepatic fibrosis and HCC.

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Phytosterols and Triterpenoids for Prevention and Treatment of Metabolic-related Liver Diseases and Hepatocellular Carcinoma

Current Pharmaceutical Biotechnology ◽

10.2174/1389201020666190219122357 ◽

2019 ◽

Vol 20 (3) ◽

pp. 197-214 ◽

Cited By ~ 8

Author(s):

Isabel Sánchez-Crisóstomo ◽

Eduardo Fernández-Martínez ◽

Raquel Cariño-Cortés ◽

Gabriel Betanzos-Cabrera ◽

Rosa A. Bobadilla-Lugo

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Disease ◽

Anticancer Agents ◽

Liver Diseases ◽

Membrane Receptors ◽

New Drugs ◽

Sexual Hormones ◽

Steroid Nucleus ◽

Alcoholic Fatty Liver ◽

Prevention And Treatment

Background: Liver ailments are among the leading causes of death; they originate from viral infections, chronic alcoholism, and autoimmune illnesses, which may chronically be precursors of cirrhosis; furthermore, metabolic syndrome may worsen those hepatopathies or cause Non-alcoholic Fatty Liver Disease (NAFLD) that may advance to non-alcoholic steatohepatitis (NASH). Cirrhosis is the late-stage liver disease and can proceed to hepatocellular carcinoma (HCC). Pharmacological treatment options for liver diseases, cirrhosis, and HCC, are limited, expensive, and not wholly effective. The use of medicinal herbs and functional foods is growing around the world as natural resources of bioactive compounds that would set the basis for the development of new drugs. Review and Conclusion: Plant and food-derived sterols and triterpenoids (TTP) possess antioxidant, metabolic-regulating, immunomodulatory, and anti-inflammatory activities, as well as they are recognized as anticancer agents, suggesting their application strongly as an alternative therapy in some chronic diseases. Thus, it is interesting to review current reports about them as hepatoprotective agents, but also because they structurally resemble cholesterol, sexual hormones, corticosteroids and bile acids due to the presence of the steroid nucleus, so they all can share pharmacological properties through activating nuclear and membrane receptors. Therefore, sterols and TTP appear as a feasible option for the prevention and treatment of chronic metabolic-related liver diseases, cirrhosis, and HCC.

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Cryptotanshinone Suppresses Liver Fibrosis by Attenuating Epithelial-Mesenchymal Transition through Targeting Hedgehog Pathway

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200302112517 ◽

2020 ◽

Vol 20 ◽

Author(s):

Shurong Ren ◽

Qizhen Yue ◽

Qiubo Wang ◽

Yanli Zhang ◽

Bei Zhang

Keyword(s):

Animal Model ◽

Liver Fibrosis ◽

Liver Diseases ◽

Target Genes ◽

Epithelial Mesenchymal Transition ◽

Chronic Liver ◽

Luciferase Assay ◽

Induced Expression ◽

Mesenchymal Transition ◽

Realtime Pcr

Background: Chronic liver damages from viral infection or alcohol abuse result in liver fibrosis, which is a key pathological event in many types of liver diseases. Discovering new anti-fibrosis agents may provide alternative solutions to manage chronic liver diseases. Methods: We first used CCl4 induced liver fibrosis animal model to evaluate the beneficial effects of Cryptotanshinone (CRY). We next explored target miRNAs regulated by CRY in hepatocytes using microarray. The target miRNA candidate was confirmed with realtime-PCR. We also elucidated the downstream target and pathway directly regulated by the miRNA using luciferase assay, western blotting and Epithelial–Mesenchymal Transition (EMT) markers quantification. Lastly, we confirmed CRY induced expression changes of the target genes in vivo. Results: CRY oral administration markedly alleviated the liver injury caused by CCl4. miRNAs expression profiling and realtime-PCR validation revealed miR-539-3p was directly induced by CRY around 4 folds. The induction of miR-539-3p suppressed SMO expression and antagonized Hedgehog (Hh) pathway. Independently CRY treatment suppressed SMO and inhibited EMT process in hepatocytes. The CRY induced expression changes of both miR-539-3p (~ 2 folds increase) and SMO (~ 60% decrease) in livers were validated in animal model. Conclusion: Our study supported CRY could inhibit liver fibrosis by targeting Hh pathway during EMT. CRY could be used as anti-fibrosis agent candidate for managing chronic liver damages.

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The Role of the Gut Microbiome in Liver Cirrhosis Treatment

International Journal of Molecular Sciences ◽

10.3390/ijms22010199 ◽

2020 ◽

Vol 22 (1) ◽

pp. 199

Author(s):

Na Young Lee ◽

Ki Tae Suk

Keyword(s):

Liver Cirrhosis ◽

Liver Disease ◽

Liver Fibrosis ◽

Gut Microbiota ◽

Gut Microbiome ◽

Liver Diseases ◽

Sclerosing Cholangitis ◽

Chronic Liver ◽

Chronic Liver Diseases

Liver cirrhosis is one of the most prevalent chronic liver diseases worldwide. In addition to viral hepatitis, diseases such as steatohepatitis, autoimmune hepatitis, sclerosing cholangitis and Wilson’s disease can also lead to cirrhosis. Moreover, alcohol can cause cirrhosis on its own and exacerbate chronic liver disease of other causes. The treatment of cirrhosis can be divided into addressing the cause of cirrhosis and reversing liver fibrosis. To this date, there is still no clear consensus on the treatment of cirrhosis. Recently, there has been a lot of interest in potential treatments that modulate the gut microbiota and gut-liver axis for the treatment of cirrhosis. According to recent studies, modulation of the gut microbiome by probiotics ameliorates the progression of liver disease. The precise mechanism for relieving cirrhosis via gut microbial modulation has not been identified. This paper summarizes the role and effects of the gut microbiome in cirrhosis based on experimental and clinical studies on absorbable antibiotics, probiotics, prebiotics, and synbiotics. Moreover, it provides evidence of a relationship between the gut microbiome and liver fibrosis.

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Thyroid hormones regulate phosphate homoeostasis through transcriptional control of the renal type IIa sodium-dependent phosphate co-transporter (Npt2a) gene

Biochemical Journal ◽

10.1042/bj20090671 ◽

2010 ◽

Vol 427 (1) ◽

pp. 161-169 ◽

Cited By ~ 15

Author(s):

Mariko Ishiguro ◽

Hironori Yamamoto ◽

Masashi Masuda ◽

Mina Kozai ◽

Yuichiro Takei ◽

...

Keyword(s):

Thyroid Hormone ◽

Thyroid Hormones ◽

Molecular Mechanisms ◽

Hormone Receptors ◽

Critical Role ◽

Serum Phosphate ◽

Luciferase Assay ◽

Mobility Shift ◽

Intron 1 ◽

Sodium Dependent

The type IIa renal sodium-dependent phosphate (Na/Pi) co-transporter Npt2a is implicated in the control of serum phosphate levels. It has been demonstrated previously that renal Npt2a protein and its mRNA expression are both up-regulated by the thyroid hormone T3 (3,3′,5-tri-iodothyronine) in rats. However, it has never been established whether the induction was mediated by a direct effect of thyroid hormones on the Npt2a promoter. To address the role of Npt2a in T3-dependent regulation of phosphate homoeostasis and to identify the molecular mechanisms by which thyroid hormones modulate Npt2a gene expression, mice were rendered pharmacologically hypo- and hyper-thyroid. Hypothyroid mice showed low levels of serum phosphate and a marked decrease in renal Npt2a protein abundance. Importantly, we also showed that Npt2a-deficient mice had impaired serum phosphate responsiveness to T3 compared with wild-type mice. Promoter analysis with a luciferase assay revealed that the transcriptional activity of a reporter gene containing the Npt2a promoter and intron 1 was dependent upon TRs (thyroid hormone receptors) and specifically increased by T3 in renal cells. Deletion analysis and EMSAs (electrophoretic mobility-shift assays) determined that there were unique TREs (thyroid-hormone-responsive elements) within intron 1 of the Npt2a gene. These results suggest that Npt2a plays a critical role as a T3-target gene, to control phosphate homoeostasis, and that T3 transcriptionally activates the Npt2a gene via TRs in a renal cell-specific manner.

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Anti‐neutrophil cytoplasmic antibodies in patients with chronic liver diseases: Prevalence, antigen specificity and predictive value for diagnosis of autoimmune liver disease

Journal of Gastroenterology and Hepatology ◽

10.1046/j.1440-1746.2000.02078.x ◽

2000 ◽

Vol 15 (4) ◽

pp. 437-442 ◽

Cited By ~ 26

Author(s):

Stefan Lindgren ◽

Stefan Nilsson ◽

Lennart Nässberger ◽

Hans Verbaan ◽

Jörgen Wieslander ◽

...

Keyword(s):

Liver Disease ◽

Predictive Value ◽

Liver Diseases ◽

Chronic Liver ◽

Autoimmune Liver Disease ◽

Chronic Liver Diseases ◽

Antigen Specificity

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Imaging Software-Based Sarcopenia Assessment in Gastroenterology: Evolution and Clinical Meaning

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2021/6669480 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Giovanni Marasco ◽

Sinan Sadalla ◽

Giulio Vara ◽

Rita Golfieri ◽

Davide Festi ◽

...

Keyword(s):

Skeletal Muscle ◽

Liver Disease ◽

Liver Failure ◽

Chronic Liver Disease ◽

Liver Diseases ◽

Chronic Liver ◽

Chronic Liver Failure ◽

Cross Sectional ◽

Cross Sectional Imaging ◽

Sectional Imaging

Sarcopenia is gaining attention as a negative prognostic factor in different fields of medicine, including chronic liver failure. However, the assessment of sarcopenia in patients with liver diseases is often neglected due to unawareness of reliable tools and methods and thus is limited to research studies. Cross-sectional imaging is a diffuse diagnostic tool and is commonly performed in patients with chronic liver failure. The last advancements in radiology image analysis using dedicated software allow an easy and standardized method to assess skeletal muscle volume. Several measures can be obtained from cross-sectional imaging analysis to evaluate sarcopenia in patients affected by chronic liver disease. We aimed to review the recent advances in imaging-based sarcopenia assessment, in particular in patients with chronic liver diseases. As a result, we found that the skeletal muscle index (SMI) seems to be a reliable method to assess sarcopenia in cirrhotic patients. Even if further studies are needed to validate proper cut-offs for each clinical endpoint, physicians are invited to consider the assessment of sarcopenia in the work-up of patients with chronic liver disease.

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Asthenia and fatigue in hyperammonemia: etiopathogenesis and methods of correction

Medical Council ◽

10.21518/2079-701x-2021-21-1-95-104 ◽

2022 ◽

pp. 95-104

Author(s):

E. Yu. Plotnikova ◽

M. N. Sinkova ◽

L. K. Isakov

Keyword(s):

Liver Disease ◽

Liver Diseases ◽

Signs And Symptoms ◽

Chronic Liver ◽

Blood Levels ◽

Chronic Liver Diseases ◽

Life Threatening ◽

Underlying Causes ◽

Principles Of Treatment ◽

The Brain

Asthenia and fatigue are the most common syndromes in patients with liver disease, which significantly affects their quality of life. The prevalence of fatigue in chronic liver diseases is from 50% to 85%. While some progress has been made in understanding the processes that can cause fatigue in general, the underlying causes of fatigue associated with liver disease remain not well understood. In particular, many data suggest that fatigue associated with liver disease likely results from changes in neurotransmission in the brain against the background of hyperammonemia. Hyperammonemia is a metabolic state characterized by an increased level of ammonia, a nitrogen-containing compound. The present review describes hyperammonemia, which is likely important in the pathogenesis of fatigue associated with liver disease. Ammonia is a potent neurotoxin, its elevated blood levels can cause neurological signs and symptoms that can be acute or chronic, depending on the underlying pathology. Hyperammonemia should be recognized early, and immediately treated to prevent the development of life-threatening complications, such as, swelling of the brain and coma. The article gives pathophysiological mechanisms of influence of hyperammonemia on state of psychovegetative status of patients with liver diseases, also lists basic principles of treatment. A significant part of the article is devoted to L-ornithine-L-aspartate, which is effective in asthenia and fatigue to reduce the level of hyperammonemia through a variety of well-studied mechanisms in chronic liver diseases.

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The Course Of Chronic Liver Disease In Patients With Covid-2019 (Literature Review And Own Data)

The American Journal of Medical Sciences and Pharmaceutical Research ◽

10.37547/tajmspr/volume03issue09-12 ◽

2021 ◽

Vol 03 (09) ◽

pp. 69-74

Author(s):

Muxamedova Z.R. ◽

Keyword(s):

Liver Disease ◽

Literature Review ◽

Liver Diseases ◽

Chronic Liver ◽

Chronic Liver Diseases ◽

Biochemical Activity ◽

Severe Liver ◽

Risk Of Mortality ◽

The World ◽

Severe Liver Damage

The pandemic of the new coronavirus COVID-19 has switched medicine around the world on the primary fight against this infection. Patients with chronic liver diseases require increased attention of doctors during an epidemic, since against the background of an exacerbation of their disease, not only the risk of contracting the COVID 19 viral infection increases, but also its more severe course. Patients with confirmed COVID-19 with severe liver damage - high biochemical activity. According to some reports, patients with a severe course of COVID-19 have an increase in ALT levels, a decrease in the number of platelets, a decrease in the level of albumin, and a connection (although not all indicators) with a higher risk of mortality is possible.

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