Influence of thyroid hormone mechanisms on the progression of metabolic dysfunction associated with fatty liver disease (MAFLD)

In the last decades, with the increase in the consumption of industrialized foods, (rich in fat) added to the lack of physical exercise, we obtained an exponential increase in the prevalence of obesity worldwide. Related to this, diseases secondary to obesity have been gaining prominence, this is the case of metabolic dysfunction associated with fatty liver disease (MAFLD), one of the most common forms of chronic liver disease. In recent years there has been an increase in its prevalence, it is estimated that around 20-30% in the western population and 5-18% in the East have some stage of MAFLD, in South America it is estimated at 30%. The etiology of the disease begins with obesity, insulin resistance, type 2 diabetes mellitus (DM-2) and dyslipidemia, which are the primary causes for its development. The natural history of MAFLD begins with the deposition of fat in the liver, followed by the first stages of hepatic steatosis, causing chronic inflammation and compensatory tissue repair that can progress to nonalcoholic steatohepatitis (NASH). Subsequently, collagen accumulation occurs leading to cirrhosis and long-term hepatocellular carcinoma (HCC). Although there is already a great knowledge about the pathophysiology of the disease and its predisposing factors, there are still mechanisms involved in the development and progression of MAFLD that have been little explored. In this sense, the metabolism of thyroid hormones (THs) may play an important role associated with the disease. THs are essential for growth, development and metabolism in virtually every system in the body. Although thyroxine (T4) is the main product, triiodothyronine (T3) is the biologically active one. Being regulated by the activity of the iodothyronine deiodases family. Types 1 (Dio1) and 2 (Dio2) convert intracellular T4 to T3, while type 3 (Dio3) converts T3 to rT3 (inactive T3). In the liver, the role of THs directly influence the metabolism of lipids and carbohydrates, via hepatic lipogenesis, lipid oxidation, cholesterol homeostasis. In normal situations, hepatocytes show a high expression of Dio1 and low expression of Dio3, maintaining the adequate conversion of THs and their hepatic activity preserved. Recently, changes in the availability of T3 have been observed, showing a possible association with MAFLD progression. However, little is known about the mechanisms involved in the metabolism of THs in the pathophysiology of MAFLD.Nas últimas décadas, com o aumento do consumo de alimentos industrializados, (ricos em gordura) somados com a falta da pratica de exercício físico obtivemos um aumento exponencial da prevalência de obesidade mundial. Relacionado a isso, doenças secundarias a obesidade vem ganhando destaque, esse é o caso da doença hepática gordurosa associada à disfunção metabólica (MAFLD), uma das formas mais comuns de doenças hepáticas crônicas. Nos últimos anos houve um incremento da sua prevalência, estima-se que em torno de 20-30% na população ocidental e 5-18% no Oriente tenham algum estagio da MAFLD, na América do Sul ela é estimada em 30%. A etiologia da doença inicia-se com a obesidade, resistência insulínica, diabetes mellitus do tipo 2 (DM-2) e dislipidemia sendo essas as causas primárias para o seu desenvolvimento. A história natural da MAFLD começa com a deposição de gordura no fígado, seguido dos primeiros estagio da esteatose hepática, ocasionando inflamação crônica e reparação compensatória do tecido podendo progredir a esteato-hepatite não-alcoólica (EHNA). Posteriormente ocorre o acúmulo de colágeno levando a cirrose e a longo prazo carcinoma hepatocelular (CHC). Embora já exista um grande conhecimento sobre a fisiopatologia da doença e seus fatores predisponentes, ainda existem mecanismos envolvidos no desenvolvimento e na progressão da MAFLD que foram pouco explorados. Neste sentido, o metabolismo dos hormônios tireoidianos (HTs) podem ter papel importante associado à doença. Os HTs são essenciais para o crescimento, desenvolvimento e metabolismo em praticamente todos os sistemas do corpo. Apesar da Tiroxina (T4) ser o principal produto, o triiodotironina (T3) é o biologicamente ativo. Sendo regulados pela atividade da família das iodotironinas desiodases. As do tipo 1 (Dio1) e 2 (Dio2) convertem T4 intracelular em T3, enquanto a do tipo 3 (Dio3) converte T3 em rT3 (T3 inativo). No fígado o papel dos HTs influenciam diretamente o metabolismo de lipídios e carboidratos, via lipogênese hepática, oxidação lipídica, homeostase do colesterol. Em situações normais os hepatócitos apresentam uma grande expressão de Dio1 e baixa expressão de Dio3, mantendo a conversão dos HTs adequada e sua atividade hepática preservada. Recentemente, alteração na disponibilidade dos T3 vem sendo observadas, apresentando uma possível associação com a progressão MAFLD. Contudo, pouco se sabe sobre os mecanismos envolvidos no metabolismo dos HTs na fisiopatologia da MAFLD

Relationship among low T3 levels, type 3 deiodinase, oxidative stress, and mortality in sepsis and septic shock : defining patient outcomes

Low T3 syndrome occurs frequently in patients with sepsis. Type 3 deiodinase (DIO3) is present in immune cells, but there is no description of its presence in patients with sepsis. Here, we aimed to determine the prognostic impact of thyroid hormones levels (TH), measured on ICU admission, on mortality and evolution to chronic critical illness (CCI) and the presence of DIO3 in white cells. We used a prospective cohort study with a follow-up for 28 days or deceased. Low T3 levels at admission were present in 86.5% of the patients. DIO3 was induced by 55% of blood immune cells. The cutoff value of 60 pg/mL for T3 displayed a sensitivity of 81% and specificity of 64% for predicting death, with an odds ratio of 4.89. Lower T3 yielded an area under the receiver operating characteristic curve of 0.76 for mortality and 0.75 for evolution to CCI, thus displaying better performance than commonly used prognostic scores. The high expression of DIO3 in white cells provides a novel mechanism to explain the reduction in T3 levels in sepsis patients. Further, low T3 levels independently predict progression to CCI and mortality within 28 days for sepsis and septic shock patients

Uncovering actions of type 3 deiodinase in the metabolic dysfunction-associated fatty liver disease (MAFLD)

Metabolic dysfunction-associated fatty liver disease (MAFLD) has gained worldwide attention as a public health problem. Nonetheless, lack of enough mechanistic knowledge restrains effective treatments. It is known that thyroid hormone triiodothyronine (T3) regulates hepatic lipid metabolism, and mitochondrial function. Liver dysfunction of type 3 deiodinase (D3) contributes to MAFLD, but its role is not fully understood. Objective: To evaluate the role of D3 in the progression of MAFLD in an animal model. Methodology: Male/adult Sprague Dawley rats (n = 20) were allocated to a control group (2.93 kcal/g) and high-fat diet group (4.3 kcal/g). Euthanasia took place on the 28th week. D3 activity and expression, Uncoupling Protein 2 (UCP2) and type 1 deiodinase (D1) expression, oxidative stress status, mitochondrial, Krebs cycle and endoplasmic reticulum homeostasis in liver tissue were measured. Results: We observed an increase in D3 activity/expression (p < 0.001) related to increased thiobarbituric acid reactive substances (TBARS) and carbonyls and diminished reduced glutathione (GSH) in the MAFLD group (p < 0.05). There was a D3-dependent decrease in UCP2 expression (p = 0.01), mitochondrial capacity, respiratory activity with increased endoplasmic reticulum stress in the MAFLD group (p < 0.001). Surprisingly, in an environment with lower T3 levels due to high D3 activity, we observed an augmented alpha-ketoglutarate dehydrogenase (KGDH) and glutamate dehydrogenase (GDH) enzymes activity (p < 0.05). Conclusion: Induced D3, triggered by changes in the REDOX state, decreases T3 availability and hepatic mitochondrial capacity. The Krebs cycle enzymes were altered as well as endoplasmic reticulum stress. Taken together, these results shed new light on the role of D3 metabolism in MAFLD

Short-term exercise training improves cardiac function associated to a better antioxidant response and lower type 3 iodothyronine deiodinase activity after myocardial infarction

Aims: We assessed the effects of a short-term exercise training on cardiac function, oxidative stress markers, and type 3 iodothyronine deiodinase (D3) activity in cardiac tissue of spontaneously hypertensive rats (SHR) following experimental myocardial infarction (MI). Methods: Twenty-four SHR (aged 3 months) were allocated to 4 groups: sham+sedentary, sham+trained, MI+sedentary and MI+trained. MI was performed by permanent ligation of the coronary artery. Exercise training (treadmill) started 96 hours after MI and lasted for 4 weeks (~60% maximum effort, 4x/week and 40 min/day). Cardiac function (echocardiography), thioredoxin reductase (TRx), total carbonyl levels, among other oxidative stress markers and D3 activity were measured. A Generalized Estimating Equation was used, followed by Bonferroni’s test (p<0.05). Results: MI resulted in an increase in left ventricular mass (p = 0.002) with decreased cardiac output (~22.0%, p = 0.047) and decreased ejection fraction (~41%, p = 0.008) as well as an increase in the carbonyl levels (p = 0.001) and D3 activity (~33%, p<0.001). Exercise training resulted in a decrease in left ventricular mass, restored cardiac output (~34%, p = 0.048) and ejection fraction (~20%, p = 0.040), increased TRx (~85%, p = 0.007) and reduced carbonyl levels (p<0.001) and D3 activity (p<0.001). Conclusions: Our short-term exercise training helped reverse the effects of MI on cardiac function. These benefits seem to derive from a more efficient antioxidant response and lower D3 activity in cardiac tissue

Non-thyroidal illness syndrome predicts outcome in adult critically ill patients : a systematic review and meta-analysis

We performed a systematic review and meta-analysis to comprehensively determine the prevalence and the prognostic role of non-thyroidal illness syndrome (NTIS) in critically ill patients. We included studies that assessed thyroid function by measuring the serum thyroid hormone (TH) level and in-hospital mortality in adult septic patients. Reviews, case reports, editorials, letters, animal studies, duplicate studies, and studies with irrelevant populations and inappropriate controls were excluded. A total of 6869 patients from 25 studies were included. The median prevalence rate of NTIS was 58% (IQR 33.2-63.7). In univariate analysis, triiodothyronine (T3) and free T3 (FT3) levels in non-survivors were relatively lower than that of survivors (8 studies for T3; standardized mean difference (SMD) 1.16; 95% CI, 0.41-1.92; I2 = 97%; P < 0.01). Free thyroxine (FT4) levels in non-survivors were also lower than that of survivors (12 studies; SMD 0.54; 95% CI, 0.31-0.78; I2 = 83%; P < 0.01). There were no statistically significant differences in thyrotropin levels between non-survivors and survivors. NTIS was independently associated with increased risk of mortality in critically ill patients (odds ratio (OR) = 2.21, 95% CI, 1.64-2.97, I2 = 65% P < 0.01). The results favor the concept that decreased thyroid function might be associated with a worse outcome in critically ill patients. Hence, the measurement of TH could provide prognostic information on mortality in adult patients admitted to ICU

Efeito do treinamento físico sobre a composição corporal e função cardíaca em ratos espontaneamente hipertensos submetidas à indução do infarto agudo do miocárdio

1

Efeito do treinamento físico sobre a composição corporal e função cardíaca em ratos espontaneamente hipertensos submetidas à indução do infarto agudo do miocárdio

1

Aerobic training prior to myocardial infarction increases cardiac GLUT4 and partially preserves heart function in spontaneously hypertensive rats

We assessed cardiac function (echocardiographic) and GLUT4 expression (Western Blot) in response to a 10-week aerobic training (treadmill) prior to acute myocardial infarction by ligation of the left coronary artery (AMI) in spontaneously hypertensive rats. Animals were allocated to sedentary+sham, sedentary+AMI, training+sham and training+AMI. Aerobic training prior to AMI partially preserves heart function. AMI and/or aerobic training increased GLUT4 expression. However, those animals trained prior to AMI showed a greater increase in GLUT4 in cardiomyocytes.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Uncovering Actions of Type 3 Deiodinase in the Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)

Metabolic dysfunction-associated fatty liver disease (MAFLD) has gained worldwide attention as a public health problem. Nonetheless, lack of enough mechanistic knowledge restrains effective treatments. It is known that thyroid hormone triiodothyronine (T3) regulates hepatic lipid metabolism, and mitochondrial function. Liver dysfunction of type 3 deiodinase (D3) contributes to MAFLD, but its role is not fully understood. Objective: To evaluate the role of D3 in the progression of MAFLD in an animal model. Methodology: Male/adult Sprague Dawley rats (n = 20) were allocated to a control group (2.93 kcal/g) and high-fat diet group (4.3 kcal/g). Euthanasia took place on the 28th week. D3 activity and expression, Uncoupling Protein 2 (UCP2) and type 1 deiodinase (D1) expression, oxidative stress status, mitochondrial, Krebs cycle and endoplasmic reticulum homeostasis in liver tissue were measured. Results: We observed an increase in D3 activity/expression (p p p = 0.01), mitochondrial capacity, respiratory activity with increased endoplasmic reticulum stress in the MAFLD group (p p < 0.05). Conclusion: Induced D3, triggered by changes in the REDOX state, decreases T3 availability and hepatic mitochondrial capacity. The Krebs cycle enzymes were altered as well as endoplasmic reticulum stress. Taken together, these results shed new light on the role of D3 metabolism in MAFLD