Drug-induced and postnatal hypothyroidism impairs the accumulation of diacylglycerol in liver and liver cell plasma membranes

Krasilnikova, O. A.; Kavok, Nataliya; Babenko, N. A.

doi:10.1186/1472-6793-2-12

Cited by 11 publications

(3 citation statements)

References 40 publications

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“…DG accumulation had been attributed to multiple routes, including lipid efflux, ceramide, polyphosphoinositide, and PC hydrolysis, in addition to reduced hepatic lipogenesis, all of which resulted in reduced levels of PC and TG ( 32 ). Sustained elevation of DG level is believed to be associated with decreased protein kinase C (PKC) activity ( 33 ). PKC comprises a family of closely related enzymes that are activated by the second messenger calcium (Ca 2+ ) and DG, depending on the duration and magnitude of these signals.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the level of intracellular DG must be closely regulated. Upon LT 4 administration, PKC is reactivated, the amount of DG synthesized de novo will be decreased, and the level of TG is expected to increase ( 33 , 39 , 40 ). In the current study, the levels of three of four identified DGs were downregulated and the level of one of two identified TGs was upregulated after treatment.…”

Section: Discussionmentioning

confidence: 99%

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Metabolomic profile of patients on levothyroxine treatment for hypothyroidism

Benabdelkamel

Jaber

Dahabiyeh

et al. 2023

European Thyroid Journal

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Background: Hypothyroidism is clinically characterized by decrease in levels of the circulating thyroid hormones namely thyroxine and triiodothyronine. The main treatment for hypothyroidism is thyroid hormone replacement using levothyroxine to normalize serum thyroid hormone levels. Objectives: In this study, we explored the metabolic changes in the plasma of patients with hypothyroidism after reaching a euthyroid state with levothyroxine treatment. Methods: Plasma samples from 18 patients diagnosed as overt hypothyroidism were collected before and after levothyroxine treatment upon reaching a euthyroid state and were analyzed by high-resolution mass spectrometry-based metabolomics. Multivariate and univariate analyses evaluated data to highlight potential metabolic biomarkers. Results: LC-MS-based metabolomics revealed significant decrease in the levels of ceramide, phosphatidylcholine, triglycerides, acylcarnitine, and peptides after levothyroxine treatment; this could indicate a change in the fatty acid transportation system and an enhanced β oxidation, compared with a hypothyroid state. At the same time, the decrease in the peptides suggested a shift in protein synthesis. In addition, there was a considerable rise in glycocholic acid following therapy, suggesting the involvement of thyroid hormones in stimulating bile acid production and secretion. Conclusions: A metabolomic analysis of patients with hypothyroidism revealed significant changes in several metabolites and lipids after treatment. This study showed the value of the metabolomics technique in providing a complementary understanding of the pathophysiology of hypothyroidism and as a crucial tool for examining the molecular impact of LT4 treatment on hypothyroidism. It was an important tool for investigating the therapeutic effects of levothyroxine on hypothyroidism at the molecular level.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Metabolomic profile of patients on levothyroxine treatment for hypothyroidism

Benabdelkamel

Jaber

Dahabiyeh

et al. 2023

European Thyroid Journal

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“…It is further known that phosphorylation of the NKA catalytic subunit inhibits enzyme activity [204]. Protein kinase C (PKC) is critical to phosphorylation [219] and as previously described it is well proven that PKC phosphorylation of the α subunit of NKA leads to a decrease in its enzyme activity [206,207,208,209,210,211,212,213]. Conversely, inhibition of PKC has been found to stimulate NKA enzyme activity [220,221].…”

Section: Molecular Mechanisms By Which Fluoride Inhibits Na+ K+-amentioning

confidence: 99%

Fluoride Exposure Induces Inhibition of Sodium-and Potassium-Activated Adenosine Triphosphatase (Na+, K+-ATPase) Enzyme Activity: Molecular Mechanisms and Implications for Public Health

Waugh¹

2019

IJERPH

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In this study, several lines of evidence are provided to show that Na + , K + -ATPase activity exerts vital roles in normal brain development and function and that loss of enzyme activity is implicated in neurodevelopmental, neuropsychiatric and neurodegenerative disorders, as well as increased risk of cancer, metabolic, pulmonary and cardiovascular disease. Evidence is presented to show that fluoride (F) inhibits Na + , K + -ATPase activity by altering biological pathways through modifying the expression of genes and the activity of glycolytic enzymes, metalloenzymes, hormones, proteins, neuropeptides and cytokines, as well as biological interface interactions that rely on the bioavailability of chemical elements magnesium and manganese to modulate ATP and Na + , K + -ATPase enzyme activity. Taken together, the findings of this study provide unprecedented insights into the molecular mechanisms and biological pathways by which F inhibits Na + , K + -ATPase activity and contributes to the etiology and pathophysiology of diseases associated with impairment of this essential enzyme. Moreover, the findings of this study further suggest that there are windows of susceptibility over the life course where chronic F exposure in pregnancy and early infancy may impair Na + , K + -ATPase activity with both short- and long-term implications for disease and inequalities in health. These findings would warrant considerable attention and potential intervention, not to mention additional research on the potential effects of F intake in contributing to chronic disease.

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Thyroid hormones regulate DNA‐synthesis and cell‐cycle proteins by activation of PKCα and p42/44 MAPK in chick embryo hepatocytes

Alisi

Spagnuolo

Napoletano

et al. 2004

Journal Cellular Physiology

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The molecular mechanism by which thyroid hormones exert their effects on cell growth is still unknown. In this study, we used chick embryo hepatocytes at different stages of development as a model to investigate the effect of the two thyroid hormones, T3 and T4, and of their metabolite T2, on the control of cell proliferation. We observed that T2 provokes increase of DNA-synthesis as well as T3 and T4, independently of developmental stage. We found that this stimulatory effect on the S phase is reverted by specific inhibitors of protein kinase C (PKC) and p42/44 mitogen-activated protein kinase (p42/44 MAPK), Ro 31-8220 or PD 98059. Furthermore, the treatment with thyroid hormones induces the activation of PKCalpha and p42/44 MAPK, suggesting their role as possible downstream mediators of cell response mediated by thyroid hormones. The increase of DNA-synthesis is well correlated with the increased levels of cyclin D1 and cdk4 that control the G1 phase, and also with the activities of cell-cycle proteins involved in the G1 to S phase progression, such as cyclin E/A-cdk2 complexes. Interestingly, the activity of cyclin-cdk2 complexes is strongly repressed in the presence of PKC and p42/44 MAPK inhibitors. In conclusion, we demonstrated that the thyroid hormones could modulate different signaling pathways that are able to control cell-cycle progression, mainly during G1/S transition.

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Drug-induced and postnatal hypothyroidism impairs the accumulation of diacylglycerol in liver and liver cell plasma membranes

Cited by 11 publications

References 40 publications

Metabolomic profile of patients on levothyroxine treatment for hypothyroidism

Metabolomic profile of patients on levothyroxine treatment for hypothyroidism

Fluoride Exposure Induces Inhibition of Sodium-and Potassium-Activated Adenosine Triphosphatase (Na+, K+-ATPase) Enzyme Activity: Molecular Mechanisms and Implications for Public Health

Thyroid hormones regulate DNA‐synthesis and cell‐cycle proteins by activation of PKCα and p42/44 MAPK in chick embryo hepatocytes

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