Transforming Growth Factor β1 (TGF-β1) Activates Hepcidin mRNA Expression in Hepatocytes

Chen, Simeng; Feng, Tingting; Spasić, Maja Vujić; Altamura, Sandro; Breitkopf‐Heinlein, Katja; Altenöder, Jutta; Weiss, Thomas S.; Dooley, Steven; Muckenthaler, Martina U.

doi:10.1074/jbc.m115.691543

Cited by 31 publications

(24 citation statements)

References 57 publications

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“…Another host mechanism to limit NTBI availability under inflammatory conditions is to block cellular iron egress by reducing ferroportin expression82. This inflammation-induced reduction of ferroportin is mainly driven by upregulation of hepcidin transcription via IL-6R-activated JAK/STAT3-signalling (Figure 2, Table 1), and via TGF-β1−TGF-β1R-mediated activation of SMAD signalling, which is distinct from BMP6-induced SMAD signalling83. Alternatively, ferroportin reduction is also controlled by hepcidin-independent mechanisms, such as signalling via Toll-like receptors 2 and 6, allowing for a rapid systemic response under inflammatory conditions84.…”

Section: Iron and The Pathophysiology Of Diseasementioning

confidence: 99%

Targeting iron metabolism in drug discovery and delivery

Crielaard

Lammers

Rivella

2017

Nat Rev Drug Discov

279

205

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Iron fulfils a central role in many essential biochemical processes in human physiology, which makes proper processing of iron crucial. Although iron metabolism is subject to relatively strict physiological control, in recent years numerous disorders, such as cancer and neurodegenerative diseases, have been linked to deregulated iron homeostasis. Because of its involvement in the pathogenesis of these diseases, iron metabolism constitutes a promising and largely unexploited therapeutic target for the development of new pharmacological treatments. Several iron metabolism-targeted therapies are already under clinical evaluation for haematological disorders, and these and newly developed therapeutic agents will likely have substantial benefit in the clinical management of iron metabolism-associated diseases, for which few efficacious treatments are often available.

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Section: Iron and The Pathophysiology Of Diseasementioning

confidence: 99%

Targeting iron metabolism in drug discovery and delivery

Crielaard

Lammers

Rivella

2017

Nat Rev Drug Discov

279

205

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“…Again, this is a postulation and remains to be proven. Note that systemic hepcidin levels are not only determined by systemic and hepatocellular iron but also by hypoxia [53], erythropoiesis [54], inflammation (IL-6, TGF-β1) [55], diurnal/circadian rhythm [42], growth hormone [42], tissue specificity, gluconeogenic signals [56] and pathological status [8]. Thus, it is possible that the disconnect between HAMP mRNA and peptide levels (particularly in the hepatocytes) exist to accommodate the alterations in cellular and physiological conditions, and thereby contribute to the fine tuning of hepcidin in response to the aforementioned factors.…”

Section: Discussionmentioning

confidence: 99%

Hepcidin secretion was not directly proportional to intracellular iron-loading in recombinant-TfR1 HepG2 cells: short communication

et al. 2020

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Hepcidin is the master regulator of systemic iron homeostasis and its dysregulation is observed in several chronic liver diseases. Unlike the extracellular iron-sensing mechanisms, the intracellular iron-sensing mechanisms in the hepatocytes that lead to hepcidin induction and secretion are incompletely understood. Here, we aimed to understand the direct role of intracellular iron-loading on hepcidin mRNA and peptide secretion using our previously characterised recombinant HepG2 cells that over-express the cell-surface iron-importer protein transferrin receptor-1. Gene expression of hepcidin (HAMP) was determined by real-time PCR. Intracellular iron levels and secreted hepcidin peptide levels were measured by ferrozine assay and immunoassay, respectively. These measurements were compared in the recombinant and wild-type HepG2 cells under basal conditions at 30 min, 2 h, 4 h and 24 h. Data showed that in the recombinant cells, intracellular iron content was higher than wild-type cells at 30 min (3.1-fold, p < 0.01), 2 h (4.6-fold, p < 0.01), 4 h (4.6-fold, p < 0.01) and 24 h (1.9-fold, p < 0.01). Hepcidin (HAMP) mRNA expression was higher than wild-type cells at 30 min (5.9-fold; p = 0.05) and 24 h (6.1fold; p < 0.03), but at 4 h, the expression was lower than that in wild-type cells (p < 0.05). However, hepcidin secretion levels in the recombinant cells were similar to those in wild-type cells at all time-points, except at 4 h, when the level was lower than wild-type cells (p < 0.01). High intracellular iron in recombinant HepG2 cells did not proportionally increase hepcidin peptide secretion. This suggests a limited role of elevated intracellular iron in hepcidin secretion.

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“…Trying to explain this phenomenon in humans we conjecture on a possible negative feedback mechanism that limits liver fibrosis. TGF-b1 was recently recognized as an activator of hepcidin mRNA expression in isolated human hepatocytes [42]. Hepcidin maintains serum iron concentration by controlling dietary uptake of iron from duodenal enterocytes.…”

Section: Discussionmentioning

confidence: 99%

The immunoreactivity of TGF-b1 in non-alcoholic fatty liver disease

Kempiński¹,

Neubauer²,

Poniewierka³

et al. 2019

Folia Histochem Cytobiol.

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Introduction. Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease which becomes a rapidly growing health problem in the Western countries. The development of the disease is most often connected to obesity. NAFLD is also considered as the hepatic manifestation of metabolic syndrome. Transforming growth factor b1 (TGF-b1) plays an important role in the pathogenesis of liver fibrosis, being involved in activation of hepatic stellate cells, stimulation of collagen gene transcription, and suppression of matrix metalloproteinase expression. The objective of the study was to evaluate by immunohistochemistry the expression of TGF-b1 in the liver tissue of NAFLD patients and correlate it with anthropometric, biochemical and routine histological parameters. Material and methods. The study group consisted of 48 patients with diagnosed NAFLD. Liver steatosis, NAFLD Activity Score (NAS) and METAVIR score of fibrosis were evaluated in liver biopsies. The immunoreactivity of TGF-b1 was evaluated semi-quantitatively separately in portal, septal, lobular hepatocytic and lobular sinusoidal liver compartments. The results were analyzed in regard to patients' clinical and biochemical parameters. Results. Neither steatosis nor NAS correlated with TGF-b1 expression in any liver compartment, whereas METAVIR score of fibrosis was associated with increased immunoreactivity of TGF-b1 in most of the studied liver compartments. TGF-b1 immunoreactivity showed positive correlation with patients' age and its expression in septal compartment disclosed positive correlation with body mass index, and waist and hip circumference. Hyaluronic acid serum level was positively and iron concentration was negatively associated with TGF-b1 expression in the selected consecutive liver compartments. Conclusions. The immunohistochemical expression of TGF-b1 may be complementary to routine methods of liver fibrosis evaluation.

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Transforming Growth Factor β1 (TGF-β1) Activates Hepcidin mRNA Expression in Hepatocytes

Cited by 31 publications

References 57 publications

Targeting iron metabolism in drug discovery and delivery

Targeting iron metabolism in drug discovery and delivery

Hepcidin secretion was not directly proportional to intracellular iron-loading in recombinant-TfR1 HepG2 cells: short communication

The immunoreactivity of TGF-b1 in non-alcoholic fatty liver disease

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