Iron-dependent BMP6 Regulation in Liver Sinusoidal Endothelial Cells Is Instructed by Hepatocyte-derived Secretory Signals

Colucci, Silvia; Altamura, Sandro; Marques, Oriana; Müdder, Katja; Agarvas, Anand R.; Hentze, Matthias W.; Muckenthaler, Martina U.

doi:10.1097/hs9.0000000000000773

Cited by 7 publications

(10 citation statements)

References 18 publications

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“…Our data are partially consistent with both models, reporting a robust ROS‐dependent induction of Bmp6 in NPCs cultures and an additional activation imposed on hepatocytes. Some discrepancies between our findings and the data of Colucci et al 13 may arise due to differences in LSEC purification methods (we cultured LSECs with other NPCs and FACS‐sorted them for analysis, whereas Colucci et al applied two‐step stringent isolation protocol before LSEC seeding) and thus the potential contribution of other NPCs (Kupffer or stellate cells) to Bmp6 transcriptional responses in our hands. Nevertheless, we propose that Bmp6 induction in the presence of hepatocytes partially requires p38 MAPK signaling.…”

Section: Discussioncontrasting

confidence: 97%

“…47 Finally, our study adds valuable data to the still ongoing debate of whether Bmp6 induction in LSECs is cell autonomous 10 or requires the presence of hepatocyte-derived signals. 13 Our data are partially consistent with both models, reporting a robust ROS-dependent induction of Bmp6 in NPCs cultures and an additional activation imposed on hepatocytes. Some discrepancies between our findings and the data of Colucci et al 13…”

Section: Discussionsupporting

confidence: 88%

“…3.5 | LSECs exhibit a stronger induction of the Bmp6 in co-culture with hepatocytes in p38 MAPK-dependent manner Previous reports 7,13 and our aging model suggested that the regulation of Bmp6 transcription in LSECs may be affected by hepatocyte iron levels. Although in our hands primary LSECs induced Bmp6 expression upon iron exposure in a cell-autonomous manner, we aimed to verify if this response could be modified by the presence of hepatocytes.…”

Section: Induction Of Bmp6 Gene Expression By Iron Is Not Dependent O...mentioning

confidence: 90%

“…7 Consistent with these observations, a recent study demonstrated that primary LSECs induce Bmp6 upon iron exposure only in the presence of hepatocyte-derived protein factor and fail to increase Bmp6 transcription upon pharmacological NRF2 activation. 13 Taken together, the above observations suggest that the precise signaling mechanisms governing the Bmp6 transcriptional response to iron-rich conditions remain not completely understood.…”

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confidence: 99%

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Iron‐triggered signaling via ETS1 and the p38/JNK MAPK pathway regulates Bmp6 expression

Zurawska,

Jończy,

Niklewicz

et al. 2024

American J Hematol

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BMP6 is an iron‐sensing cytokine whose transcription in liver sinusoidal endothelial cells (LSECs) is enhanced by high iron levels, a step that precedes the induction of the iron‐regulatory hormone hepcidin. While several reports suggested a cell‐autonomous induction of Bmp6 by iron‐triggered signals, likely via sensing of oxidative stress by the transcription factor NRF2, other studies proposed the dominant role of a paracrine yet unidentified signal released by iron‐loaded hepatocytes. To further explore the mechanisms of Bmp6 transcriptional regulation, we used female mice aged 10–11 months, which are characterized by hepatocytic but not LSEC iron accumulation, and no evidence of systemic iron overload. We found that LSECs of aged mice exhibit increased Bmp6 mRNA levels as compared to young controls, but do not show a transcriptional signature characteristic of activated NFR2‐mediated signaling in FACS‐sorted LSECs. We further observed that primary murine LSECs derived from both wild‐type and NRF2 knock‐out mice induce Bmp6 expression in response to iron exposure. By analyzing transcriptomic data of FACS‐sorted LSECs from aged versus young mice, as well as early after iron citrate injections, we identified ETS1 as a candidate transcription factor involved in Bmp6 transcriptional regulation. By performing siRNA‐mediated knockdown, small‐molecule treatments, and chromatin immunoprecipitation in primary LSECs, we show that Bmp6 transcription is regulated by iron via ETS1 and p38/JNK MAP kinase‐mediated signaling, at least in part independently of NRF2. Thereby, these findings identify the new components of LSEC iron sensing machinery broadly associated with cellular stress responses.

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Section: Discussioncontrasting

confidence: 97%

Section: Discussionsupporting

confidence: 88%

Section: Induction Of Bmp6 Gene Expression By Iron Is Not Dependent O...mentioning

confidence: 90%

mentioning

confidence: 99%

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Iron‐triggered signaling via ETS1 and the p38/JNK MAPK pathway regulates Bmp6 expression

Zurawska,

Jończy,

Niklewicz

et al. 2024

American J Hematol

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“…However, LSECs in hemochromatosis Hjv KO mice express high Bmp6 levels despite being iron-deficient due to FPN1 stabilization by low hepatocyte hepcidin production, suggesting that other mechanisms are involved in Bmp6 upregulation [ 63 ]. Interestingly, a recent paper demonstrates that in the presence of iron, hepatocytes secrete a still-unknown protein that functions as a BMP6 activator, suggesting that cell-to-cell communication between hepatocytes and LSECs is essential for iron sensing and Bmp6 regulation [ 64 ]. Thus, hepcidin regulation by BMPs represents a beautiful example of the importance of intraorgan crosstalk between different cell types, such as hepatocytes and LSECs.…”

Section: Systemic Iron Homeostasis: the Hepcidin-ferroportin Axismentioning

confidence: 99%

Managing the Dual Nature of Iron to Preserve Health

Silvestri

Pettinato

Furiosi

et al. 2023

IJMS

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Because of its peculiar redox properties, iron is an essential element in living organisms, being involved in crucial biochemical processes such as oxygen transport, energy production, DNA metabolism, and many others. However, its propensity to accept or donate electrons makes it potentially highly toxic when present in excess and inadequately buffered, as it can generate reactive oxygen species. For this reason, several mechanisms evolved to prevent both iron overload and iron deficiency. At the cellular level, iron regulatory proteins, sensors of intracellular iron levels, and post-transcriptional modifications regulate the expression and translation of genes encoding proteins that modulate the uptake, storage, utilization, and export of iron. At the systemic level, the liver controls body iron levels by producing hepcidin, a peptide hormone that reduces the amount of iron entering the bloodstream by blocking the function of ferroportin, the sole iron exporter in mammals. The regulation of hepcidin occurs through the integration of multiple signals, primarily iron, inflammation and infection, and erythropoiesis. These signals modulate hepcidin levels by accessory proteins such as the hemochromatosis proteins hemojuvelin, HFE, and transferrin receptor 2, the serine protease TMPRSS6, the proinflammatory cytokine IL6, and the erythroid regulator Erythroferrone. The deregulation of the hepcidin/ferroportin axis is the central pathogenic mechanism of diseases characterized by iron overload, such as hemochromatosis and iron-loading anemias, or by iron deficiency, such as IRIDA and anemia of inflammation. Understanding the basic mechanisms involved in the regulation of hepcidin will help in identifying new therapeutic targets to treat these disorders.

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Iron homeostasis and insulin sensitivity: unraveling the complex interactions

Sobieska,

Buczyńska,

Krętowski

et al. 2024

Rev Endocr Metab Disord

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Diabetes has arisen as a noteworthy global health issue, marked by escalating incidence and mortality rates. Insulin, crucial for preserving euglycemia, acts as a vital energy provider for various tissues. Iron metabolism notably plays a significant role in the development of insulin resistance, a key factor in the onset of various metabolic disorders. The intricate interaction between iron and insulin signaling encompasses complex regulatory mechanisms at the molecular level, thereby impacting cellular reactions to insulin. The intricate interplay between insulin and glucagon, essential for precise regulation of hepatic glucose production and systemic glucose levels, may be influenced by certain microelements for instance zinc, copper, iron, boron, calcium, cobalt, chromium, iodine, magnesium and selenium. While significant progress has been achieved in elucidating the pathophysiological connections between iron overload and glucose metabolism, our understanding of the involvement of the Fenton reaction and oxidative stress in insulin resistance influencing many chronical conditions remains limited. Furthermore, the exploration of the multifaceted roles of insulin in the human body continues to be a subject of active investigation by numerous scientific researchers. This review comprehensively outlines the potential adverse impact of iron overload on insulin function and glucose metabolism. Additionally, we provide a synthesis of findings derived from various research domains, encompassing population studies, animal models, and clinical investigations, to scrutinize the multifaceted relationship between iron and insulin sensitivity. Moreover, we delineate instances of correlations between serum iron levels and various medical conditions, including the diabetes also gestational diabetes and obesity.

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Iron-dependent BMP6 Regulation in Liver Sinusoidal Endothelial Cells Is Instructed by Hepatocyte-derived Secretory Signals

Cited by 7 publications

References 18 publications

Iron‐triggered signaling via ETS1 and the p38/JNK MAPK pathway regulates Bmp6 expression

Iron‐triggered signaling via ETS1 and the p38/JNK MAPK pathway regulates Bmp6 expression

Managing the Dual Nature of Iron to Preserve Health

Iron homeostasis and insulin sensitivity: unraveling the complex interactions

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