Regulatory expression of bone morphogenetic protein 6 by 2,2′-dipyridyl

Noguchi, Taiki; Ikeda, Mayuko; Murakami, Masaru; Masuzawa, Mikio; Imamura, Toru; Hashimoto, Osamu; Matsui, Tohru; Funaba, Masayuki

doi:10.1016/j.bbagen.2020.129610

Cited by 11 publications

(18 citation statements)

References 62 publications

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“…Recently, Nrf2 has been suggested as a potential key molecule in mediating iron sensing and controlling BMP6 in LSECs ( 38 ). Moreover, another study demonstrated a strong dependence of BMP6 expression in murine ECs in response to iron in the absence of serum ( 36 ). We also noticed that BMP6 expression in HUVECs was stronger modulated in the presence of low serum (2% versus 10% FCS) (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…Although the role of both LSECs and ECs in systemic iron regulation has been only marginally studied, a few studies on the blood–brain barrier and retina suggest that they may be involved in iron sensing and transport ( 32 , 33 ). Moreover, ECs are highly sensitive to iron changes ( 34 , 35 , 36 ) and, finally, they secrete the autocrine protein BMP-binding endothelial regulator (BMPER), able to antagonize BMP activity and regulate hepcidin ( 37 ). Finally, a recent study provided the first insights into molecular iron sensing by ECs.…”

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confidence: 99%

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Bone morphogenetic protein 6–mediated crosstalk between endothelial cells and hepatocytes recapitulates the iron-sensing pathway in vitro

Wang

Chen

et al. 2021

Journal of Biological Chemistry

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Liver sinusoidal endothelial cell–derived bone morphogenetic protein 6 (BMP6) and the BMP6–small mothers against decapentaplegic homolog (SMAD) signaling pathway are essential for the expression of hepcidin, the secretion of which is considered the systemic master switch of iron homeostasis. However, there are continued controversies related to the strong and direct suppressive effect of iron on hepatocellular hepcidin in vitro in contrast to in vivo conditions. Here, we directly studied the crosstalk between endothelial cells (ECs) and hepatocytes using in vitro coculture models that mimic hepcidin signaling in vivo . Huh7 cells were directly cocultured with ECs, and EC conditioned media (CM) were also used to culture Huh7 cells and primary mouse hepatocytes. To explore the reactions of ECs to surrounding iron, they were grown in the presence of ferric ammonium citrate and heme, two iron-containing molecules. We found that both direct coculture with ECs and EC-CM significantly increased hepcidin expression in Huh7 cells. The upstream SMAD pathway, including phosphorylated SMAD1/5/8, SMAD1, and inhibitor of DNA binding 1, was induced by EC-CM, promoting hepcidin expression. Efficient blockage of this EC-mediated hepcidin upregulation by an inhibitor of the BMP6 receptor ALK receptor tyrosine kinase 2/3 or BMP6 siRNA identified BMP6 as a major hepcidin regulator in this coculture system, which highly fits the model of hepcidin regulation by iron in vivo . In addition, EC-derived BMP6 and hepcidin were highly sensitive to levels of not only ferric iron but also heme as low as 500 nM. We here establish a hepatocyte–endothelial coculture system to fully recapitulate iron regulation by hepcidin using EC-derived BMP6.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Bone morphogenetic protein 6–mediated crosstalk between endothelial cells and hepatocytes recapitulates the iron-sensing pathway in vitro

Wang

Chen

et al. 2021

Journal of Biological Chemistry

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“…To determine the factors affecting hepcidin transcription, we performed SSRT, a screening method to identify factors regulating the transcription of reporter genes, 25 in HepG2 cells (Figure 1A). We used hepcidin (−2018)‐luc as a reporter, because transcriptional regulation of murine hepcidin has been well characterized.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional activation of hepcidin by the microphthalmia/transcription factor E family

Matsumura

Murakami

Funaba

2022

Cell Biochemistry & Function

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Hepcidin negatively regulates the circulating iron levels by inhibiting the intestinal absorption of iron as well as iron release from macrophages. Hepcidin activity is largely determined by its expression, which is regulated at the transcriptional level. Hepcidin transcription is induced not only by the iron status‐related bone morphogenetic protein (BMP)‐2/6, but also by inflammatory cytokines, such as interleukin (IL)‐1β and IL‐6. The present study reveals that the microphthalmia (MiT)/transcription factor E (TFE) family members are novel regulators of hepcidin transcription. Melanocyte‐inducing transcription factor (MITF)‐A, a member of the MiT/TFE family, was identified as a positive regulator of hepcidin transcription via stimulus screening for transcription regulators. An E‐box (5′‐CATGTG‐3′) spanning nt‐645 to nt‐640 of the murine hepcidin promoter was identified as an MITF‐A‐responsive element. Responsiveness to MITF‐A on hepcidin transcription decreased when the cells were stimulated with BMP2 or IL‐1β. These results suggest a functional interaction between the MITF pathway and BMP‐ or IL‐1β‐mediated signaling. TFEB and TFE3, members of the MiT/TFE family, also stimulated hepcidin transcription, but the main region responsible for hepcidin transcription was distinct from that induced by MITF‐A. The region spanning nt‐581 to nt‐526 was involved in TFEB/TFE3‐mediated hepcidin transcription. Considering that members of the MiT/TFE family act as regulators of starvation‐induced lysosomal biogenesis, hepcidin expression may be controlled by additional pathways apart from those identified so far.

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“…[ 92 ] Although the role of both LSECs and endothelial cells (EC) in systemic iron regulation has been only marginally studied, a few studies on the blood-brain barrier and retina suggest that they may be involved in iron sensing and transport. [ 160 , 161 ] Moreover, ECs are highly sensitive to iron changes [ 162 , 164 ] and, finally, they secrete the autocrine protein BMP-binding endothelial cell precursor-derived regulator (BMPER), able to antagonize BMPs activity and regulate hepcidin. [ 165 ] Finally, a recent study provided the first insights into molecular iron sensing by ECs.…”

Section: Novel Insights Into the Crosstalk Of Macrophages Endothelial...mentioning

confidence: 99%

Novel insights into alcoholic liver disease: Iron overload, iron sensing and hemolysis

Mueller

Chen

Mueller

et al. 2022

Journal of Translational Internal Medicine

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The liver is the major target organ of continued alcohol consumption at risk and resulting alcoholic liver disease (ALD) is the most common liver disease worldwide. The underlying molecular mechanisms are still poorly understood despite decades of scientific effort limiting our abilities to identify those individuals who are at risk to develop the disease, to develop appropriate screening strategies and, in addition, to develop targeted therapeutic approaches. ALD is predestined for the newly evolving translational medicine, as conventional clinical and health care structures seem to be constrained to fully appreciate this disease. This concept paper aims at summarizing the 15 years translational experience at the Center of Alcohol Research in Heidelberg, namely based on the long-term prospective and detailed characterization of heavy drinkers with mortality data. In addition, novel experimental findings will be presented. A special focus will be the long-known hepatic iron accumulation, the somewhat overlooked role of the hematopoietic system and novel insights into iron sensing and the role of hepcidin. Our preliminary work indicates that enhanced red blood cell (RBC) turnover is critical for survival in ALD patients. RBC turnover is not primarily due to vitamin deficiency but rather to ethanol toxicity directly targeted to erythrocytes but also to the bone marrow stem cell compartment. These novel insights also help to explain long-known aspects of ALD such as mean corpuscular volume of erythrocytes (MCV) and elevated aspartate transaminase (GOT/AST) levels. This work also aims at identifying future projects, naming unresolved observations, and presenting novel hypothetical concepts still requiring future validation.

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Regulatory expression of bone morphogenetic protein 6 by 2,2′-dipyridyl

Cited by 11 publications

References 62 publications

Bone morphogenetic protein 6–mediated crosstalk between endothelial cells and hepatocytes recapitulates the iron-sensing pathway in vitro

Bone morphogenetic protein 6–mediated crosstalk between endothelial cells and hepatocytes recapitulates the iron-sensing pathway in vitro

Transcriptional activation of hepcidin by the microphthalmia/transcription factor E family

Novel insights into alcoholic liver disease: Iron overload, iron sensing and hemolysis

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