Inhibition of hepcidin transcription by growth factors

Department of Pathology, University of California, Los Angeles, CA 90095-1690, USA.
Hepatology (Impact Factor: 11.06). 07/2012; 56(1):291-9. DOI: 10.1002/hep.25615
Source: PubMed


The hepatic peptide hormone hepcidin controls the duodenal absorption of iron, its storage, and its systemic distribution. Hepcidin production is often insufficient in chronic hepatitis C and alcoholic liver disease, leading to hyperabsorption of iron and its accumulation in the liver. Hepatocyte growth factor (HGF) and epidermal growth factor (EGF) mediate hepatic regeneration after liver injury. We examined the effect of these growth factors on hepcidin synthesis by hepatocytes. HGF and EGF treatment of primary mouse hepatocytes, as well as EGF administration in mice, suppressed hepcidin messenger RNA (mRNA) synthesis. The suppression of hepcidin by these growth factors was transcriptional, and was mediated by a direct effect of HGF and EGF on the bone morphogenetic protein (BMP) pathway regulating hepcidin synthesis. We further show that growth factors interfered with nuclear localization of activated sons of mothers against decapentaplegic (Smad) and increased the nuclear pool of the BMP transcriptional corepressor TG-interacting factor (TGIF). In a kinase screen with small-molecule kinase inhibitors, inhibitors in the PI3 kinase pathway and in the mitogen-activated ERK kinase/extracellular signal-regulated kinase (MEK/ERK) pathway prevented HGF suppression of hepcidin in primary mouse hepatocytes. CONCLUSION: HGF and EGF suppress hepatic hepcidin synthesis, in part through PI3 kinase MEK/ERK kinase pathways which may be modulating the nuclear localization of BMP pathway transcriptional regulators including activated Smads1/5/8 and the corepressor TGIF. EGF, HGF, and possibly other growth factors that activate similar pathways may contribute to hepcidin suppression in chronic liver diseases, promote iron accumulation in the liver, and exacerbate the destructive disease processes.

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    • "HGF's inhibitory activity on Hepcidin expression can be suppressed by pre-treatment with small molecule inhibitors of Met (PHA665752), MEK1/2 (U0126), or PI3Kinase (LY2940021) [24]. Furthermore intraperitoneal injection of EGF in wild type mice reduces the induction of Hepcidin expression in response to iron loading [24]. Given these findings , we propose that SU6668, GTP 14564, AG1296, AS252424, 10058- F, and pterostilbene enhance Hepcidin transcript levels in HepG2 cells by inhibiting growth-factor dependent signaling. "
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    ABSTRACT: Hepcidin, a peptide hormone produced in the liver, decreases intestinal iron absorption and macrophage iron release via effects on ferroportin. Bone morphogenic protein and Stat3 signaling regulate Hepcidin's transcription. Hepcidin is a potential drug target for patients with iron overload syndromes because its levels are inappropriately low in these individuals. To generate a tool for identifying small molecules that modulate Hepcidin expression, we stably transfected human hepatocytes (HepG2) cells with a reporter construct containing 2.7 kb of the human Hepcidin promoter upstream of a firefly reporter gene. We used high throughput methods to screen 10,169 chemicals in duplicate for their effect on Hepcidin expression and cell viability. Regulators were identified as chemicals that caused a change > 3 standard deviations above or > 1 standard deviation below the mean of the other chemicals (z-score > 3 or < 1), while not adversely affecting cell viability, quantified by fluorescence assay. Following validation assays, we identified 16 chemicals in a broad range of functional classes that promote Hepcidin expression. All of the chemicals identified increased expression of bone morphogenic protein-dependent and/or Stat3-dependent genes, however none of them strongly increased phosphorylation of Smad1,5,8 or Stat3.
    Blood Cells Molecules and Diseases 12/2014; 53(4). DOI:10.1016/j.bcmd.2014.06.002 · 2.65 Impact Factor
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    • "A number of other hormones, growth factors and signaling pathways have recently been implicated in hepcidin regulation including testosterone, estrogen, hepatocyte growth factor (HGF), epidermal growth factor (EGF), endoplasmic reticulum stress, gluconeogenic signals and the Ras/RAF and mTOR signaling pathways (Oliveira et al., 2009; Vecchi et al., 2009, 2014; Goodnough et al., 2012; Hou et al., 2012; Yang et al., 2012; Guo et al., 2013; Latour et al., 2014; Mleczko-Sanecka et al., 2014). Notably, the majority of these pathways appear to regulate hepcidin through an intersection with the BMP-SMAD pathway at some level (Goodnough et al., 2012; Guo et al., 2013; Latour et al., 2014; Mleczko-Sanecka et al., 2014) (Figure 1). "
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    ABSTRACT: Mutations in hemojuvelin (HJV) are the most common cause of the juvenile-onset form of the iron overload disorder hereditary hemochromatosis. The discovery that HJV functions as a co-receptor for the bone morphogenetic protein (BMP) family of signaling molecules helped to identify this signaling pathway as a central regulator of the key iron hormone hepcidin in the control of systemic iron homeostasis. This review highlights recent work uncovering the mechanism of action of HJV and the BMP-SMAD signaling pathway in regulating hepcidin expression in the liver, as well as additional studies investigating possible extra-hepatic functions of HJV. This review also explores the interaction between HJV, the BMP-SMAD signaling pathway and other regulators of hepcidin expression in systemic iron balance.
    Frontiers in Pharmacology 05/2014; 5:104. DOI:10.3389/fphar.2014.00104 · 3.80 Impact Factor
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    • "Total RNA was isolated from liver and analyzed by real-time RT-PCR as described previously [25]. "
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    ABSTRACT: Anemia of cancer (AC) may contribute to cancer-related fatigue and impair quality of life. Improved understanding of the pathogenesis of AC could facilitate better treatment, but animal models to study AC are lacking. We characterized four syngeneic C57BL/6 mouse cancers that cause AC. Mice with two different rapidly-growing metastatic lung cancers developed the characteristic findings of anemia of inflammation (AI), with dramatically different degrees of anemia. Mice with rapidly-growing metastatic melanoma also developed a severe anemia by 14 days, with hematologic and inflammatory parameters similar to AI. Mice with a slow-growing peritoneal ovarian cancer developed an iron-deficiency anemia, likely secondary to chronically impaired nutrition and bleeding into the peritoneal cavity. Of the four models, hepcidin mRNA levels were increased only in the milder lung cancer model. Unlike in our model of systemic inflammation induced by heat-killed Brucella abortus, ablation of hepcidin in the ovarian cancer and the milder lung cancer mouse models did not affect the severity of anemia. Hepcidin-independent mechanisms play an important role in these murine models of AC.
    PLoS ONE 03/2014; 9(3):e93283. DOI:10.1371/journal.pone.0093283 · 3.23 Impact Factor
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