Academic journal article Genetics

Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis Elegans

Academic journal article Genetics

Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis Elegans

Article excerpt

DUE to its essential roles in numerous cellular functions across nearly all living organisms, including oxygen transport, electron transport, DNA synthesis, and enzyme catalysis, exploring how iron is stored and regulated has been a growing focus in numerous fi elds. Dietary iron is absorbed primarily by duodenal enterocytes via the divalent metal-ion transporter 1 (DMT1) after it is reduced at the apical membrane. Subsequently, it is either stored in ferritin, which dynamically regulates iron sequestration, storage, and release or it is transported from enterocytes into the blood stream via the basolateral transporter ferroportin (Fleming and Ponka 2012). Consequently, the total amount of iron in the body is determined by its intake and storage, which are all finely regulated by many factors and signaling pathways at various levels (Fleming and Ponka 2012; Hubler et al. 2015), many of which not entirely understood.

Human epidemiology studies revealed that elevated levels of ferritin may be an indication of systemic iron overload (Cook et al. 1974; Zimmermann 2008) and are positively associated with obesity (Wenzel et al. 1962; Gillum 2001; Iwasaki et al. 2005) and obesity-related diseases such as diabetes, hypertension, dyslipidaemia, or nonalcoholic fatty liver disease (Jehn et al. 2004; Bozzini et al. 2005; Mascitelli et al. 2009; Dongiovanni et al. 2011; Kim et al. 2011; see Zafon et al. 2010 for review). Precisely why elevations in ferritin levels or systemic iron overload are associated with these conditions is not entirely clear, with potential explanations ranging from excess iron causing oxidative stress, endoplasmic reticulum (ER) stress, inflammation, and dysfunction of adipose tissue (Hubler et al. 2015; Nikonorov et al. 2015).

When including other environmental or dietary factors, the relationship between obesity, its comorbidities, and iron becomes more complex. Iron is required for the adipogenesis of the 3T3-L1 preadipocytes (Moreno-Navarrete et al. 2014a), and it increases the rate of adipocyte lipolysis (Rumberger et al. 2004). In the mouse liver, iron significantly upregulates the transcripts of seven enzymes in the cholesterol biosynthesis pathway, resulting into cholesterol accumulation. This occurs independently of the conserved lipogenic regulator SREBP2 (Graham et al. 2010). The combination of iron and lipid-rich diet may exacerbate this situation because lipids also cause oxidative and ER stress, as well as inflammation. Collectively, this helps explain why dietary iron supplementation concurrent with a high-fat diet (HFD) greatly increases adiposity in rats (Tinkov et al. 2013), as well as hepatic fat accumulation in the liver of mice (Choi et al. 2013). The association seems to also hold true in reverse. Several studies found that reduction of iron by several different methods led to amelioration of adiposity and improvement of obesity and obesity-related diseases (Zhang et al. 2005; Fleming and Ponka 2012; Tajima et al. 2012; Moreno-Navarrete et al. 2014a,b). Unfortunately, the mechanisms of this association between iron and lipid accumulation or obesity remain largely unclear.

Though human clinical studies would likely shed a great deal of light on this relationship, such studies are not always practical or even possible. Alternatively, Caenorhabditis elegans may offer an ideal model due to the highly conserved nature of many proteins involved in iron homeostasis, including iron uptake (SMF-3, a homolog of DMT1), storage (FTN-1 and FTN-2, encoding ferritin), and export (FPN-1.1, FPN-1.2, FPN-1.3, encoding ferroportin), as well as potential orthologs for DCYTB ferrireductase and hephaestin multicopper oxidase (Anderson and Leibold 2014). Moreover, C. elegans FTN-1 and FTN-2 are more similar to human FTH than to FTL, and both FTN-1 and FTN-2 contain ferroxidase active-site residues (Gourley et al. 2003). Under iron overload, the expression of ftn-1 gene and protein, and to a lesser extent ftn-2, are induced; in contrast, the expression of SMF-3 is suppressed to reduce iron uptake (Gourley et al. …

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