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

Abstract

The trace element iron is crucial for living organisms, since it plays essential roles in numerous cellular functions. Systemic iron overload and the elevated level of ferritin, a ubiquitous intracellular protein that stores and releases iron to maintain the iron homeostasis in cells, has long been epidemiologically associated with obesity and obesity-related diseases. However, the underlying mechanisms of this association remain unclear. Here, using Caenorhabditis elegans, we show that iron overload induces the expression of sgk-1, encoding the serum and glucocorticoid-inducible kinase, to promote the level of ferritin and fat accumulation. Mutation of cyp-23A1, encoding a homolog of human cytochrome P450 CYP7B1 that is related to neonatal hemochromatosis, further enhances the elevated expression of ftn-1, sgk-1, and fat accumulation. sgk-1 positively regulates the expression of acs-20 and vit-2, genes encoding homologs of the mammalian FATP1/4 fatty acid transport proteins and yolk lipoproteins, respectively, to facilitate lipid uptake and translocation for storage under iron overload. This study reveals a completely novel pathway in which sgk-1 plays a central role to synergistically regulate iron and lipid homeostasis, offering not only experimental evidence supporting a previously unverified link between iron and obesity, but also novel insights into the pathogenesis of iron and obesity-related human metabolic diseases. KEYWORDS iron; serum and glucocorticoid inducible kinase SGK-1; lipid uptake; obesity; C. elegans D UE 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 fields. 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 w...

Zinc mediates the SREBP-SCD axis to regulate lipid metabolism in Caenorhabditis elegans

“…Surprisingly, we found that the expression of ftn-1 and smf-3, encoding ferritin and divalent metal-ion transporter 1 (DMT1), respectively, was reversely responsive to zinc concentration. Previous reports, including ours, show that the expression of the ftn-1 gene and protein are induced; in contrast, the expression of smf-3 is suppressed to reduce iron uptake under iron overload (56)(57)(58). QPCR confirmed that the mRNA expression of ftn-1 and smf-3 indeed displayed an opposite pattern in by guest, on September 25, 2020 www.jlr.org…”

Prohibitin depletion extends lifespan of a TORC2/SGK-1 mutant through autophagy

“…The increased presence of ERES indicates impaired lipid droplet and lipoprotein biogenesis, as evidenced by the reduced content of lipid and yolk observed in sgk-1 mutants (Figure 4A)(also visible in Figure S1). This agrees with the role of SGK-1 in lipogenesis and vitellogenesis in C. elegans [36, 86, 87]. Interaction of lipid droplets with yolk forming particles and vacuoles also appeared altered at day 1 of adulthood and abnormal myelinated structures were visible (Figure S7)(also visible in Figure S1).…”

“…Our TEM analysis showed that sgk-1 mutants are defective in lipid droplet and yolk/lipoprotein production, as well as pseudocelomic lipoprotein accumulation (Figure 4, S7 and S8) which is in concordance with the reduced lipid content and vitelogenesis observed in sgk-1 mutants [36, 86, 87] and with the regulation of lipogenesis by mTORC2 through SREBP1 [71]. Moreover, TORC2 in different systems has been linked to functions in different membrane-contact sites (MCS) such as ER-plasma membrane [24] and ER-mitochondria [89].…”

“…Here we show that depletion of key transcription factors involved in lipogenesis and cholesterol metabolism, NHR-8 and SBP-1 [65, 69, 70], further enhance phenotypes associated to sgk-1 mutants, including worm size reduction, developmental delay, and induction of the UPR mt (Figure 3D and S5). Similarly, impaired vitellogenesis is also observed in both nhr-8 and sgk-1 mutants [36, 65, 87]. These results show that altered lipogenesis or membrane cholesterol signaling contribute to mitochondrial stress and might be common processes regulated by SGK-1, NHR-8 and SBP-1.…”

Time to move the fat

“…Vitellogenins shuttle the lipids from somatic tissue to oocytes and embryos to support reproduction. Several other recent studies have revealed diverse roles for and regulation of vitellogenins (Goszczynski et al 2016;Seah et al 2016;Wang et al 2016). Previous work has also indicated a critical regulation of this process by the insulin/IGF-like signaling (IIS) pathway to coordinate nutrient availability and animal growth/development (DePina et al 2011).…”