Cytochromes P450: Roles in Diseases

Pikuleva, Irina A.; Waterman, Michael R.

doi:10.1074/jbc.r112.431916

Cited by 93 publications

(55 citation statements)

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“…Cytochromes P450 are hemoproteins containing a heme cofactor and are known to be involved in numerous processes, such as lipid metabolism and detoxification (Pikuleva and Waterman 2013). Within 77 of 81 tested cytochrome P450 genes, we found that only cyp-23A1, like sgk-1, synergistically, but oppositely, regulated iron and lipid metabolism.…”

Section: Discussionmentioning

confidence: 67%

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

Wang¹,

Jiang

et al. 2016

Genetics

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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...

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Section: Discussionmentioning

confidence: 67%

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

Wang¹,

Jiang

et al. 2016

Genetics

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“…The gene CYP4A22, another PPAR signaling gene upregulated in postpubertal heifers, belongs to a cytochrome P450 family that is important for steroid synthesis (Pikuleva and Waterman, 2013). Pituitary gland expression of a cytochrome P450 family member suggests that this aromatase would be related to the mechanisms of action of gonadal steroids on pituitary gland differentiation and secretion, as shown by immunohistochemistry in rats (Carretero et al, 2003).…”

Section: Pituitary Gland Genes: Differentially Expressed and Interactingmentioning

confidence: 99%

Global differential gene expression in the pituitary gland and the ovaries of pre- and postpubertal Brahman heifers

Nguyen¹,

Reverter²,

Cánovas³

et al. 2017

Journal of Animal Science

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ABSTRACT:To understand genes, pathways, and networks related to puberty, we characterized the transcriptome of two tissues: the pituitary gland and ovaries. Samples were harvested from pre-and postpubertal Brahman heifers (same age group). Brahman heifers (Bos indicus) are older at puberty compared with Bos taurus, a productivity issue. With RNA sequencing, we identified differentially expressed (DEx) genes and important transcription factors (TF) and predicted coexpression networks. The number of DEx genes detected in the pituitary gland was 284 (P < 0.05), and VWC2L was the most DEx gene (fold change = 4.12, P = 0.01). The gene VWC2L promotes bone mineralization through transforming growth factor-β (TGFβ) signaling. Further studies of the link between bone mineralization and puberty could target VWC2L. In ovaries, 3,871 genes were DEx (P < 0.05). Four highly DEx genes were noteworthy for their function: SLC6A13 (a γ-aminobutyric acid [GABA] transporter), OXT (oxytocin), and NPY (neuropeptide Y) and its receptor NPY2R. These genes had higher ovarian expression in postpubertal heifers. The GABA and its receptors and transporters were expressed in the ovaries of many mammals, suggesting a role for this pathway beyond the brain. The OXT pathway has been known to influence the timing of puberty in rats, via modulation of GnRH. The effects of NPY at the hypothalamus, pituitary gland, and ovaries have been documented. Neuropeptide Y and its receptors are known factors in the release of GnRH, similar to OXT and GABA, although their roles in ovarian tissue are less clear. Pathways previously related to puberty such as TGFβ signaling (P = 6.71 × 10 −5 ), Wnt signaling (P = 4.1 × 10 −2 ), and peroxisome proliferator-activated receptor (PPAR) signaling (P = 4.84 × 10 −2 ) were enriched in our data set. Seven genes were identified as key TF in both tissues: HIC2, ZIC4, ZNF219, ZSCAN26, LHX1, OLIG1, and a novel gene. An ovarian subnetwork created with TF and significant ovarian DEx genes revealed five zinc fingers as regulators: ZNF507, ZNF12, ZNF512, ZNF184, and ZNF432. Recent work of hypothalamic gene expression also pointed to zinc fingers as TF for bovine puberty. Although some zinc fingers may be ubiquitously expressed, the identification of DEx genes in common across tissues points to key regulators of puberty. The hypothalamus and pituitary gland had eight DEx genes in common. The hypothalamus and ovaries had 89 DEx genes in common. The pituitary gland and ovaries had 48 DEx genes in common. Our study confirmed the complexity of puberty and suggested further investigation on genes that code zinc fingers.

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“…This field has a long history, with early hypotheses about mobile forms of reactive oxygen being involved and moving on to the concept of a high-valent ironoxygen complex solving the problem of spin-forbidden reactions of oxygen. Recent work on the intermediate Compound I (11,16) is discussed, including alternative proposals.…”

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confidence: 99%

“…The fourth minireview in the series, written by Irina A. Pikuleva and Michael R. Waterman (16), deals with the roles of P450s in diseases (aside from the prominent roles for P450s in drug metabolism) (17). Numerous examples of genetic defects in the metabolism of sex steroids, glucocorticoids, cholesterol, bile acids, vitamin D, and eicosanoids are now understood in the context of our knowledge of P450s.…”

mentioning

confidence: 99%

New Trends in Cytochrome P450 Research at the Half-Century Mark

Guengerich

2013

Journal of Biological Chemistry

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Cytochrome P450 enzymes have major roles in the metabolism of steroids, drugs, carcinogens, eicosanoids, and numerous other chemicals. The P450s are collectively considered the most diverse catalysts known in biochemistry, although they operate from a basic structural fold and catalytic mechanism. The four minireviews in this thematic series deal with the unusual aspects of catalytic reactions and electron transfer pathway organization, the structural diversity of P450s, and the expanding roles of P450s in disease and medicine.

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Cytochromes P450: Roles in Diseases

Cited by 93 publications

References 95 publications

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

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

Global differential gene expression in the pituitary gland and the ovaries of pre- and postpubertal Brahman heifers

New Trends in Cytochrome P450 Research at the Half-Century Mark

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