Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent clinical reports indicate that impaired glucose tolerance is a common phenomenon in primary aldosteronism. Aldosterone stimulates NF-kappaB and activating protein-1 (AP-1) to cause oxidative injury. Elevated oxidative stress impairs insulin signaling. We recently showed that the heme oxygenase (HO) system lowers blood pressure (BP) in deoxycorticosterone-acetate (DOCA)+salt hypertension, a model of primary aldosteronism. However, the effect of the HO system on insulin sensitivity in this model remains largely unclear. Here we report the effects of the HO-inducer hemin and the HO-blocker [chromium mesoporphyrin (CrMP)] on insulin sensitivity/glucose metabolism. Our experimental design included the following 10 groups: (A) controls [(i) surgery-free or normal Sprague-Dawley (SD), (ii) uninephrectomized (UnX)-sham, (iii) UnX+salt (0.9%NaCl+0.2%KCl) and (iv) UnX+DOCA]; (B) DOCA+salt; (C) hemin+DOCA+salt; (D) hemin+CrMP+DOCA+salt; (E) CrMP+DOCA+salt; (F) vehicle-treated rats and (G) normal SD+hemin. Hemin therapy lowered BP and increased plasma insulin and the insulin-sensitizing protein adiponectin with slight but significant reduction of glycemia, while CrMP abolished the hemin effects. Furthermore, hemin improved intraperitoneal glucose and insulin tolerance, suggesting that although DOCA+salt-hypertensive rats were normoglycemic, insulin signaling may be impaired. In contrast, the HO-inhibitor CrMP aggravated insulin resistance and exacerbated glucose and insulin tolerance. Interestingly, the enhanced insulin sensitization in hemin-treated animals was accompanied by reduced urinary/gastrocnemius muscle 8-iso-prostaglandin F(2alpha) (8-isoprostane), inflammatory/oxidative transcription factors like NF-kappaB, AP-1, JNK, and heme content, whereas HO-1, HO-activity, cGMP, and plasma/gastrocnemius muscle antioxidants including bilirubin, ferritin, SOD, catalase, and the total antioxidant capacity were increased. Similarly, hemin enhanced pancreatic HO, cGMP, and cAMP but suppressed 8-isoprostane and attenuated pancreatic histopathological lesions including fibrosis, interstitial edema, acinar cell necrosis, vacuolization, and mononuclear cell infiltration, with corresponding improvement of insulin production. Our results suggest that impaired insulin signaling may be a forerunner to hyperglycemia in aldosteronism. By preserving pancreatic morphology, potentiating insulin signaling, and lowering BP, the HO system may prevent metabolic and cardiovascular complications in aldosteronism.
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PMID:The heme oxygenase system attenuates pancreatic lesions and improves insulin sensitivity and glucose metabolism in deoxycorticosterone acetate hypertension. 1986 34

Accumulating clinical evidence indicates that impaired glucose tolerance is a common phenomenon in essential hypertension. Although recent evidence underscores the role of heme-oxygenase (HO) in diabetes, its effects on insulin sensitivity and glucose metabolism in spontaneously hypertensive rat (SHR), a model of essential hypertension with characteristics of metabolic syndrome including insulin resistance/impaired glucose metabolism remains largely unclear. Here we report the effects of the HO inducer, hemin, and the HO blocker, chromium-mesoporphyrin on insulin sensitivity and glucose metabolism in SHRs. Adult SHRs were severely hypertensive but normoglycemic. Hemin therapy lowered blood pressure, increased plasma insulin, decreased glycemia, and enhanced insulin sensitivity by improving glucose tolerance (ip glucose tolerance test) and insulin tolerance (ip insulin tolerance test) but reduced insulin resistance (homeostasis model assessment index). These effects were accompanied by increased gastrocnemius muscle HO-1, HO activity, cGMP, cAMP alongside antioxidants including bilirubin, ferritin, superoxide dismutase, catalase, and the total antioxidant capacity, whereas oxidative/inflammatory mediators like 8-isoprostane, nuclear-factor-kappaB, activating-protein-1, activating-protein-2, c-Jun-NH2-terminal-kinase, and heme were abated. Furthermore, hemin reduced proteinuria/albuminuria and enhanced the depressed levels of adiponectin, AMP-activated protein-kinase, and glucose transporter-4 in SHRs, suggesting that although SHRs are normoglycemic, insulin signaling and renal function may be impaired. Contrarily, the HO inhibitor chromium-mesoporphyrin exacerbated oxidative stress, aggravated insulin resistance, glucose tolerance, insulin tolerance and nephropathy. Hemin also enhanced HO signaling in Wistar Kyoto and Sprague Dawley rats and increased insulin sensitivity albeit less intensely than in SHRs, suggesting greater selectivity of HO in SHRs with dysfunctional insulin signaling. These results suggest that perturbations of insulin signaling may be a forerunner to hyperglycemia in essential hypertension. By concomitantly potentiating insulin-sensitizing agents, suppressing insulin/glucose intolerance, and abating oxidative stress, HO inducers may prevent metabolic and cardiovascular complications in essential hypertension.
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PMID:Up-regulating the heme oxygenase system with hemin improves insulin sensitivity and glucose metabolism in adult spontaneously hypertensive rats. 2001 31

ZIP14 (slc39A14) is a zinc transporter induced in response to pro-inflammatory stimuli. ZIP14 induction accompanies the reduction in serum zinc (hypozincemia) of acute inflammation. ZIP14 can transport Zn(2+) and non-transferrin-bound Fe(2+) in vitro. Using a Zip14(-/-) mouse model we demonstrated that ZIP14 was essential for control of phosphatase PTP1B activity and phosphorylation of c-Met during liver regeneration. In the current studies, a global screening of ZIP transporter gene expression in response to LPS-induced endotoxemia was conducted. Following LPS, Zip14 was the most highly up-regulated Zip transcript in liver, but also in white adipose tissue and muscle. Using ZIP14(-/-) mice we show that ZIP14 contributes to zinc absorption from the gastrointestinal tract directly or indirectly as zinc absorption was decreased in the KOs. In contrast, Zip14(-/-) mice absorbed more iron. The Zip14 KO mice did not exhibit hypozincemia following LPS, but do have hypoferremia. Livers of Zip14-/- mice had increased transcript abundance for hepcidin, divalent metal transporter-1, ferritin and transferrin receptor-1 and greater accumulation of iron. The Zip14(-/-) phenotype included greater body fat, hypoglycemia and higher insulin levels, as well as increased liver glucose and greater phosphorylation of the insulin receptor and increased GLUT2, SREBP-1c and FASN expression. The Zip14 KO mice exhibited decreased circulating IL-6 with increased hepatic SOCS-3 following LPS, suggesting SOCS-3 inhibited insulin signaling which produced the hypoglycemia in this genotype. The results are consistent with ZIP14 ablation yielding abnormal labile zinc pools which lead to increased SOCS-3 production through G-coupled receptor activation and increased cAMP production as well as signaled by increased pSTAT3 via the IL-6 receptor, which inhibits IRS 1/2 phosphorylation. Our data show the role of ZIP14 in the hepatocyte is multi-functional since zinc and iron trafficking are altered in the Zip14(-/-) mice and their phenotype shows defects in glucose homeostasis.
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PMID:Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response (endotoxemia). 2311 Feb 40

Dietary iron supplementation is associated with increased appetite. Here, we investigated the effect of iron on the hormone leptin, which regulates food intake and energy homeostasis. Serum ferritin was negatively associated with serum leptin in a cohort of patients with metabolic syndrome. Moreover, the same inverse correlation was observed in mice fed a high-iron diet. Adipocyte-specific loss of the iron exporter ferroportin resulted in iron loading and decreased leptin, while decreased levels of hepcidin in a murine hereditary hemochromatosis (HH) model increased adipocyte ferroportin expression, decreased adipocyte iron, and increased leptin. Treatment of 3T3-L1 adipocytes with iron decreased leptin mRNA in a dose-dependent manner. We found that iron negatively regulates leptin transcription via cAMP-responsive element binding protein activation (CREB activation) and identified 2 potential CREB-binding sites in the mouse leptin promoter region. Mutation of both sites completely blocked the effect of iron on promoter activity. ChIP analysis revealed that binding of phosphorylated CREB is enriched at these two sites in iron-treated 3T3-L1 adipocytes compared with untreated cells. Consistent with the changes in leptin, dietary iron content was also directly related to food intake, independently of weight. These findings indicate that levels of dietary iron play an important role in regulation of appetite and metabolism through CREB-dependent modulation of leptin expression.
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PMID:Adipocyte iron regulates leptin and food intake. 2630 6


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