Increased Adipose Tissue Expression of Hepcidin in Severe Obesity Is Independent From Diabetes and NASH

University of Nice-Sophia Antipolis, Nice, Provence-Alpes-Côte d'Azur, France
Gastroenterology (Impact Factor: 16.72). 09/2006; 131(3):788-96. DOI: 10.1053/j.gastro.2006.07.007
Source: PubMed


Hepcidin is an acute-phase response peptide. We have investigated the possible involvement of hepcidin in massive obesity, a state of chronic low-grade inflammation. Three groups of severely obese patients with or without diabetes or nonalcoholic steatohepatitis were investigated.
Hepcidin expression was studied in liver and adipose tissue of these patients. Hepcidin regulation was investigated in vitro by adipose tissue explant stimulation studies.
Hepcidin was expressed not only in the liver but also at the messenger RNA (mRNA) and the protein levels in adipose tissue. Moreover, mRNA expression was increased in adipose tissue of obese patients. The presence of diabetes or NASH did not modify the hepcidin expression levels in liver and adipose tissue. In adipose tissue, mRNA expression correlated with indexes of inflammation, interleukin-6, and C-reactive protein. Interleukin-6 also promoted in vitro hepcidin expression. A low transferrin saturation ratio was observed in 68% of the obese patients; moreover, 24% of these patients presented with anemia. The observed changes in iron status could be due to the role of hepcidin as a negative regulator of intestinal iron absorption and macrophage iron efflux. Interestingly, a feedback control mechanism on hepcidin expression related to low transferrin saturation occurred in the liver but not in the adipose tissue.
Hepcidin is a proinflammatory adipokine and may play an important role in hypoferremia of inflammation in obese condition.

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    • "Induction by IL-6 involves signal transduction by JAK kinase regulation of Signal Activator of Transcription [8] [9], adding to the complexity of transcriptional responses dictating hepcidin regulation [10] [11]. Although production by the liver most likely accounts for the majority of hepcidin in the systemic circulation the regulatory peptide can be synthesized in other tissues including heart [12] [13], kidney [14], adipose tissue [15], spinal cord [16], myeloid cells [17], splenic and alveolar macrophages [18], and monocytes [19]. "
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    ABSTRACT: Hepcidin has a regulatory role in inflammation, the immune system, and iron metabolism. It has been shown that proinflammatory cytokine interleukin 6 (IL-6) is an important inducer of hepcidin synthesis during infection and inflammation. Aim of the work To study the relationship between serum hepcidin level and hypoxemia in the COPD patients and its relation to COPD severity. Patients and methods A prospective case control study to compare serum hepcidin levels and other parameters in 70 COPD patients treated at the Pulmonology Department, King Fahad Hospital Dammam, with 34 age and sex matched healthy controls. All subjects participating in the study underwent a complete physical examination and detailed pulmonary function tests (PFTs). A sample from the radial artery for arterial blood gas analysis was done. As well as a panel of other tests including hemoglobin, hematocrit (hct), Iron, CRP, ferritin and total iron binding capacity. A hepcidin prohormone enzyme immunoassay kit (RE 54051, IBL) was used for serum hepcidin measurement. Results COPD patients had significantly lower serum hepcidin level compared to the control group (204.60 ± 53.12 and 280.81 ± 50.61, respectively). Furthermore there was a significantly greater reduction in serum hepcidin level in patients with severe COPD compared to patients with mild COPD. A positive correlation was found between serum hepcidin levels and arterial oxygen saturation (SaO2, %) and FEV1 level (P = 0.005). There was a negative correlation between serum hepcidin level and the ages of patients and packs of cigarettes consumed per year (P = 0.003). Conclusion Our study demonstrated a significant reduction in serum hepcidin levels in COPD patients, and the degree of reduction correlated with the severity of COPD and hypoxemia.
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    • "The association was observed in normal weight men and not in overweight or obese men, most likely because of decreased iron absorption due to increased hepcidin in the chronic inflammatory state associated with obesity (Greenberg and Obin, 2006). Adipocyte hepcidin expression is known to be positively correlated with obesity (Bekri et al., 2006). This association is still to be properly evaluated in women. "
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    ABSTRACT: Disruptions in iron homeostasis are linked to a broad spectrum of chronic conditions including cardiovascular, malignant, metabolic, and neurodegenerative disease. Evidence supporting this contention derives from a variety of analytical approaches, ranging from molecular to population-based studies. This review focuses on key epidemiological studies that assess the relationship between body iron status and chronic diseases, with particular emphasis on atherosclerosis ,metabolic syndrome and diabetes. Multiple surrogates have been used to measure body iron status, including serum ferritin, transferrin saturation, serum iron, and dietary iron intake. The lack of a uniform and standardized means of assessing body iron status has limited the precision of epidemiological associations. Intervention studies using depletion of iron to alter risk have been conducted. Genetic and molecular techniques have helped to explicate the biochemistry of iron metabolism at the molecular level. Plausible explanations for how iron contributes to the pathogenesis of these chronic diseases are beginning to be elucidated. Most evidence supports the hypothesis that excess iron contributes to chronic disease by fostering excess production of free radicals. Overall, epidemiological studies, reinforced by basic science experiments, provide a strong line of evidence supporting the association between iron and elevated risk of cardiovascular disease and diabetes. In this narrative review we attempt to condense the information from existing literature on this topic.
    Full-text · Article · May 2014 · Frontiers in Pharmacology
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    • "Ward et al. reported elevated tumor hepcidin expression within 34% of cases compared to non-involved healthy mucosa; however, other factors that regulate hepcidin expression including inflammation, iron status and dietary iron intake were not examined, limiting interpretations of their findings [15]. Given that few studies have examined the role of extra-hepatic hepcidin in regulating systemic or tissue-level iron metabolism, further investigations are warranted to understand mechanisms related to iron metabolism in colonic tumors [15,37-39]. "
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    ABSTRACT: Background Increased cellular iron exposure is associated with colorectal cancer (CRC) risk. Hepcidin, a liver peptide hormone, acts as the primary regulator of systemic iron status by blocking iron release from enterocytes into plasma. Concentrations are decreased during low iron status and increased during inflammation. The role of hepcidin and the factors influencing its regulation in CRC remains largely unknown. This study explored systemic and tumor level iron regulation in men with CRC. Methods The participants were 20 CRC cases and 20 healthy control subjects. Colonic tissue (adenocarcinoma [cases] healthy mucosa [controls]) was subjected to quantitative PCR (hepcidin, iron transporters and IL-6) and Perls’ iron staining. Serum was analyzed using ELISA for hepcidin, iron status (sTfR) and inflammatory markers (CRP, IL-6, TNF-α). Anthropometrics, dietary iron intake and medical history were obtained. Results Cases and controls were similar in demographics, medication use and dietary iron intake. Systemically, cases compared to controls had lower iron status (sTfR: 21.6 vs 11.8 nmol/L, p < 0.05) and higher marker of inflammation (CRP: 8.3 vs 3.4 μg/mL, p < 0.05). Serum hepcidin was mildly decreased in cases compared to controls; however, it was within the normal range for both groups. Within colonic tissue, 30% of cases (6/20) presented iron accumulation compared to 5% of controls (1/20) (χ2 = 5.0; p < 0.05) and higher marker of inflammation (IL-6: 9.4-fold higher compared to controls, p < 0.05). Presence of adenocarcinoma iron accumulation was associated with higher serum hepcidin (iron accumulation group 80.8 vs iron absence group 22.0 ng/mL, p < 0.05). Conclusions While CRC subjects had serum hepcidin concentrations in the normal range, it was higher given their degree of iron restriction. Inappropriately elevated serum hepcidin may reduce duodenal iron absorption and further increase colonic adenocarcinoma iron exposure. Future clinical studies need to assess the appropriateness of dietary iron intake or iron supplementation in patients with CRC.
    Full-text · Article · May 2014 · Nutrition & Metabolism
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