Metal ions are essential cofactors for a wealth of biological processes, including oxidative phosphorylation, gene regulation and free-radical homeostasis. Failure to maintain appropriate levels of metal ions in humans is a feature of hereditary haemochromatosis, disorders of metal-ion deficiency, and certain neurodegenerative diseases. Despite their pivotal physiological roles, however, there is no molecular information on how metal ions are actively absorbed by mammalian cells. We have now identified a new metal-ion transporter in the rat, DCT1, which has an unusually broad substrate range that includes Fe2+, Zn2+, Mn2+, Co2+, Cd2+, Cu2+, Ni2+ and Pb2+. DCT1 mediates active transport that is proton-coupled and depends on the cell membrane potential. It is a 561-amino-acid protein with 12 putative membrane-spanning domains and is ubiquitously expressed, most notably in the proximal duodenum. DCT1 is upregulated by dietary iron deficiency, and may represent a key mediator of intestinal iron absorption. DCT1 is a member of the 'natural-resistance-associated macrophage protein' (Nramp) family and thus its properties provide insight into how these proteins confer resistance to pathogens.
Patients with alcoholic liver disease frequently exhibit iron overload in association with increased hepatic fibrosis. Even moderate alcohol consumption elevates body iron stores; however, the underlying molecular mechanisms are unknown. Hepcidin, a circulatory peptide synthesized in the liver, is a key mediator of iron metabolism. Ethanol metabolism significantly down-regulated both in vitro and in vivo hepcidin mRNA and protein expression. 4-Methylpyrazole, a specific inhibitor of the alcohol-metabolizing enzymes, abolished the effects of ethanol on hepcidin. However, ethanol did not alter the expression of transferrin receptor1 and ferritin or the activation of iron regulatory RNA-binding proteins, IRP1 and IRP2. Mice maintained on 10 -20% ethanol for 7 days displayed down-regulation of liver hepcidin expression without changes in liver triglycerides or histology. This was accompanied by elevated duodenal divalent metal transporter1 and ferroportin protein expression. Injection of hepcidin peptide negated the effect of ethanol on duodenal iron transporters. Ethanol down-regulated hepcidin promoter activity and the DNA binding activity of CCAAT/enhancer-binding protein ␣ (C/EBP␣) but not . Interestingly, the antioxidants vitamin E and N-acetylcysteine abolished both the alcohol-mediated down-regulation of C/EBP␣ binding activity and hepcidin expression in the liver and the up-regulation of duodenal divalent metal transporter 1. Collectively, these findings indicate that alcohol metabolism-mediated oxidative stress regulates hepcidin transcription via C/EBP␣, which in turn leads to increased duodenal iron transport.
Kinetic analysis of the uptake of carbon-14-labeled oleate in a single-pass perfusion of rat liver and saturable and specific binding of iodine-125-labeled albumin to hepatocytes in suspension suggest the existence of a receptor for albumin on the liver cell surface. The putative receptor appears to mediate uptake of albumin-bound fatty acids by the cell and may account for the efficient hepatic extraction of many other substances tightly bound to albumin.
Tumor necrosis factor-alpha ("Fa), a cytokine that is produced in a variety of inflammatory diseases associated with cholestasis, is believed to be the primary mediator of the systemic effects of endotoxin. Thus, we have investigated the role of TNFa in the pathogenesis of endotoxin-induced cholestasis in intact animals, and in the uptake of taurocholate by cultured hepatocytes. Male Sprague-Dawley rats received either intravenous (IV) endotoxin (7.5 mgkg) or monoclonal anti-TNFa antibody followed by endotoxin. Basal bile flow and bile salt excretion were measured for a 2-hour period, after which all animals received an lV bolus of taurocholate (10 pmoU100 g body weight). Endotoxin decreased basal bile flow by 41% and bile salt stimulated bile flow by 38% (n = 12; P < .01). Basal bile salt excretion was decreased 86% after endotoxin administration. Passive immunization with anti-TNFa antibody blocked this endotoxinassociated cholestasis. In addition, rat hepatocytes were isolated and cultured in the presence of either endotoxin (10 pg/mL) or TNFa (100 ng/mL) for 24 hours. These primary hepatocyte cultures exhibited a dose-and timedependent, noncompetitive, inhibition of taurocholate uptake. We postulate that TNFa is an important mediator of the cholestasis of sepsis. (HEPATOLOGY 1995;22:1273-1278.) Tumor necrosis factor-alpha (TNFa) is a cytokine that is released by macrophages, endothelial cells, and Kupffer cells, and is an important mediator of the inflammatory response. This cytokine is capable of diverse and extensive effects in many biological systems, and both the immunologic and metabolic effects have .4bbreviations: TNFcr, tumor necrosis factor-alpha; HPLC, high-performance liquid chromatography; DPBS, Dulbecco's phosphate-buffered saline; IV, intravenous; V,,, , maximal uptake velocity.
Alcohol reduces and iron increases liver hepcidin synthesis. This study investigates the interaction of alcohol and iron in the regulation of hepcidin messenger RNA (mRNA) expression in animal models. Mice were administered 10% ethanol for 7 days after an iron-overloaded diet. Rats were administered regular or ethanol-Lieber De Carli diets for 7 weeks with or without carbonyl iron. Hfe ؊/؊ mice were used as a model for genetic iron overload. Hepcidin mRNA expression was determined by real-time polymerase chain reaction (PCR) and northern blotting. Iron elevated and alcohol decreased liver hepcidin expression in mice and rats. Interestingly, despite iron overload, alcohol was capable of suppressing the up-regulation of hepcidin mRNA expression in both models. Liver iron and ferritin protein expression was elevated in alcohol-treated rats, but was not elevated further in rats treated with both iron and alcohol. Duodenal ferroportin protein expression was increased both in alcohol-treated mice and in mice treated with alcohol and iron. Hfe ؊/؊ mice treated with ethanol for 7 days exhibited a further decrease in hepcidin mRNA expression. The iron-induced increase in DNA-binding activity of the transcription factor CCAAT/ enhancer binding protein alpha (C/EBP alpha) was also suppressed by alcohol. Conclusion: Alcohol abolishes the iron-induced up-regulation of both liver hepcidin transcription and the DNA-binding activity of C/EBP alpha. Of note, hepcidin protects the body from the harmful effects of iron overload. Our findings therefore suggest that alcohol negates the protective effect of hepcidin, which may have implications for the liver injury observed in alcoholic liver disease and genetic hemochromatosis in combination with alcohol. (HEPATOLOGY 2007;46:1979-1985 H epcidin is a circulatory peptide that is synthesized in the liver and acts as the key regulator of iron metabolism by modulating iron absorption through the duodenum and the release of iron from macrophages. 1,2 We have recently demonstrated that acute alcohol-induced oxidative stress down-regulates liver hepcidin transcripts in mice by altering the DNA-binding activity of the transcription factor CCAAT/enhancer binding protein (C/EBP) alpha. 3 Alcohol-mediated down-regulation of liver hepcidin mRNA expression occurred without associated changes in liver histology or triglycerides. 3 Mice exposed to ethanol for 7 days exhibited elevated iron transporter protein expression in the duodenum. This was abolished by injecting mice with hepcidin peptide. 3 Bridle et al. also have reported reduced hepcidin mRNA expression in rats with chronic alcohol exposure. 4 These results demonstrated a role for alcohol in the regulation of iron metabolism by regulating the expression of hepcidin in the liver.Liver hepcidin messenger RNA (mRNA) expression is regulated inversely by iron and alcohol. 2-4 Namely, iron up-regulates, whereas alcohol down-regulates, liver hepcidin expression. However, the combined effect of alcohol and iron in the regulation of hepcidin expres...
Chronic viral hepatitis frequently goes undetected until cirrhosis develops. Although the effect of interferon on the natural history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection in asymptomatic persons is unknown, treatment may modify the course of the infection, producing cures in some. In September 1992, screening for HBV and HCV was offered in 40 centers throughout the United States. Demographic features, potential risk factors, and symptoms were studied. Blood samples were obtained for the determination of serum alanine aminotransferase levels and for markers of HBV and HCV infection. Thirteen thousand nine hundred ninety seven subjects were screened. The prevalence of infection with HBV or HCV was 24.8% (HBV 17.8%; HCV 7.0%; and both 2.8%). Hepatitis B and C disease was present in 0.7% and 4.4% of the population, respectively. Risk factors for HBV and HCV infection were similar in: blood transfusions, hemodialysis, IV drug use, and sex with an IV drug user. For HBV infection, sex with multiple partners, increasing age, and birth in South East Asia or Africa were additional risk factors. The cost to find a case of HCV infection is less than the costs for finding many other treatable diseases. Screening for HBV, though more costly, is reasonably efficient, and simultaneous screening for HBV and HCV provides greater efficiency. It is practical to consider screening for HBV and HCV in the United States, particularly if any risk factor is present. Improved treatment strategies will make screening even more cost effective.
The single-pass hepatic uptake of long-chain fatty acids and other substances bound tightly to albumin in plasma is surprisingly efficient. Recent kinetic studies for several of these substances suggest that uptake is mediated primarily by direct interaction of the albumin-ligand complex with the hepatocyte surface rather than by the small fraction of unbound ligand, as has been generally believed. Furthermore, 125I-albumin has been found to bind specifically, saturably, and reversibly to isolated hepatocytes, adipocytes, and erythrocytes. Although the nature and possible regulation of these binding sites remain to be fully elucidated, the putative albumin receptor may play an important role in the bidirectional transfer of many classes of endogenous and exogenous substances between albumin and cells.
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