title: Copper deficiency exacerbates bile duct ligation-induced liver injury and fibrosis in rats.
abstract: Copper levels are elevated in a variety of liver fibrosis conditions. Lowering copper to a certain level protects against fibrosis. However, whether severe copper deficiency is protective against liver fibrosis is not known. The purpose of the present study is to evaluate this question by inducing severe copper deficiency using the copper chelator, tetrathiomolybdate (TM), in a bile duct ligation (BDL) rat model. Male Sprague-Dawley rats were divided into four groups: sham, sham plus TM, BDL, and BDL plus TM. TM was given in a daily dose of 10 mg/kg by body weight by means of intragastric gavage, beginning 5 days after BDL. All animals were killed 2 weeks after surgery. Severe copper deficiency was induced by TM overdose in either sham or BDL rats, as shown by decreased plasma ceruloplasmin activity. Liver injury and fibrosis were exacerbated in BDL rats with TM treatment, as illustrated by robustly increased plasma aspartate aminotransferase and hepatic collagen accumulation. Iron stores, as measured by plasma ferritin, were significantly increased in copper-deficient BDL rats. Moreover, hepatic heme oxygenase-1 expression was markedly down-regulated by copper deficiency in BDL rats. In addition, hepatic gene expression involving mitochondrial biogenesis and β-oxidation was significantly up-regulated in BDL rats, and this increase was abolished by copper deficiency. In summary, severe copper deficiency exacerbates BDL-induced liver injury and liver fibrosis, probably caused by increased iron overload and decreased antioxidant defenses and mitochondrial dysfunction.
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Song
authors.forename: Zhanxiang
authors.initials: Z
authors.lastname: Zhou
authors.forename: Theresa
authors.initials: T
authors.lastname: Chen
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McClain
mesh_terms: D020533:Angiogenesis Inhibitors / Q000633:toxicity; D000818:Animals; D001652:Bile Ducts / Q000502:physiology*; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D002779:Cholestasis / Q000473:pathology; D003300:Copper / Q000172:deficiency* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008103:Liver Cirrhosis / Q000473:pathology*; D055370:Lung Injury / Q000473:pathology*; D008297:Male; D008982:Molybdenum / Q000633:toxicity; D009752:Nutritional Status; D009929:Organ Size / Q000502:physiology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012436:S-Adenosylmethionine / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D012313:RNA; D003300:Copper; D012436:S-Adenosylmethionine; D008982:Molybdenum; C020809:tetrathiomolybdate; D007501:Iron; D051547:Heme Oxygenase-1; D005978:Glutathione