Department of Medicine, Division of Gastroenterology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.
J Pharmacol Exp Ther. 2011 Oct;339(1):298-306. doi: 10.1124/jpet.111.184325. Epub 2011 Jul 22.
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.
铜水平在各种肝纤维化情况下升高。将铜降低到一定水平可预防纤维化。但是，严重铜缺乏是否对肝纤维化有保护作用尚不清楚。本研究的目的是通过使用铜螯合剂四硫钼酸盐（TM）在胆管结扎（BDL）大鼠模型中诱导严重铜缺乏来评估这个问题。雄性 Sprague-Dawley 大鼠分为四组：假手术组、假手术加 TM 组、BDL 组和 BDL 加 TM 组。TM 以 10mg/kg 的每日剂量通过胃内灌胃给予，BDL 后 5 天开始。所有动物均在手术后 2 周处死。TM 过量给药会在假手术或 BDL 大鼠中诱导严重铜缺乏，表现为血浆铜蓝蛋白活性降低。BDL 大鼠 TM 治疗会加剧肝损伤和纤维化，表现为血浆天冬氨酸转氨酶和肝胶原积累显著增加。铁储存，如血浆铁蛋白所示，在铜缺乏的 BDL 大鼠中显著增加。此外，铜缺乏可显著下调 BDL 大鼠的肝血红素加氧酶-1 表达。此外，BDL 大鼠的线粒体生物发生和β-氧化相关的肝基因表达显著上调，这种增加被铜缺乏所消除。总之，严重的铜缺乏会加重 BDL 诱导的肝损伤和肝纤维化，可能是由铁过载增加、抗氧化防御和线粒体功能障碍减少引起的。
