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.