Uncoupling protein‐2 induction in rat hepatocytes after acute carbon tetrachloride liver injury

Abstract

This study is focused on the role of UCP-2 in hepatic oxidative metabolism following acute CCl(4) administration to rats. UCP-2 mRNA, almost undetectable in the liver of controls, was significantly increased 24 h after CCl(4) administration, peaked at 72 h and then tended to disappear. UCP-2 protein, undetectable in controls, increased 48-72 h after CCl(4) treatment. Experiments with isolated liver cells indicated that in control rats UCP-2 was expressed in non-parenchymal cells and not in hepatocytes, whereas in CCl(4)-treated rats UCP-2 expression was induced in hepatocytes and was not affected in non-parenchymal cells. Addition of CCl(4) to the culture medium of hepatocytes from control rats failed to induce UCP-2 expression. Liver mitochondria from CCl(4)-treated rats showed an increase of H(2)O(2) release at 12-24 h, followed by a rise of TBARS. Vitamin E protected liver from CCl(4) injury and reduced the expression of UCP-2. Treatment with GdCl(3) prior to CCl(4), in order to inhibit Kupffer cells, reduced TBARS and UCP-2 mRNA increase in hepatic mitochondria. Our data indicate that CCl(4) induces the expression of UCP-2 in hepatocytes with a redox-dependent mechanism involving Kupffer cells. A role of UCP-2 in moderating CCl(4)-induced oxidative stress during tissue regeneration after injury is suggested.

The Protective Role of Per2 Against Carbon Tetrachloride-Induced Hepatotoxicity

“…Increase in Ucp2 mRNA in the liver of CCl 4 -treated animals was associated with a rise in Ucp2 protein. 27 Thus, as we observed, the elevation Ucp2 expression caused a more severe drop in ATP content of Per2-null livers, which was obligated for death of hepatocytes after CCl 4 treatment.…”

“…The oxidation stress induced by CCl 4 metabolites was correlated to induction of Ucp2 via the stimulation of PPAR-␣ expression. 27,29 Ucp2 is a member of a family of proton transporters located in the mitochondrial inner membrane and involved in the regulation of superoxide and ATP synthesis. 23 The up-regulation of Ucp2 enhanced the cyanide-induced mitochondrial dysfunction, leading to execution of necrosis.…”

“…13,25,26 CCl 4 induces the expression of Ucp2 mRNA and Ucp2 protein in hepatocytes. 27 Analysis of expression of Ucp2 gene at the mRNA level indicated that Per2-null mice displayed a marked elevation both at 0 and 24 hours after CCl 4 injection compared with wildtype mice ( Figure 5A), suggesting Per2 functions as suppressor of Ucp2 gene expression. Therefore overexpression of Per2 should lower Ucp2 gene expression.…”

A Contradictory Role of A1 Adenosine Receptor in Carbon Tetrachloride- and Bile Duct Ligation-Induced Liver Fibrosis in Mice

“…In the early stage after CCl 4 , loss of A 1 AR function resulted in decreased levels of CYP2E1, reducing hepatotoxicity by CCl 4 . Meanwhile, we observed impaired UCP2 expression in A 1 AR(Ϫ/Ϫ) mice after CCl 4 compared with that in WT mice, which might be implicated in the decreased death of hepatocytes after CCl 4 treatment (Demori et al, 2008).…”

“…4, C and D). Down-regulation of CYP2E1 after CCl 4 injection was considered as an adaptive mechanism for decreasing toxicity (Wong et al, 1998), and CCl 4 induces the expression of UCP2, which reduced the efficiency of cellular ATP synthesis and had been proposed as a causative factor in CCl 4 -induced cell death (Demori et al, 2008). Thus, the decreased sensitivity of A 1 AR(Ϫ/Ϫ) mice to CCl 4 -induced liver injury may involve down-regulation of CYP2E1 and UCP2 expression in the early stage.…”