Article ; Online: Protective role of HO-1 and carbon monoxide in ethanol-induced hepatocyte cell death and liver injury in mice.
2014 Volume 61, Issue 5, Page(s) 1029–1037
Abstract: Background & aims: Alcoholic liver disease is associated with inflammation and cell death. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with anti-apoptotic and anti-inflammatory properties. Here we tested the hypothesis that induction of HO-1 or ...
| Abstract | Background & aims: Alcoholic liver disease is associated with inflammation and cell death. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with anti-apoptotic and anti-inflammatory properties. Here we tested the hypothesis that induction of HO-1 or treatment with a carbon monoxide releasing molecule (CORM) during chronic ethanol exposure protects and/or reverses ethanol-induced liver injury. Methods: Female C57BL/6J mice were allowed free access to a complete liquid diet containing ethanol or to pair-fed control diets for 25days. Mice were treated with cobalt protoporphyrin (CoPP) to induce HO-1 expression during ethanol feeding or once liver injury had been established. Mice were also treated with CORM-A1, a CO-releasing molecule (CORM), after ethanol-induced liver injury was established. The impact of HO-1 induction on ethanol-induced cell death was investigated in primary cultures of hepatocytes. Results: Induction of HO-1 during or after ethanol feeding, as well as treatment with CORM-A1, ameliorated ethanol-induced increases in AST and expression of mRNAs for inflammatory cytokines. Treatment with CoPP or CORM-A1 also reduced hepatocyte cell death, indicated by decreased accumulation of CK18 cleavage products and reduced RIP3 expression in hepatocytes. Exposure of primary hepatocyte cultures to ethanol increased their sensitivity to TNFα-induced cell death; this response was attenuated by necrostatin-1, an inhibitor of necroptosis, but not by caspase inhibitors. Induction of HO-1 with CoPP or CORM-3 treatment normalized the sensitivity of hepatocytes to TNFα-induced cell death after ethanol exposure. Conclusions: Therapeutic strategies to increase HO-1 and/or modulate CO availability ameliorated chronic ethanol-induced liver injury in mice, at least in part by decreasing hepatocellular death. |
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| MeSH term(s) | Alanine Transaminase/metabolism ; Animals ; Aspartate Aminotransferases/metabolism ; Boranes/pharmacology ; Carbon Monoxide/metabolism ; Carbonates/pharmacology ; Cell Death/drug effects ; Cells, Cultured ; Chemical and Drug Induced Liver Injury/metabolism ; Chemical and Drug Induced Liver Injury/pathology ; Cytokines/genetics ; Cytokines/metabolism ; Enzyme Induction/drug effects ; Ethanol/toxicity ; Female ; Gene Expression/drug effects ; Heme Oxygenase-1/biosynthesis ; Heme Oxygenase-1/metabolism ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Hepatocytes/pathology ; Male ; Membrane Proteins/biosynthesis ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Protoporphyrins/pharmacology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Tumor Necrosis Factor-alpha/metabolism | |||||
| Chemical Substances | Boranes ; Carbonates ; Cytokines ; Membrane Proteins ; Protoporphyrins ; RNA, Messenger ; Tumor Necrosis Factor-alpha ; sodium boranocarbonate ; Ethanol (3K9958V90M) ; cobaltiprotoporphyrin (63AAN3JDZE) ; Carbon Monoxide (7U1EE4V452) ; Heme Oxygenase-1 (EC 1.14.14.18) ; Hmox1 protein, mouse (EC 1.14.14.18) ; Aspartate Aminotransferases (EC 2.6.1.1) ; Alanine Transaminase (EC 2.6.1.2) | |||||
| Language | English | |||||
| Publishing date | 2014-06-16 | |||||
| Publishing country | Netherlands | |||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 605953-3 | |||||
| ISSN | 1600-0641 ; 0168-8278 | |||||
| ISSN (online) | 1600-0641 | |||||
| ISSN | 0168-8278 | |||||
| DOI | 10.1016/j.jhep.2014.06.007 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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