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Uncoupling protein-2 deficiency promotes oxidant stress and delays liver regeneration in mice
Masayoshi Horimoto1, Péter Fülöp, Zoltán Derdák
1Liver Research Center, Rhode Island Hospital and Brown Medical School, Providence, RI 02903, USA.
Abstract:
The control of liver regeneration remains elusive. Because reactive oxygen species (ROS) are able to mediate cell growth arrest and activate proteins that inhibit the cell cycle, ROS production may have a negative impact on liver regeneration. We examined how liver regeneration is affected by uncoupling protein-2 (UCP2), an inner mitochondrial membrane carrier that senses and negatively regulates superoxide production. Liver regeneration was monitored up to 5 days and was found to be significantly delayed in UCP2(-/-) mice after partial hepatectomy. Apoptosis rates in UCP2(+/+) and UCP2(- /-) liver remnants were similar, while parameters of cell proliferation indicated a diminished response in UCP2(- /-) mice with corresponding changes in the expression of key cell cycle regulatory proteins and prolonged activation of stress-responsive protein kinase p38. Levels of malondialdehyde, a marker of ROS generation and oxidant stress, were elevated in UCP2(- /-) livers at every examined time point. Liver remnants of UCP2(+ /+) mice 48 hours post-hepatectomy showed a fourfold increase in the expression of UCP2 protein primarily detected in hepatocytes. In conclusion, our results suggest that absent or insufficient UCP2 function in the regenerating liver results in increased ROS production and negatively modulates the control of cell cycle.
Insights
Uncoupling protein-2 (UCP2) deficiency impairs liver regeneration by increasing reactive oxygen species (ROS) and disrupting cell cycle control. UCP2 is crucial for normal liver repair following injury.
Area of Science:
- Mitochondrial biology
- Hepatology
- Cellular stress response
Background:
- Liver regeneration is a complex process crucial for organ repair.
- Reactive oxygen species (ROS) can inhibit cell cycle progression and liver regeneration.
- Uncoupling protein-2 (UCP2) regulates mitochondrial superoxide production.
Purpose of the Study:
- To investigate the role of UCP2 in regulating liver regeneration.
- To determine the impact of UCP2 deficiency on ROS levels and cell cycle control during liver repair.
Main Methods:
- Partial hepatectomy was performed on UCP2 knockout (UCP2(-/-)) and wild-type (UCP2(+/+)) mice.
- Liver regeneration was monitored for 5 days, assessing apoptosis, cell proliferation, and cell cycle protein expression.
- Malondialdehyde levels were measured as a marker of oxidative stress.
Main Results:
- Liver regeneration was significantly delayed in UCP2(-/-) mice compared to UCP2(+/+) mice.
- UCP2 deficiency led to elevated malondialdehyde levels, indicating increased ROS production and oxidative stress.
- Diminished cell proliferation and altered cell cycle protein expression were observed in UCP2(-/-) livers.
- Prolonged activation of p38 stress-responsive kinase was noted in UCP2(-/-) mice.
Conclusions:
- UCP2 deficiency impairs liver regeneration.
- Increased ROS production and disrupted cell cycle control contribute to delayed regeneration in the absence of UCP2.
- UCP2 plays a critical role in managing oxidative stress and regulating cell cycle during liver regeneration.
