Uncoupling protein-2 deficiency promotes oxidant stress and delays liver regeneration in mice

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.

Targeted expression of uncoupling protein 2 to mouse liver increases the susceptibility to lipopolysaccharide/galactosamine-induced acute liver injury

“…Expression of UCP2 in liver sections was detected as described. 16 The in situ labeling of apoptotic cells was performed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay with commercial kits (Roche).…”

“…15 In contrast, UCP2 deficiency promotes oxidative stress and impairs liver regeneration in mice. 16 Macrophages from UCP2 knockout (KO) mice have increased ROS production, persistent nuclear factor-kappa B (NF-B) activation, 17 and augmented LPS-induced mitogen-activated protein kinase (MAPK) activation. 18 These mice have a higher incidence of colon tumor, 19 likely due to the enhanced inflammatory response.…”

Heterogeneous Nuclear Ribonucleoprotein K Enhances Insulin-induced Expression of Mitochondrial UCP2 Protein

“…Interest in this carrier has been further fueled by the discovery of a common polymorphism of the ucp2 gene that has been associated with metabolic disorders (9, 10) and hypertension (11). Although there is mounting evidence that UCP2 protein plays a key role in regulating metabolic processes (12), reactive oxygen species production (13), and response to tissue injury (14,15), the mechanisms that regulate its expression are not well known.…”

Influence of Vitamin E and Selenium on UCP2 and Other Correlation Factors in Non-alcoholic Fatty Liver of Rats

“…2 The content of ALT、AST、TG and TC in rat serum (X±S) (Rousset et al, 2007)。 有研究表明 NAFLD 时脂肪变的肝细胞 UCP2 表达增强，并可能与高脂饮食、游离脂肪酸增多、 过氧化酶体增殖物激活受体 γ 活化， 氧化应激增强， 内毒素血症，以及肿瘤坏死因子增多等诸多因素密 切 相 关 (Collins et al, 2005;Baffy et al, 2002;Horimoto et al, 2004)；如 Lee et al(1999) …”