Oxidative Stress In Fatty Liver Research Articles

Computational Modeling of Oxidative Stress in Fatty Livers Elucidates the Underlying Mechanism of the Increased Susceptibility to Ischemia/Reperfusion Injury

QuestionDonor liver organs with moderate to high fat content (i.e. steatosis) suffer from an enhanced susceptibility to ischemia/reperfusion injury (IRI) during liver transplantation. Responsible for the cellular injury is an increased level of oxidative stress, however the underlying mechanistic network is still not fully understood. MethodWe developed a phenomenological mathematical model of key processes of hepatic lipid metabolism linked to pathways of oxidative stress. The model allows the simulation of hypoxia (i.e. ischemia-like conditions) and reoxygenation (i.e. reperfusion-like conditions) for various degrees of steatosis and predicts the level of hepatic lipid peroxidation (LPO) as a marker of cell damage caused by oxidative stress. Results & ConclusionsOur modeling results show that the underlying feedback loop between the formation of reactive oxygen species (ROS) and LPO leads to bistable systems behavior. Here, the first stable state corresponds to a low basal level of ROS production. The system is directed to this state for healthy, non-steatotic livers. The second stable state corresponds to a high level of oxidative stress with an enhanced formation of ROS and LPO. This state is reached, if steatotic livers with a high fat content undergo a hypoxic phase. Theoretically, our proposed mechanistic network would support the prediction of the maximal tolerable ischemia time for steatotic livers: Exceeding this limit during the transplantation process would lead to severe IRI and a considerable increased risk for liver failure.

Mitochondrial‐Targeted Antioxidant Treatment in a Mouse Model of Non‐Alcoholic Fatty Liver Disease

As obesity has become a more common problem in childhood, the prevalence of non‐alcoholic fatty liver disease (NAFLD) among children has increased. Approximately 70‐80% of obese children have some degree of NAFLD, a precursor for liver failure and/or hepatocellular carcinoma as well as an independent risk factor for cardiovascular disease. While the molecular mechanisms of this disease are beginning to be elucidated, there is no standard pharmacologic therapy. Oxidative stress is a significant factor in disease progression, thus antioxidant therapy has potential utility. In the current study, 10 week old normal (Db/db) and obese diabetic mice with NAFLD (db/db) were treated for six weeks with vehicle or Mitotempol, a mitochondrial‐targeted antioxidant. The effect on oxidative stress, inflammation and metabolism in liver was evaluated through measurement of gene (RT‐PCR) and protein expression (immunoblots), along with hepatic triglyceride levels. Enzymes involved in oxidative stress were not affected by treatment. However, lipocalin‐2, a marker of oxidative stress and inflammation, was significantly decreased following treatment. We also observed a decrease in levels of NFκB and caspase‐3. While there was no change in hepatic triglyceride levels or expression of seven genes involved in fatty acid metabolism, an increase in expression of 4 genes involved in glucose metabolism/transport occurred following Mitotempol treatment. The current study shows that treatment with Mitotempol does not affect hepatic lipid metabolism, but does decrease markers of oxidative stress and inflammation. Mitotempol may be effective in targeting oxidative stress in fatty liver and warrants further evaluation as a potential therapy.

Integrated Autofluorescence Characterization of a Modified-Diet Liver Model with Accumulation of Lipids and Oxidative Stress

Oxidative stress in fatty livers is mainly generated by impaired mitochondrial β-oxidation, inducing tissue damages and disease progression. Under suitable excitation, light liver endogenous fluorophores can give rise to autofluorescence (AF) emission, the properties of which depend on the organ morphofunctional state. In this work, we characterized the AF properties of a rat liver model of lipid accumulation and oxidative stress, induced by a 1–9-week hypercaloric methionine-choline deficient (MCD) diet administration. The AF analysis (excitation at 366 nm) was performed in vivo, via fiber optic probe, or ex vivo. The contribution of endogenous fluorophores involved in redox reactions and in tissue organization was estimated through spectral curve fitting analysis, and AF results were validated by means of different histochemical and biochemical assays (lipids, collagen, vitamin A, ROS, peroxidised proteins, and lipid peroxidation -TBARS-, GSH, and ATP). In comparison with the control, AF spectra changes found already at 1 week of MCD diet reflect alterations both in tissue composition and organization (proteins, lipopigments, and vitamin A) and in oxidoreductive pathway engagement (NAD(P)H, flavins), with a subsequent attempt to recover redox homeostasis. These data confirm the AF analysis potential to provide a comprehensive diagnostic information on negative effects of oxidative metabolism alteration.

Modulation of Oxidative Stress in Fatty Liver of Rat with Metabolic Syndrome by Hibiscus Sabdariffa

Modulation of Oxidative Stress in Fatty Liver of Rat with Metabolic Syndrome by Hibiscus Sabdariffa

Lack of UCP2 reduces fas-mediated liver injury in ob/ob mice and reveals importance of cell-specific UCP2 expression

Fatty liver is vulnerable to conditions that challenge hepatocellular energy homeostasis. Lipid-laden hepatocytes highly express uncoupling protein-2 (UCP2), a mitochondrial carrier that competes with adenosine triphosphate (ATP) synthesis by mediating proton leak. However, evidence for a link between UCP2 expression and susceptibility of liver to acute injury is lacking. We asked whether absence of UCP2 protects ob/ob mice from Fas-mediated acute liver damage. UCP2-deficient ob/ob mice (ob/ob:ucp2-/-) and UCP2-competent littermates (ob/ob:ucp2+/+) received a single dose of agonistic anti-Fas antibody (Jo2). Low-dose Jo2 (0.15 mg/kg intraperitoneally) caused less serum alanine aminotransferase (ALT) elevation and lower apoptosis rates in ob/ob:ucp2-/- mice. High-dose Jo2 (0.40 mg/kg intraperitoneally) proved uniformly fatal; however, ob/ob:ucp2-/- mice survived longer with less depletion of liver ATP stores, indicating that fatty hepatocytes may benefit from lack of UCP2 during Jo2 challenge. Although UCP2 reportedly controls mitochondrial oxidant production, its absence had no apparent effect on fatty liver tissue malondialdehyde levels augmented by Jo2. This finding prompted us to determine UCP2 expression in Kupffer cells, a major source of intrahepatic oxidative stress. UCP2 expression was found diminished in Kupffer cells of untreated ob/ob:ucp2+/+ mice, conceivably contributing to increased oxidative stress in fatty liver and limiting the impact of UCP2 ablation. In conclusion, whereas UCP2 abundance in fatty hepatocytes exacerbates Fas-mediated injury by compromising ATP stores, downregulation of UCP2 in Kupffer cells may account for persistent oxidative stress in fatty liver. Our data support a cell-specific approach when considering the therapeutic effects of mitochondrial uncoupling in fatty liver disease.

Role of oxidative stress in the increased activation of signal transducers and activators of transcription-3 in the fatty livers of obese Zucker rats

BackgroundFatty livers have chronic oxidative stress, which could activate several transcription factors. We hypothesized that fatty livers of obese rats have increased activation of signal transducers and activators of transcription-1 and transcription-3 (Stat-1 and Stat-3) and that tocopherol treatment will decrease Stat activation. MethodsObese (Ob) and lean (Ln) Zucker rats with or without tocopherol treatment were used. Western blots of liver nuclear and cytoplasmic extracts to assess phosphorylated and total Stat-3 and tyrosine kinases Jak-2 and Tyk-2, immunohistochemistry to assess distribution of phosphoStat-3, and gel shift assays to assess Stat and nuclear factor kappa B binding were performed. Interleukin-6 serum levels and hepatic transcripts were determined by immunoassay and reverse polymerase chain reaction with Southern blotting, respectively. ResultsLivers of Ob animals had increased nuclear phosphoStat-3, decreased cytoplasmic Stat-3, and increased Stat-3 binding. Serum interleukin-6 was not measurable in either Ob or Ln animals and hepatic transcript levels were not significantly different. Tocopherol administration decreased nuclear phosphoStat-3, increased cytoplasmic Stat-3, and decreased Stat-3 binding activity. ConclusionsChronic oxidative stress in fatty livers is associated with increased Stat-3 activation and decreased cytosolic Stat-3. Tocopherol treatment decreases Stat-3 activation and increases cytosolic Stat-3. Tocopherol-induced changes in Stat-3 may play a role in its beneficial effects in hepatic ischemia in fatty livers.

Oxidative stress in fatty livers of obese Zucker rats: Rapid amelioration and improved tolerance to warm ischemia with tocopherol

Fatty livers in humans and rats are less tolerant of ischemia, endotoxin, and alcohol. We hypothesized that fatty livers of obese (Ob) Zucker rats are oxidatively stressed and oxidative stress could be relieved by antioxidant treatment, leading to improved tolerance to ischemia. Total glutathione (GSH), tocopherol (TOC), ascorbic acid (AA), catalase (CAT), superoxide dismutase (SOD), and selenium–glutathione peroxidase (Se-GPx) were measured in the livers of Ob and lean (Ln) Zucker rats before and after treatment with high-dose TOC and ascorbate. Also, survival in treated Ob rats following a lethal 90 minutes of partial in vivo warm ischemia was examined. Fatty livers of Ob rats contained significantly less GSH, TOC, and CAT, in comparison with livers of Ln rats. Immunoblotting showed significantly decreased CAT protein without changes in mRNA in fatty livers. There were no significant differences in AA, SOD, and Se-GPx between the 2 groups. Pretreatment with TOC and ascorbate over 48 hours completely corrected the decreases in GSH, TOC, and CAT. Most importantly, TOC with or without ascorbate pretreatment significantly improved survival in Ob rats following ischemia in a dose-dependent manner. In conclusion, TOC administration corrected the oxidative stress in fatty livers of Ob Zucker rats and improved survival following lethal ischemia. Additional studies are needed to determine the efficacy of TOC—a relatively inexpensive agent—in treating patients with fatty livers in a variety of clinical conditions, possibly including liver transplantation. (HEPATOLOGY 2001;34:13-18.)

Mitochondrial adaptations to chronic oxidative stress in fatty livers of obese mice

Mitochondrial adaptations to chronic oxidative stress in fatty livers of obese mice