7 research outputs found
Gene expression in the liver of Long-Evans cinnamon rats during the development of hepatitis
High spatial resolution LA-ICP-MS demonstrates massive liver copper depletion in Wilson disease rats upon Methanobactin treatment
The neuropathology of fatal encephalomyelitis in human Borna virus infection
After many years of controversy, there is now recent and solid evidence that classical Borna disease virus 1 (BoDV-1) can infect humans. On the basis of six brain autopsies, we provide the first systematic overview on BoDV-1 tissue distribution and the lesion pattern in fatal BoDV-1-induced encephalitis. All brains revealed a non-purulent, lymphocytic sclerosing panencephalomyelitis with detection of BoDV-1-typical eosinophilic, spherical intranuclear Joest-Degen inclusion bodies. While the composition of histopathological changes was constant, the inflammatory distribution pattern varied interindividually, affecting predominantly the basal nuclei in two patients, hippocampus in one patient, whereas two patients showed a more diffuse distribution. By immunohistochemistry and RNA in situ hybridization, BoDV-1 was detected in all examined brain tissue samples. Furthermore, infection of the peripheral nervous system was observed. This study aims at raising awareness to human bornavirus encephalitis as differential diagnosis in lymphocytic sclerosing panencephalomyelitis. A higher attention to human BoDV-1 infection by health professionals may likely increase the detection of more cases and foster a clearer picture of the disease
Liver mitochondrial membrane crosslinking and destruction in a rat model of Wilson disease
Wilson disease (WD) is a rare hereditary condition that is caused by a genetic defect
in the copper-transporting ATPase ATP7B that results in hepatic copper accumulation
and lethal liver failure. The present study focuses on the structural mitochondrial
alterations that precede clinical symptoms in the livers of rats lacking Atp7b, an
animal model for WD. Liver mitochondria from these
Atp7b–/– rats contained
enlarged cristae and widened intermembrane spaces, which coincided with a massive
mitochondrial accumulation of copper. These changes, however, preceded detectable
deficits in oxidative phosphorylation and biochemical signs of oxidative damage,
suggesting that the ultrastructural modifications were not the result of oxidative
stress imposed by copper-dependent Fenton chemistry. In a cell-free system containing
a reducing dithiol agent, isolated mitochondria exposed to copper underwent
modifications that were closely related to those observed in vivo. In this cell-free
system, copper induced thiol modifications of three abundant mitochondrial membrane
proteins, and this correlated with reversible intramitochondrial membrane
crosslinking, which was also observed in liver mitochondria from
Atp7b–/– rats. In vivo,
copper-chelating agents reversed mitochondrial accumulation of copper, as well as
signs of intra-mitochondrial membrane crosslinking, thereby preserving the functional
and structural integrity of mitochondria. Together, these findings suggest that the
mitochondrion constitutes a pivotal target of copper in WD
Activation of autophagy, observed in liver tissues from patients with Wilson disease and from Atp7b-deficient animals, protects hepatocytes from copper-induced apoptosis
Wilson disease is an inherited disorder of copper metabolism that leads to copper accumulation and toxicity in liver and brain. It is caused by mutations in the ATPase copper transporting beta gene (ATP7B), which encodes a protein that transports copper out of heaptocytes into the bile. We studied ATP7B-deficient cells and animals to identify strategies to reduce copper toxicity in patients with Wilson disease
A High-Calorie Diet Aggravates Mitochondrial Dysfunction and Triggers Severe Liver Damage in Wilson Disease RatsSummary
Background & Aims: In Wilson disease, ATP7B mutations impair copper excretion into bile. Hepatic copper accumulation may induce mild to moderate chronic liver damage or even acute liver failure. Etiologic factors for this heterogeneous phenotype remain enigmatic. Liver steatosis is a frequent finding in Wilson disease patients, suggesting that impaired copper homeostasis is linked with liver steatosis. Hepatic mitochondrial function is affected negatively both by copper overload and steatosis. Therefore, we addressed the question of whether a steatosis-promoting high-calorie diet aggravates liver damage in Wilson disease via amplified mitochondrial damage. Methods: Control Atp7b+/- and Wilson disease Atp7b-/- rats were fed either a high-calorie diet (HCD) or a normal diet. Copper chelation using the high-affinity peptide methanobactin was used in HCD-fed Atp7b-/- rats to test for therapeutic reversal of mitochondrial copper damage. Results: In comparison with a normal diet, HCD feeding of Atp7b-/- rats resulted in a markedly earlier onset of clinically apparent hepatic injury. Strongly increased mitochondrial copper accumulation was observed in HCD-fed Atp7b-/- rats, correlating with severe liver injury. Mitochondria presented with massive structural damage, increased H2O2 emergence, and dysfunctional adenosine triphosphate production. Hepatocellular injury presumably was augmented as a result of oxidative stress. Reduction of mitochondrial copper by methanobactin significantly reduced mitochondrial impairment and ameliorated liver damage. Conclusions: A high-calorie diet severely aggravates hepatic mitochondrial and hepatocellular damage in Wilson disease rats, causing an earlier onset of the disease and enhanced disease progression. Keywords: Copper-Storage Disease, Steatosis, Steatohepatitis, Mitochondria, Methanobacti