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Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are hepatic manifestations of the metabolic syndrome. Many currently used animal models of NAFLD/NASH lack clinical features of either NASH or metabolic syndrome such as hepatic inflammation and fibrosis (e.g., high-fat diets) or overweight and insulin resistance (e.g., methionine-choline-deficient diets), or they are based on monogenetic defects (e.g., ob/ob mice). In the current study, a Western-type diet containing soybean oil with high n-6-PUFA and 0.75% cholesterol (SOD + Cho) induced steatosis, inflammation and fibrosis accompanied by hepatic lipid peroxidation and oxidative stress in livers of C57BL/6-mice, which in addition showed increased weight gain and insulin resistance, thus displaying a phenotype closely resembling all clinical features of NASH in patients with metabolic syndrome. In striking contrast, a soybean oil-containing Western-type diet without cholesterol (SOD) induced only mild steatosis but not hepatic inflammation, fibrosis, weight gain or insulin resistance. Another high-fat diet, mainly consisting of lard and supplemented with fructose in drinking water (LAD + Fru), resulted in more prominent weight gain, insulin resistance and hepatic steatosis than SOD + Cho, but livers were devoid of inflammation and fibrosis. Although both LAD + Fru-and SOD + Cho-fed animals had high plasma cholesterol, liver cholesterol was elevated only in SOD + Cho animals. Cholesterol induced expression of chemotactic and inflammatory cytokines in cultured Kupffer cells and rendered hepatocytes more susceptible to apoptosis. In summary, dietary cholesterol in the SOD + Cho diet may trigger hepatic inflammation and fibrosis. SOD + Cho-fed animals may be a useful disease model displaying many clinical features of patients with the metabolic syndrome and NASH.
Quantitative information on vegetation and climate history from the late glacial-Holocene on the Tibetan Plateau is extremely rare. Here, we present palynological results of a 4.30-m-long sediment record collected from Koucha Lake in the Bayan Har Mountains, northeastern Tibetan Plateau. Vegetation change has been traced by biomisation, ordination of pollen data, and calculation of pollen ratios. The application of a pollen-climate calibration set from the eastern Tibetan Plateau to Koucha Lake pollen spectra yielded quantitative climate information. The area was covered by alpine desert/steppe, characteristic of a cold and dry climate (with 50% less precipitation than today) between 16,700 and 14,600 cal yr BP. Steppe vegetation, warm (similar to 1 degrees C higher than today) and wet conditions prevailed between 14,600 and 6600 cal yr BR These findings contradict evidence from other monsoon-influenced areas of Asia, where the early Holocene is thought to have been moist. Low effective moisture on the northeastern Tibetan Plateau was likely due to high temperature and evaporation, even though precipitation levels may have been similar to present- day values. The vegetation changed to tundra around 6600 cal yr BP, indicating that wet and cool climate conditions occurred on the northeastern Tibetan Plateau during the second half of the Holocene.
Rapid population growth and economic development have led to increased anthropogenic pressures on the Tibetan Plateau, causing significant land cover changes with potentially severe ecological consequences. To assess whether or not these pressures are also affecting the remote montane-boreal lakes on the SE Tibetan Plateau, fossil pollen and diatom data from two lakes were synthesized. The interplay of aquatic and terrestrial ecosystem response was explored in respect to climate variability and human activity over the past 200 years. Nonmetric multidimensional scaling and Procrustes rotation analysis were undertaken to determine whether pollen and diatom responses in each lake were similar and synchronous. Detrended canonical correspondence analysis was used to develop quantitative estimates of compositional species turnover. Despite instrumental evidence of significant climatic warming on the southeastern Plateau, the pollen and diatom records indicate very stable species composition throughout their profiles and show only very subtle responses to environmental changes over the past 200 years. The compositional species turnover (0.36-0.94 SD) is relatively low in comparison to the species reorganizations known from the periods during the mid-and early-Holocene (0.64-1.61 SD) on the SE Plateau, and also in comparison to turnover rates of sediment records from climate-sensitive regions in the circum arctic. Our results indicate that climatically induced ecological thresholds are not yet crossed, but that human activity has an increasing influence, particularly on the terrestrial ecosystem in our study area. Synergistic processes of post-Little Ice Age warming, 20th century climate warming and extensive reforestations since the 19th century have initiated a change from natural oak-pine forests to seminatural, likely less resilient pine-oak forests. Further warming and anthropogenic disturbances would possibly exceed the ecological threshold of these ecosystems and lead to severe ecological consequences.
Farber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments are clinically available and affected patients have a severely shortened lifespan. Due to the low incidence, the pathogenesis of FD is still poorly understood. Here, we report a novel acid ceramidase mutant mouse model that enables the study of pathogenic mechanisms of FD and ceramide accumulation. Asah1(tmEx1) mice were generated by deletion of the acid ceramidase signal peptide sequence. The effects on lysosomal targeting and activity of the enzyme were assessed. Ceramide and sphingomyelin levels were quantified by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and disease manifestations in several organ systems were analyzed by histology and biochemistry. We show that deletion of the signal peptide sequence disrupts lysosomal targeting and enzyme activity, resulting in ceramide and sphingomyelin accumulation. The affected mice fail to thrive and die early. Histiocytic infiltrations were observed in many tissues, as well as lung inflammation, liver fibrosis, muscular disease manifestations and mild kidney injury. Our new mouse model mirrors human FD and thus offers further insights into the pathogenesis of this disease. In the future, it may also facilitate the development of urgently needed therapies.