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@PHDTHESIS{Lambertz:782556,
      author       = {Lambertz, Jessica},
      othercontributors = {Weiskirchen, Ralf and Hollert, Henner and van Dongen, Joost
                          Thomas},
      title        = {{L}ipocalin 2 in perpetuating hepatic lipid homeostasis
                      challenged by high fructose diet},
      school       = {RWTH Aachen University},
      type         = {Dissertation},
      address      = {Aachen},
      reportid     = {RWTH-2020-01951},
      pages        = {1 Online-Ressource (123 Seiten) : Illustrationen,
                      Diagramme},
      year         = {2019},
      note         = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
                      University 2020; Dissertation, RWTH Aachen University, 2019},
      abstract     = {Fructose is known as a lipogenic sugar, part of High
                      Fructose Corn Syrup (HFCS) contributing to elevated fasting
                      plasma free fatty acids and plasma triglycerides, redounding
                      to the development of metabolic disturbances and diabetes.
                      About $90\%$ of ingested fructose is metabolized in the
                      liver. Chronic fructose consumption can promote hepatic
                      lipid synthesis and triosephosphate can provide further
                      substrates for de novo lipogenesis. Furthermore, fructose
                      was shown to be involved in the development and worsening of
                      kidney damage going along with systemic inflammation,
                      tubular injury and renal dysfunction. The intake of excess
                      dietary fructose most often leads to non-alcoholic fatty
                      liver disease (NAFLD). Regarding the development of NAFLD
                      with the “two-hit theory”, steatosis is the first hit
                      and steatohepatitis, which requires the presence of factors
                      such as oxidative stress, characterizes the second hit.
                      Chronic consumption of fructose results in lipogenic gene
                      expression in this organ. Nevertheless, how fructose is
                      involved in NAFLD progression is still not fully understood,
                      limiting therapy. Lipocalin 2 (LCN2) is a small secreted
                      transport protein that binds to fatty acids, phospholipids,
                      steroids, retinol, and pheromones. LCN2 regulates lipid and
                      energy metabolism in obesity and is upregulated in response
                      to insulin. It was previously discovered that LCN2 has
                      hepatoprotective effects and upregulation is a reliable
                      marker of liver damage and inflammation. To investigate if
                      LCN2 has impact on the metabolism of fructose and thereby
                      arising liver and kidney damage, we fed wild type and
                      Lcn2-deficient mice for 4 and 8 weeks on diets that were
                      enriched in fructose either by adding this sugar to the
                      drinking water $(30\%$ (w/v)), or by feeding a chow
                      containing $60\%$ (w/w) fructose. Feeding high fructose was
                      hypothesized to cause time-depended liver- and kidney damage
                      in mice and more severe steatosis in mice lacking LCN2 after
                      prolonged feeding of fructose was expected. In this study,
                      male and female mice were analysed separately in order to
                      investigate gender-specific differences during progression
                      of disease. Body weight and daily intake of food and water
                      of these mice was measured regularly during the study. Fat
                      content in liver sections was visualized using Oil Red
                      O-stain, and expression levels of genes involved in fat and
                      sugar metabolism, as well as inflammatory marker genes were
                      measured by qRT-PCR and Western blot analysis.
                      Fructose-induced steatosis and liver damage was more
                      prominent in female than in male mice, but the most severe
                      hepatic damage occurred in female mice lacking LCN2. Slight
                      kidney damage was only observed in Lcn2-deficient mice.
                      Unexpectedly, consumption of elevated fructose did not
                      induce de novo lipogenesis or inflammation. Instead,
                      fructose appears to directly affect liver homeostasis,
                      thereby manipulating fat metabolism. In conclusion, this
                      study shows that LCN2 acts in a lipid-independent manner to
                      protect the liver against fructose-induced damage. Female
                      mice showed higher steatosis and damage after fructose
                      treatment than their male counterparts, confirming the
                      potential influence of estrogen on lipid homeostasis
                      reported in previous studies. Fructose might disturb liver
                      homeostasis by promoting lipid uptake into the liver, while
                      LCN2 counteracts this lipid uptake.},
      cin          = {526000-3 / 163720 / 160000},
      ddc          = {570},
      cid          = {$I:(DE-82)526000-3_20140620$ / $I:(DE-82)163720_20140620$ /
                      $I:(DE-82)160000_20140620$},
      typ          = {PUB:(DE-HGF)11},
      doi          = {10.18154/RWTH-2020-01951},
      url          = {https://publications.rwth-aachen.de/record/782556},
}