The liver is the central metabolic hub in organisms and a complex, intertwining regulatory network guarantees efficient liver processes. The morphogenic Hedgehog pathway was recently shown to play a role in regulating the underlying genetic program. Transgenic mouse models with hepatocyte-specific inactivation of Hedgehog signaling showed alterations in insulin-like growth factor homeostasis and in energy metabolism associated with increased lipid accumulation in the liver. In this thesis, it was possible to connect the observed infertility of female knockout mice with an unexpected activation of sex steroid
synthesis in the liver. Associated with increased steroidogenic gene expression exclusively in hepatocytes, the plasma testosterone level was significantly elevated, which led to androgenization and an anovulatory phenotype. With these characteristics, the mouse model mimicked the human polycystic ovarian syndrome and suggested an influence of liver and hepatic Hedgehog signaling on reproduction under disease conditions.
Further, murine liver metabolism was challenged with starvation starting at different times of day. The transcriptomic results were analyzed with a self-organizing map approach, allowing an intuitive interpretation of data and a thus far unknown diurnally different response of hepatic regulatory mechanisms due to starvation was revealed. In contrast to the manifoldly published and observed switch from energy-consuming to energy-providing processes due to starvation started in the morning, evening starvation led to a novel hepatic expression
signature with decreased gluconeogenic gene expression and increased levels of lipid and steroid metabolism-related genes. These differences can be explained by the equally diurnally regulated expression of the corresponding regulatory transcription factors and hormones. Additionally, lipidome analysis confirmed the diurnal differences after starvation.
Thus, this study emphasized the immense impact of circadian regulation on liver metabolism and suggests high accuracy when starvation is the focus of research to avoid varying results.:BIBLIOGRAPHISCHE DARSTELLUNG ................................................................................ II
LIST OF ABBREVIATIONS .................................................................................................. III
TABLE OF CONTENTS ....................................................................................................... IV
SUMMARY ............................................................................................................................ 1
ZUSAMMENFASSUNG ......................................................................................................... 5
INTRODUCTION ................................................................................................................... 9
Liver architecture and metabolism ..................................................................................... 9
Diverse possibilities of liver metabolism regulation .......................................................... 10
Connection of Hedgehog signaling to hepatic metabolism ............................................... 10
Impact of feeding schemes on hepatic metabolism .......................................................... 13
Aims of the thesis ............................................................................................................ 14
References ...................................................................................................................... 15
CHAPTER 1 ........................................................................................................................ 18
CHAPTER 2 ........................................................................................................................ 39
PERSPECTIVE ................................................................................................................... 64
CURRICULUM VITAE ........................................................................................................... V
PUBLICATIONS AND PRESENTATIONS ............................................................................ VI
Publications ...................................................................................................................... VI
Oral presentations ............................................................................................................ VI
Poster presentations ........................................................................................................ VII
AUTHOR CONTRIBUTION STATEMENT .......................................................................... VIII
SELBSTSTÄNDIGKEITSERKLÄRUNG .............................................................................. XII
DANKSAGUNG .................................................................................................................. XIII
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:34718 |
| Date | 26 July 2019 |
| Creators | Rennert, Christiane |
| Contributors | Universität Leipzig |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | German, English |
| Detected Language | English |
| Type | info:eu-repo/semantics/acceptedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 10.3389/fphys.2018.01180, 10.1007/s00204-017-1999-5 |
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