Erschienen:
[Erscheinungsort nicht ermittelbar]: Inst för biovetenskaper och näringslära / Dept of Biosciences and Nutrition, 2019
Sprache:
Englisch
Identifikator:
Entstehung:
Hochschulschrift:
Dissertation, Inst för biovetenskaper och näringslära / Dept of Biosciences and Nutrition, 2019
Anmerkungen:
Beschreibung:
Liver lipid metabolism is coordinated via transcriptional networks composed of transcription factors and coregulators. Disturbance of such networks leads to metabolic dysregulation and is linked to the progression of obesity-related metabolic disorders, such as non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease. Lipid-sensing nuclear receptors, particularly liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs), play a crucial role in cholesterol and triglyceride regulation and have emerged as significant targets for drug development. The major obstacles of targeting nuclear receptors are the undesired and often unpredictable side effects due to their genome-wide activities in multiple cell-types. Therefore, investigating the associated coregulators and the posttranslational modifications might help to better understand the gene-, cell-type- and signalspecific regulation of nuclear receptors, especially upon pathophysiological conditions. Of particular interest is G-protein pathway suppressor 2 (GPS2), subunit of a fundamental corepressor complex, which seems involved in cholesterol homeostasis and antiinflammatory crosstalk in a variety of tissues. Although lipid dysregulation and inflammation are two major mechanisms to promote metabolic disorders, the role of GPS2 in the development of those diseases remained enigmatic. The objective of this thesis was therefore to characterize the roles and relationship of GPS2, along with the corepressor complex, to individual transcription factors/nuclear receptors at the physiological and genomic level with an emphasis on obesity-associated metabolic disorders. In Paper I, we discovered a hitherto unknown function of GPS2 in the progression of NAFLD to non-alcoholic steatohepatitis (NASH). We demonstrated that GPS2 selectively repressed PPARα activity in liver lipid catabolism via the corepressor complex. Hepatocytespecific Gps2 knockout mice were protected from diet-induced liver steatosis and fibrosis, by enhancing fatty acid oxidation and ketogenesis as result of PPARα de-repression and epigenome alterations. Further, by studying human NAFLD/NASH biopsies we found that GPS2 expression positively correlated with fibrogenic and inflammatory gene expression. Thus, the selective modulation of GPS2-PPARα interactions could be of therapeutic interest for NAFLD/NASH. In Paper II, we identified GPS2 as a pivotal regulator of lipopolysaccharides (LPS)-induced ABCA1 expression and cholesterol efflux, independent of LXR and the corepressor complex, in inflammatory macrophages. This study advanced our understanding of GPS2 in linking obesity-associated inflammation to cardiovascular diseases. As GPS2 is downregulated whilst the circulating endotoxin is elevated in obesity, the LPS-GPS2-ABCA1 axis may provide a potential link to explain the increased cardiovascular risk in obesity and T2D. In Paper III, we demonstrated that LXRα phosphorylation played a crucial role in NAFLD progression in mice. In phosphorylation-deficient LXRα knockin mice, diet-induced NAFLD was attenuated by repressing the expression of multiple inflammatory and fibrotic mediators. We uncovered a unique group of diet-specific phosphorylation-sensitive LXRα target genes in liver, different from those affected by loss of LXRα. Moreover, evidence is provided that phosphorylation may modulate the interaction of LXRα with the corepressor complex. This study highlights the role of post-translational modifications in defining the gene-selective transcriptional activity of nuclear receptors. In conclusion, this thesis revealed novel insights into the multifaceted regulatory roles of nuclear receptors and GPS2 in altering transcriptional and epigenomic networks linked to metabolic and inflammatory processes. These insights may contribute to the better understanding of the development of obesity-associated metabolic disorders and to novel intervention strategies.