Role of Fsp27 in lípid homeostasis during nutrient deprivation

[eng] This Thesis has been divided into three different chapters, the regulation of Fsp27 during the fasting adaptation, the transcriptional regulation of Fsp27 in liver and finally the role of FSP27 as a lipid-droplet protein in PPARalpha signaling, with the purpose to achieve the following objectives: 1) To describe the expression pattern of FSP27 during fasting adaptation in different tissues and different fasting times. 2) To define the transcriptional mechanisms responsible for hepatic expression of FSP27 during fasting specially the ones that cause the fall of Fsp27beta expression during late fasting. 3) To identify the role of Fsp27beta in PPARalpha signaling by studying its ability to control the store/release of specific endogenous ligands of PPARalpha from lipid droplets. The results of this work show that Fsp27beta is the main isoform expressed in tissues that actively oxidize fatty acids such as liver and BAT, but also in small intestine. Fsp27beta is a target gene of CREBH, but not of PPARaplha and there is no cross talk between both transcription factors in the regulation of hepatic expression of Fsp27beta. Nonetheless, Fsp27beta expression depends on the level of CREBH acetylation. It has been also described that FSP27beta expression is necessary for the hepatic accumulation of TAG in liver and plays a fundamental role in the development of the physiological hepatic steatosis that occurs during fasting during. Finally, this work demonstrates that the hepatic expression of FSP27beta is necessary for the correct signaling of PPARalpha during fasting at least in part because FSP27beta plays a key role in the storage/release of phospholipids proposed as endogenous ligands of PPARalpha form the liver lipid droplets. In vitro, Fsp27beta interferes with the PPARalpha signaling as it was determined by the use of a TK-luciferase reporter under the control of three PPRE. Lack of Fsp27beta expression Increases the concentration of PPARalpha endogenous ligands in serum, which triggers the PPARalpha signaling of in peripheral tissues such as BAT, while decreasing its signaling in the liver. Concretely, Fsp27beta plays a role in the down-regulation of PPARaplha target genes in BAT during fasting. As a conclusion we propose that during early fasting, fatty acids delivered by WAT will induce, through CREBH-FSP27beta axis, the formation of LDs in liver, needed to produce a transitory steatosis and, in addition, avoid the release of endogenous PPARalpha ligan