Resumen de Role of fsp27 in lípid homeostasis during nutrient deprivation

Isabel Alexandra Pinto Carrilho do Rosário

• 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 PPARα 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 Fsp27β expression during late fasting.

  3) To identify the role of Fsp27β in PPARα signaling by studying its ability to control the store/release of specific endogenous ligands of PPARα from lipid droplets.

  The results of this work show that Fsp27β is the main isoform expressed in tissues that actively oxidize fatty acids such as liver and BAT, but also in small intestine.

  Fsp27β is a target gene of CREBH, but not of PPARα and there is no cross talk between both transcription factors in the regulation of hepatic expression of Fsp27β.

  Nonetheless, Fsp27β expression depends on the level of CREBH acetylation.

  It has been also described that FSP27β 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 FSP27β is necessary for the correct signaling of PPARα during fasting at least in part because FSP27β plays a key role in the storage/release of phospholipids proposed as endogenous ligands of PPARα form the liver lipid droplets. In vitro, Fsp27β interferes with the PPARα signaling as it was determined by the use of a TK-luciferase reporter under the control of three PPRE. Lack of Fsp27β expression Increases the concentration of PPARα endogenous ligands in serum, which triggers the PPARα signaling of in peripheral tissues such as BAT, while decreasing its signaling in the liver. Concretely, Fsp27β plays a role in the down-regulation of PPARα target genes in BAT during fasting.

  As a conclusion we propose that during early fasting, fatty acids delivered by WAT will induce, through CREBH-FSP27β axis, the formation of LDs in liver, needed to produce a transitory steatosis and, in addition, avoid the release of endogenous PPARα ligands from the liver. Conversely, during the late fasting, SIRT1 activity, also through CREBH modulation, will mediate FSP27 clearance from a liver that is already prepared to oxidize fatty acids. In turn, the increased FAO capacity from liver could alleviated ER stress contributing to CREBH downregulation. During fed states, the absence of Fsp27β in liver will allow the new synthetized fat to leave the liver and actuate as PPARα agonist in extrahepatic tissues like BAT.