Involvement of the transcription factor Pparß in the modulation of intestinal epithelial metabolism by the nutritional environment

Gwendoline Grasset

23 May 2024

Thesis defence

Pratical info

13h30 - 23h00
Room Schapira
Research professionnals and doctors
Reduced mobility access

Under the supervision of Pascale Bossard, team Intestinal self-renewal and tumorigenesis

Abstract

Among the etiologies associated with colorectal cancer (CRC), a high-fat diet (HFD) plays a major role in their development. The target cell of CRC is the intestinal stem cell (ISC) at the origin of the renewal capacity of this epithelium and its regeneration following different stresses. The functionality of these ISCs is controlled by signals coming from their niche but also by the nutritional environment: fasting promotes their self-renewal, plays a protective role against DNA damage while an HFD increases the activity of ISCs, gives them independence in regard to their niche and makes them permissive for tumor transformation. Knowing that the nutritional environment affects the fate of ISCs, that nutrition is a major modulator of the metabolic activity, the hypothesis put forward was that these diets modified the behavior of ISCs via metabolic alterations. However, metabolic reprogramming is a key event of tumor transformation. It is therefore possible that the metabolic activity of ISCs is also a major player in tumor transformation. ISCs would have a rather oxidative metabolism with a strong mitochondrial concentration, the precise nature of the oxidized substrate needs to be clarified. Various data suggested that the substrate oxidized by ISCs is lipidic and involved the fatty acid oxidation pathway (FAO) controlled by the transcription factor Pparß. Therefore, I wanted to understand the role of Pparß in the intestinal epithelium, its involvement in the metabolic activity of ISCs and their fate in order to determine the underlying molecular mechanisms linking nutrition and intestinal homeostasis. The expression profiles of Pparß, FAO enzymes and their modulation by the nutritional environment were therefore studied in the intestinal epithelium as well as the metabolic activity of this tissue and also more specifically of the ISCs using a mouse model allowing their sorting. Thus, I demonstrated that they had an FAO capacity modulated by nutritional status. Via the conditional and inducible invalidation of Pparß in the intestinal epithelium, I underlined, on one hand, the key role of Pparß in the FAO activity of ISCs and also, in their oxidative capacities for glucose which were lowered. The FAO involved in two different nutritional situations having either a protective effect on the ISCs (fast) or protumorigenic effects (HFD), suggests that the ISC genic program induced under these two nutritional situations could constitute two distinct epigenomes. Metabolism generates metabolites contributing to the control of the epigenome: among the many epigenetic marks, the acetylation status of histones linked to the Acetyl-CoA pool has been analysed since FAO is a major producer of Acetyl-CoA. The acetylation status depends also on the enzymatic activity of histone de-acetylases (HDAC), antagonists of histone acetyltransferases (HAT), inhibited by beta-hydroxybutyrate, a product of ketogenesis dependent on the FAO activity and under the control of Pparß. The acetylation profiles of histone H3, analysed under different nutritional conditions in the intestinal crypts show that they were affected by the nutritional status in a Pparß-dependant manner. In addition, by radiotracer analyses, I was able to demonstrate that the alterations in histone acetylation profiles were related to the activity of the FAO pathway and not to glucose oxidation and this, in a Pparß-dependent manner. Therefore, Pparß contributes to the effects of nutrition on histone acetylation profiles in the intestinal epithelium via its ability to modulate the metabolic activity of this tissue.