Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity

Marion Régnier (1) , Arnaud Polizzi (2) , Sarra Smati (1, 3) , Céline Lukowicz (1) , Anne Fougerat (2) , Yannick Lippi (4) , Edwin Fouché (5) , Frédéric Lasserre (2) , Claire Naylies (4) , Colette Bétoulières (6) , Valentin Barquissau (3) , Etienne Mouisel (3) , Justine Bertrand-Michel (7) , Aurélie Batut (7) , Talal Al Saati (8) , Cécile Canlet (9) , Marie Tremblay-Franco (9) , Sandrine Ellero-Simatos (2) , Dominique Langin (3, 10) , Catherine Postic (11) , Walter Wahli (1, 12, 13) , Nicolas Loiseau (2) , Hervé Guillou (2) , Alexandra Montagner (1, 3)

1 ToxAlim - ToxAlim
2 ToxAlim-TIM - Toxicologie Intégrative & Métabolisme
3 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
4 E23 TRiX - Transcriptomic impact of Xenobiotics
5 ToxAlim-PPCA - Prévention et promotion de la cancérogénèse par les aliments
6 Ezop - Plateforme Ezop
7 MetaToul Lipidomics
8 Service d'Histopathologie Expérimentale [Toulouse]
9 E20 - Metatoul AXIOM
10 Laboratoire de Biochimie [CHU Toulouse]
11 IC UM3 (UMR 8104 / U1016) - Institut Cochin
12 Nanyang Technological University [Singapour]
13 UNIL - Université de Lausanne = University of Lausanne

Peroxisome proliferator activated receptor α (PPARα) acts as a fatty acid sensor to orchestrate the transcription of genes coding for rate-limiting enzymes required for lipid oxidation in hepatocytes. Mice only lacking Pparα in hepatocytes spontaneously develop steatosis without obesity in aging. Steatosis can develop into non alcoholic steatohepatitis (NASH), which may progress to irreversible damage, such as fibrosis and hepatocarcinoma. While NASH appears as a major public health concern worldwide, it remains an unmet medical need. In the current study, we investigated the role of hepatocyte PPARα in a preclinical model of steatosis. For this, we used High Fat Diet (HFD) feeding as a model of obesity in C57BL/6 J male Wild-Type mice (WT), in whole-body Pparα- deficient mice (Pparα-/-) and in mice lacking Pparα only in hepatocytes (Pparαhep-/-). We provide evidence that Pparα deletion in hepatocytes promotes NAFLD and liver inflammation in mice fed a HFD. This enhanced NAFLD susceptibility occurs without development of glucose intolerance. Moreover, our data reveal that non-hepatocytic PPARα activity predominantly contributes to the metabolic response to HFD. Taken together, our data support hepatocyte PPARα as being essential to the prevention of NAFLD and that extra-hepatocyte PPARα activity contributes to whole-body lipid homeostasis.

Domaines: Biologie cellulaire; Endocrinologie et métabolisme

Marion Régnier, Arnaud Polizzi, Sarra Smati, Céline Lukowicz, Anne Fougerat, et al.. Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity. Scientific Reports, 2020, 10 (1), pp.6489. ⟨10.1038/s41598-020-63579-3⟩. ⟨inserm-02875414⟩