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Liver PPAR Is Crucial for Whole-Body Fatty Acid Homeostasis and Is

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Liver PPAR Is Crucial for Whole-Body Fatty Acid Homeostasis and Is Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD Alexandra Montagner, Arnaud Polizzi, Edwin Fouché, Simon Ducheix, Yannick Lippi, Frédéric Lasserre, Valentin Barquissau, Marion Régnier, Céline Lukowicz, Fadila Benhamed, et al. To cite this version: Alexandra Montagner, Arnaud Polizzi, Edwin Fouché, Simon Ducheix, Yannick Lippi, et al.. Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut, BMJ Publishing Group, 2016, 65 (7), pp.1202-1214. 10.1136/gutjnl-2015-310798. inserm-02339685 HAL Id: inserm-02339685 https://www.hal.inserm.fr/inserm-02339685 Submitted on 30 Oct 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Hepatology ORIGINAL ARTICLE Liver PPARα is crucial for whole-body fatty acid Gut: first published as 10.1136/gutjnl-2015-310798 on 1 February 2016. Downloaded from homeostasis and is protective against NAFLD Alexandra Montagner,1 Arnaud Polizzi,1 Edwin Fouché,1 Simon Ducheix,1 Yannick Lippi,1 Frédéric Lasserre,1 Valentin Barquissau,2,3 Marion Régnier,1 Céline Lukowicz,1 Fadila Benhamed,4,5,6 Alison Iroz,4,5,6 Justine Bertrand-Michel,2,3 Talal Al Saati,7 Patricia Cano,1 Laila Mselli-Lakhal,1 Gilles Mithieux,8 Fabienne Rajas,8 Sandrine Lagarrigue,9,10,11 Thierry Pineau,1 Nicolas Loiseau,1 Catherine Postic,4,5,6 Dominique Langin,2,3,12 Walter Wahli,1,13,14 Hervé Guillou1 ▸ Additional material is ABSTRACT published online only. To view Objective Peroxisome proliferator-activated receptor α Significance of this study please visit the journal online α (http://dx.doi.org/10.1136/ (PPAR ) is a nuclear receptor expressed in tissues with gutjnl-2015-310798). high oxidative activity that plays a central role in fi metabolism. In this work, we investigated the effect of What is already known on this subject? For numbered af liations see α end of article. hepatocyte PPAR on non-alcoholic fatty liver disease ▸ Peroxisome proliferator-activated receptor α (NAFLD). (PPARα) is a nuclear receptor expressed in Correspondence to Design We constructed a novel hepatocyte-specific many tissues and is responsible for several − − Dr Hervé Guillou, INRA PPARα knockout (Pparαhep / ) mouse model. Using this important metabolic controls, especially during UMR1331, ToxAlim, Chemin de Tournefeuille, novel model, we performed transcriptomic analysis fasting. Toulouse 31027, France; following fenofibrate treatment. Next, we investigated ▸ PPARα is a target for the hypolipidemic drugs [email protected] which physiological challenges impact on PPARα. of the fibrate family. or Moreover, we measured the contribution of hepatocytic ▸ PPARα is less expressed in the liver of patients Prof. Walter Wahli Lee Kong PPARα activity to whole-body metabolism and fibroblast Chian School of Medicine with non-alcoholic fatty liver diseases (NAFLD). Nanyang Technological growth factor 21 production during fasting. Finally, we ▸ Several PPAR-targeting molecules, including University The Academia, determined the influence of hepatocyte-specificPPARα dual agonists, are currently under investigation 20 College Road, Singapore deficiency in different models of steatosis and during for NAFLD treatment. 169856; ageing. [email protected] What are the new findings? Results Hepatocyte PPARα deletion impaired fatty acid http://gut.bmj.com/ ▸ α Received 25 September 2015 catabolism, resulting in hepatic lipid accumulation during Hepatocyte-restricted PPAR deletion impairs Revised 28 December 2015 fasting and in two preclinical models of steatosis. Fasting liver and whole-body fatty acid homeostasis. Accepted 4 January 2016 mice showed acute PPARα-dependent hepatocyte activity ▸ Hepatic PPARα responds to acute and chronic Published Online First during early night, with correspondingly increased adipose tissue lipolysis. 2 February 2016 circulating free fatty acids, which could be further ▸ Hepatic PPARα regulates circadian fibroblast stimulated by adipocyte lipolysis. Fasting led to mild growth factor 21 (FGF21) and fasting-induced − − hypoglycaemia and hypothermia in Pparαhep / mice FGF21, and is partially responsible for the on October 31, 2019 by guest. Protected copyright. when compared with Pparα−/− mice implying a role of FGF21 increase in steatohepatitis. PPARα activity in non-hepatic tissues. In agreement with ▸ Hepatocyte-restricted PPARα deletion is this observation, Pparα−/− mice became overweight sufficient to promote NAFLD and during ageing while Pparαhep−/− remained lean. hypercholesterolaemia during ageing, but does −/− hep−/− not lead mice to become overweight. Open Access However, like Pparα mice, Pparα fed a Scan to access more standard diet developed hepatic steatosis in ageing. free content How might it impact on clinical practice in Conclusions Altogether, these findings underscore the α the foreseeable future? potential of hepatocyte PPAR as a drug target for ▸ This work emphasises the relevance and NAFLD. potential of hepatic PPARα as a drug target for NAFLD. ▸ http://dx.doi.org/10.1136/ gutjnl-2016-311408 INTRODUCTION Precise control of fatty acid metabolism is essential. target gene transcription. The three PPAR isotypes, Defective fatty acid homeostasis regulation may PPARα,PPARβ/δ and PPARγ, display specific tissue induce lipotoxic tissue damage, including hepatic expression patterns and control different biological steatosis.1 Peroxisome proliferator-activated recep- functions,3 but all bind lipids and control lipid tors (PPARs) are transcription factors that serve as homeostasis in different tissues, including the liver.2 To cite: Montagner A, fatty acid receptors and help regulate gene expres- A healthy liver does not accumulate lipids, but it Polizzi A, Fouché E, et al. sion in response to fatty acid-derived stimuli.2 plays central roles in fatty acid anabolism and – Gut 2016;65:1202 1214. PPARs act as ligand-activated receptors, controlling export to peripheral organs, including white 1202 Montagner A, et al. Gut 2016;65:1202–1214. doi:10.1136/gutjnl-2015-310798 Hepatology adipose tissue for energy storage.4 During dietary restriction, cholesterol were determined using a COBAS-MIRA+ biochem- hepatic fatty acid catabolism is also critical for using free fatty ical analyser (Anexplo facility). acids (FFAs) released from white adipose tissues. PPARα is the Gut: first published as 10.1136/gutjnl-2015-310798 on 1 February 2016. Downloaded from most abundant isotype in hepatocytes and is involved in many Circulating glucose and ketone bodies aspects of lipid metabolism,56including fatty acid degradation, Blood glucose was measured using an Accu-Chek Go gluc- synthesis, transport, storage, lipoprotein metabolism and keto- ometer (Roche Diagnostics). β-Hydroxybutyrate content was – genesis during fasting.7 9 In addition, PPARα controls glycerol measured using Optium β-ketone test strips with Optium Xceed use for gluconeogenesis9 as well as autophagy10 in response to sensors (Abbott Diabetes Care). fasting. Moreover, PPARα regulates the expression of the fibro- blast growth factor 21 (FGF21) during starvation.11 12 In turn, Histology FGF21 acts as an endocrine hormone targeting various func- Paraformaldehyde-fixed, paraffin-embedded liver tissue was tions including metabolic control.13 Finally, PPARα helps sliced into 5 μm sections and H&E stained. Visualisation was repress the acute-phase response and inflammation in the performed using a Leica DFC300 camera. liver.14 Obesity can lead to organ and vascular complications.15 Liver lipids analysis Non-alcoholic fatty liver disease (NAFLD), which are consid- Detailed experimental protocols are provided in online supple- ered the hepatic manifestation of metabolic syndrome, range mentary file 1. from benign steatosis to severe non-alcoholic steatohepatitis (NASH), potentially further damaging organs.16 Sustained ele- Gene expression studies vation of neutral lipid accumulation (mostly triglycerides in hep- Total RNA was extracted with TRIzol reagent (Invitrogen). atocyte lipid droplets) initiates early pathological stages. Transcriptomic profiles were obtained using Agilent Whole Different fatty acid sources contribute to fatty liver develop- Mouse Genome microarrays (4×44k). Microarray data and ment, including dietary lipid intake, de novo lipogenesis and experimental details are available in the Gene Expression adipose tissue lipolysis.4 In NAFLD, 60% of fatty acids accumu- Omnibus (GEO) database (accession number GSE73298 and lated in steatotic liver are adipose-derived.17 GSE73299). For real-time quantitative PCR (qPCR), 2 mg RNA – Preclinical18 21 and clinical22 studies highlight that PPARα samples were reverse-transcribed using the High-Capacity influences NAFLD and NASH. Mice lacking PPARα develop cDNA Reverse Transcription Kit (Applied Biosystems). Online steatosis during fasting,78suggesting the importance of PPARα supplementary file 2 presents the SYBR Green assay primers. activity for using FFA released from adipocytes. However, Amplifications were performed using an ABI Prism 7300 PPARα is expressed and active in many
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