C. Chip and . Sample-preparation, ChIP samples were prepared as described previously 21 , with minor modifications. Briefly, fresh livers were chopped into small pieces and crosslinked with 1% formaldehyde (ThermoFisher, 28906) in PBS for 10 min for histone modifications, or double crosslinked with 2 mM disuccinimidyl glutarate (DSG) for 30 min, followed by 1% formaldehyde for 10 min, for TFs and GPS2. The reaction was stopped with glycine at a final concentration of 0.125 M for 5 min

, Dounce Homogenizer first with loose and later with tight pestle (Fisher Science, FB56691)

, Formaldehyde cross-linking was reversed overnight at 65°C, and the immunoprecipitated DNA was purified using the QIAquick PCR purification kit (Qiagen). Primers for the ChIP qPCR are listed in Supplementary Table 1. To prepare the ChIP-seq samples, the same ChIP protocol was followed, but using the ChIP DNA Clean and Concentrator Capped Zymo-Spin I (Zymo Research) purification kit. Two to four ChIPs were pooled during the final step of the purification to obtain concentrated material. For library preparation and sequencing, 2-10 ng of ChIPed DNA was processed using Rubicon ThruPLEX DNA-seq kit (TAKARA) or processed at the EMBL Genomics Core Facility, sc-2027, 1-5 ?g), anti-H3K4me3 (Abcam, ab8580, 1 ?g), anti-H3K27ac (Abcam, ab4729, 1 ?g), anti-PPAR? (Millipore MAB3890, 5 ?g), anti-Polymerase II (Biolegend, 664906, 5 ?g), anti-NCOR (Bethyl laboratories, A301-145A, 4 ?g), anti-SMRT (Bethyl laboratories, A301-147A, 4 ?g)

, The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project SNIC 2018/8-122. Analysis was performed as previously described 21 . Sequencing files (fastq files), provided by the EMBL, Genomics

G. Musso, M. Cassader, and R. Gambino, Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies, Nat. Rev. Drug Discov, vol.15, pp.249-274, 2016.
DOI : 10.1038/nrd.2015.3

M. Eslam, L. Valenti, and S. Romeo, Genetics and epigenetics of NAFLD and NASH: clinical impact, J. Hepatol, vol.68, pp.268-279, 2018.

T. Hardy and D. A. Mann, Epigenetics in liver disease: from biology to therapeutics, Gut, vol.65, pp.1895-1905, 2016.

J. P. Arab, S. J. Karpen, P. A. Dawson, M. Arrese, and M. Trauner, Bile acids and nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives, Hepatology, vol.65, pp.350-362, 2017.

N. Tanaka, T. Aoyama, S. Kimura, and F. J. Gonzalez, Targeting nuclear receptors for the treatment of fatty liver disease, Pharmacol. Ther, vol.179, pp.142-157, 2017.

T. Jakobsson, L. L. Vedin, and P. Parini, Potential role of thyroid receptor beta agonists in the treatment of hyperlipidemia, Drugs, vol.77, pp.1613-1621, 2017.

M. Pawlak, P. Lefebvre, and B. Staels, Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in nonalcoholic fatty liver disease, J. Hepatol, vol.62, pp.720-733, 2015.

M. Monetti, Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver, Cell. Metab, vol.6, pp.69-78, 2007.

L. Goedeke, Acetyl-CoA carboxylase inhibition reverses NAFLD and hepatic insulin resistance but promotes hypertriglyceridemia in rodents, Hepatology, vol.68, pp.2197-2211, 2018.

E. Fabbrini, S. Sullivan, and S. Klein, Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications, Hepatology, vol.51, pp.679-689, 2010.

Y. Li, AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice, Cell. Metab, vol.13, pp.376-388, 2011.

X. Ding, N. K. Saxena, S. Lin, N. A. Gupta, and F. A. Anania, Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice, Hepatology, vol.43, pp.173-181, 2006.

J. Xu, Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice, Diabetes, vol.58, pp.250-259, 2009.

G. Alvarez-sola, Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration, Gut, vol.66, pp.1818-1828, 2017.

P. Lefebvre, Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARalpha-regulated dermatopontin, JCI Insight, vol.2, p.92264, 2017.

S. K. Murphy, Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease, Gastroenterology, vol.145, pp.1076-1087, 2013.

A. Sommerfeld, A. Krones-herzig, and S. Herzig, Transcriptional co-factors and hepatic energy metabolism, Mol. Cell. Endocrinol, vol.332, pp.21-31, 2011.
URL : https://hal.archives-ouvertes.fr/hal-00654957

M. Giudici, S. Goni, R. Fan, and E. Treuter, Nuclear receptor coregulators in metabolism and disease, Handb. Exp. Pharmacol, vol.233, pp.95-135, 2016.

E. Treuter, R. Fan, Z. Huang, T. Jakobsson, and N. Venteclef, Transcriptional repression in macrophages-basic mechanisms and alterations in metabolic inflammatory diseases, FEBS Lett, vol.591, pp.2959-2977, 2017.

A. Toubal, SMRT-GPS2 corepressor pathway dysregulation coincides with obesity-linked adipocyte inflammation, J. Clin. Invest, vol.123, pp.362-379, 2013.

R. Fan, Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes, Nat. Med, vol.22, pp.780-791, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01438151

M. J. Emmett and M. A. Lazar, Integrative regulation of physiology by histone deacetylase 3, Nat. Rev. Mol. Cell Biol, vol.20, pp.102-115, 2018.

J. Oberoi, Structural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery, Nat. Struct. Mol. Biol, vol.18, pp.177-184, 2011.

J. Zhang, M. Kalkum, B. T. Chait, and R. G. Roeder, The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2, Mol. Cell, vol.9, pp.611-623, 2002.

B. Pourcet, I. Pineda-torra, B. Derudas, B. Staels, and C. Glineur, SUMOylation of human peroxisome proliferator-activated receptor alpha inhibits its trans-activity through the recruitment of the nuclear corepressor NCoR, J. Biol. Chem, vol.285, pp.5983-5992, 2010.
URL : https://hal.archives-ouvertes.fr/inserm-00439808

H. Shimizu, NCoR1 and SMRT play unique roles in thyroid hormone action in vivo, Mol. Cell. Biol, vol.35, pp.555-565, 2015.

M. Jeyakumar, X. F. Liu, H. Erdjument-bromage, P. Tempst, and M. K. Bagchi, Phosphorylation of thyroid hormone receptor-associated nuclear receptor corepressor holocomplex by the DNA-dependent protein kinase enhances its histone deacetylase activity, J. Biol. Chem, vol.282, pp.9312-9322, 2007.

Y. S. Jo, Phosphorylation of the nuclear receptor corepressor 1 by protein kinase B switches its corepressor targets in the liver in mice, Hepatology, vol.62, pp.1606-1618, 2015.

D. Feng, A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism, Science, vol.331, pp.1315-1319, 2011.

P. Dowell, Identification of nuclear receptor corepressor as a peroxisome proliferator-activated receptor alpha interacting protein, J. Biol. Chem, vol.274, pp.15901-15907, 1999.

C. Yu, The nuclear receptor corepressors NCoR and SMRT decrease peroxisome proliferator-activated receptor gamma transcriptional activity and repress 3T3-L1 adipogenesis, J. Biol. Chem, vol.280, pp.13600-13605, 2005.

D. Guan, Diet-induced circadian enhancer remodeling synchronizes opposing hepatic lipid metabolic processes, Cell, vol.174, p.812, 2018.
DOI : 10.1016/j.cell.2018.06.031

P. Kulozik, Hepatic deficiency in transcriptional cofactor TBL1 promotes liver steatosis and hypertriglyceridemia, Cell. Metab, vol.13, pp.389-400, 2011.

M. W. Robinson, C. Harmon, and C. O'farrelly, Liver immunology and its role in inflammation and homeostasis, Cell. Mol. Immunol, vol.13, pp.267-276, 2016.

P. Lefebvre, G. Chinetti, J. C. Fruchart, and B. Staels, Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis, J. Clin. Invest, vol.116, pp.571-580, 2006.

A. Montagner, Liver PPARalpha is crucial for whole-body fatty acid homeostasis and is protective against NAFLD, Gut, vol.65, pp.1202-1214, 2016.

S. Kersten, Integrated physiology and systems biology of PPARalpha, Mol. Metab, vol.3, pp.354-371, 2014.

T. Jakobsson, GPS2 is required for cholesterol efflux by triggering histone demethylation, LXR recruitment, and coregulator assembly at the ABCG1 locus, Mol. Cell, vol.34, pp.510-518, 2009.

Y. Shen, A map of the cis-regulatory sequences in the mouse genome, Nature, vol.488, pp.116-120, 2012.

J. M. Lee, Nutrient-sensing nuclear receptors coordinate autophagy, Nature, vol.516, pp.112-115, 2014.

Z. Sun, Deacetylase-independent function of HDAC3 in transcription and metabolism requires nuclear receptor corepressor, Mol. Cell, vol.52, pp.769-782, 2013.

M. D. Cardamone, A protective strategy against hyperinflammatory responses requiring the nontranscriptional actions of GPS2, Mol. Cell, vol.46, pp.91-104, 2012.

N. Venteclef, GPS2-dependent corepressor/SUMO pathways govern anti-inflammatory actions of LRH-1 and LXRbeta in the hepatic acute phase response, Genes Dev, vol.24, pp.381-395, 2010.

S. Sanyal, Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis, Proc. Natl Acad. Sci. USA, vol.104, pp.15665-15670, 2007.

D. S. Grass, Transgenic mice expressing both human apolipoprotein B and human CETP have a lipoprotein cholesterol distribution similar to that of normolipidemic humans, J. Lipid Res, vol.36, pp.1082-1091, 1995.

S. M. Armour, An HDAC3-PROX1 corepressor module acts on HNF4alpha to control hepatic triglycerides, Nat. Commun, vol.8, p.549, 2017.

C. Guo, The optimal corepressor function of nuclear receptor corepressor (NCoR) for peroxisome proliferator-activated receptor gamma requires G protein pathway suppressor 2, J. Biol. Chem, vol.290, pp.3666-3679, 2015.

P. J. Watson, L. Fairall, and J. W. Schwabe, Nuclear hormone receptor corepressors: structure and function, Mol. Cell. Endocrinol, vol.348, pp.440-449, 2012.

H. E. Xu, Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha, Nature, vol.415, pp.813-817, 2002.

M. H. Liu, A natural polymorphism in peroxisome proliferator-activated receptor-alpha hinge region attenuates transcription due to defective release of nuclear receptor corepressor from chromatin, Mol. Endocrinol, vol.22, pp.1078-1092, 2008.

M. Rakhshandehroo, B. Knoch, M. Muller, and S. Kersten, Peroxisome proliferator-activated receptor alpha target genes, PPAR Res, vol.61, pp.393-416, 2010.

M. K. Badman, Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states, Cell. Metab, vol.5, pp.426-437, 2007.

H. Li, Sodium butyrate stimulates expression of fibroblast growth factor 21 in liver by inhibition of histone deacetylase 3, Diabetes, vol.61, pp.797-806, 2012.

S. S. Lee, Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators, Mol. Cell. Biol, vol.15, pp.3012-3022, 1995.

B. S. Carvalho and R. A. Irizarry, A framework for oligonucleotide microarray preprocessing, Bioinformatics, vol.26, pp.2363-2367, 2010.

M. E. Ritchie, limma powers differential expression analyses for RNAsequencing and microarray studies, Nucleic Acids Res, vol.43, p.47, 2015.

B. Langmead, C. Trapnell, M. Pop, and S. L. Salzberg, Ultrafast and memoryefficient alignment of short DNA sequences to the human genome, Genome Biol, vol.10, p.25, 2009.

S. Heinz, Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities, Mol. Cell, vol.38, pp.576-589, 2010.

J. T. Robinson, Integrative genomics viewer, Nat. Biotechnol, vol.29, pp.24-26, 2011.

M. J. De-hoon, S. Imoto, J. Nolan, and S. Miyano, Open source clustering software, Bioinformatics, vol.20, pp.1453-1454, 2004.

R. D. Page, TreeView: an application to display phylogenetic trees on personal computers, Comput. Appl. Biosci, vol.12, pp.357-358, 1996.

M. D. Robinson, D. J. Mccarthy, and G. K. Smyth, edgeR: a Bioconductor package for differential expression analysis of digital gene expression data, Bioinformatics, vol.26, pp.139-140, 2010.

D. J. Mccarthy, Y. Chen, and G. K. Smyth, Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation, Nucleic Acids Res, vol.40, pp.4288-4297, 2012.