Supplementary Table 1. Metabolic parameters in GFP and OGT-treated mice

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1 Supplementary Table 1. Metabolic parameters in GFP and OGT-treated mice Fasted Refed GFP OGT GFP OGT Liver G6P (mmol/g) 0.03± ± ± ±0.10 A TGs (mg/g of liver) 20.08± ± ± ±4.33 A Plasma Plasma glucose (mm) 4.62± ±0.18 A 15.9± ±1.08 Insulin (µg/l) 0.32±0.07 2,04±0.48 A 0.46± ±1.06 A TGs (mm) 0.43± ±0.16 A 0.56± ±0.1 A NEFA (mm) 0.34± ±0.04 A 0.41± ±0.02 C57BL/6J mice were treated for 7 days with either GFP or OGT adenovirus. After infection, mice were fasted overnight or refed on regular diet. Results are mean ± SEM. n = 6 to 10 mice per group. A p<0.005 vs GFP. Supplementary Table 2. Metabolic parameters for C57Bl6/J GFP mice, db/db GFP and OGA mice at the fed state. C57/Bl6 GFP db/db GFP db/db OGA Liver G6P (mmol/g) 0.18±0, ±0,03 B 0.25±0,009 TGs (mg/g of liver) 6.6± ±0.60 B 25.4±0.48 A Plasma Plasma glucose (mm) 6.7± ±0.77 B 11.12±2.60 A TGs (mm) 0.86± ±0.12 B 0.86±0.12 A NEFA (mm) 0.63± ±0.09 B 0.86±0.16 A C57BL/6J mice were treated with GFP and db/db mice were treated with either GFP or OGA adenovirus for 10 days. Results are mean ± SEM. n = 4 to 6 mice per group. A p<0.01 db/db GFP vs. db/db OGA mice. B p<0.01 C57Bl6/J mice vs. db/db GFP

2 Supplementary Figure S1. Effect of glucose or glucosamine treatment on blood glucose and glucose 6-phosphate concentrations. Four groups of C57Bl/6J mice were studied: a 24h fasted group, a fasted group refed a regular diet for 18h and the last groups of mice were forced-fed with glucose (Glc, 5g/kg) or glucosamine (GlcNH 2, 2.5 g/kg) after the fasting period. Mice were sacrificed at the indicated time and analyses were performed. (A). Blood glucose concentrations. Results are the mean ± S.E.M., n=6-10/group. * P<0.01, ** P<0.005 compared to fasted mice. (B). Liver glucose 6-phosphate (G6P) concentrations. Results are the mean ± S.E.M., n=6-10/group. * P< 0.01, ** P<0.005 compared to fasted mice.

3 Supplementary Figure S2. ChREBP is ubiquitinylated and stabilized by glucosamine treatment in vitro. (A). Primary mouse hepatocytes were incubated under low glucose concentrations (G5) supplemented or not with 5 mm glucosamine (GlcNH 2 ) or in high glucose concentrations plus insulin (G25i) for 24 hours. Western blot analysis of O-GlcNAc levels is shown. β-actin was used as a loading control. Representative Western blots are shown. n=3 independent experiments (B). Primary mouse hepatocytes were incubated under low glucose concentrations (G5) supplemented or not with 5mM glucosamine (GlcNH 2 ) or in high glucose medium plus insulin (G25i) for 24 hours. Then cells were incubated with a proteasome inhibitor, MG132 (8µM) or DMSO for 8 hours. Ubiquitinylated and ChREBP proteins levels were analyzed by Western blots. Representative Western blots are shown. n=3 independent experiments. (C). qrt-pcr analysis of ChREBP (blacks bars) and L-PK (white bars) in primary mouse hepatocytes incubated with or without MG132, ( ** P<0.005 compared to G5 conditions; n=3). (D). HEK293T cells were transfected with 1 µg of ChREBP wt plasmid simultaneous to an ubiquitin HA-tagged plasmid expressing. Cells were then incubated in G25 for 24 hours. MG132 (20µM) or DMSO were added for 7 hours. ChREBP immunoprecipitates were immunoblotted with HA antibodies to detect ubiquitinylated forms of ChREBP. Representative Western blot are shown. n=3 independent experiments.

4 Supplementary Figure S3. O-GlcNAcylation of ChREBP DP is not decreased in HEK293T cells. (A). HEK239T cells were co-transfected with OGT (1µg) and ChREBP plasmids (1µg) (ChREBP wt or ChREBP DP ) and incubated for 24h under high glucose conditions plus insulin (G25i). Global O-GlcNAc levels and transfected ChREBP O-GlcNAcylation were obtained by immunoblotting experiments. O- GlcNAcylated forms of ChREBP (ChREBP OG ) were obtained through WGA beads immunoblotted with an anti-chrebp antibody. Transfected ChREBP and OGT levels were revealed by incubation with specific antibodies. β-actin was used as loading control. Representative Western blots are shown, n=4 independent experiments. (B). Quantification of the ratio of ChREBP O-GlcNAcylation (ChREBP OG ) compared to total ChREBP content is shown. Results are the mean ± S.E.M., n= 4.

5 Supplementary Figure S4. O-GlcNAcylation of ChREBP increases its transcriptional activity in HepG2 cells. HepG2 cells were transfected with a luciferase reporter construct containing 3 copies of the L-PK ChoRE and ChREBP wt. Twenty four hours post-transfection, cells were incubated with either low (G5) or high (G25) glucose concentrations supplemented or not with 5µM PUGNAc for 4h.PUGNAc is an inhibitor of the O-GlcNAcase (OGA) that hydrolyses the sugar (Figure 1A). Luciferase activity was normalized to β-galactosidase activity. n=6 independent experiments/group. *** P<0.001 compared to G5 conditions, # P<0.05 compared to G25 without PUGNAc.

6 Supplementary Figure S5. Effect of OGT overexpression on SREBP-1c expression and/or activity. (A). qrt-pcr analysis of SREBP1c expression in liver of GFP and OGT mice. * P< 0.01 compared to fasted mice. (B). Precursor (P) and mature (m) SREBP-1c were analyzed by Western blot. Lamin A/C was used as a control. Representative Western blots are shown. Lanes were run on the same gel but were noncontiguous. (C). O-GlcNAcylated forms of SREBP-1c (SREBP OG ) were obtained by WGA binding experiments. Specificity of the binding was confirmed by GlcNAc (0.5 mm) competition. A representative Western blot is shown. n=6/group.

7 Supplementary Figure S6. O-GlcNAcylation increases ChREBP stability and transcriptional activity in liver. Under low glucose concentrations, ChREBP would be ubiquitinylated leading to its subsequent proteasomal degradation (dotted lines). Under high glucose concentrations, ChREBP would first be modified by O-GlcNAcylation via its interaction with OGT thereby allowing its stabilization. Under high glucose concentrations, ChREBP would then be dephosphorylated on Ser-196 (through an activation of glucose metabolism) and translocated to the nucleus to activate its target genes. O- GlcNAcylation of ChREBP would also take a part in its transcriptional activity. In a physiopathological context (in obese db/db mice), hyperglycemia would lead to an increase in global and ChREBP O- GlcNAcylation levels causing in turn enhanced lipogenesis and development of hepatic steatosis.

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