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Figure 1. Caron S & Huaman Samanez C

Vehicle. Vehicle. Vehicle. Vehicle. Vehicle. WAY362450. CDCA. GW4064. INT-747. GW4064. **. ChREBP-Mlx. HNF4 . ChORE. DR-1. -144. -125. -169. L4. L3. (L4L3) region of the L-PK promoter. F. F. RF. RF. RF + INT-747. RF + INT-747. ***. **. *. **. ***. 25. ***. ***.

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Figure 1. Caron S & Huaman Samanez C

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  1. Vehicle Vehicle Vehicle Vehicle Vehicle WAY362450 CDCA GW4064 INT-747 GW4064 ** ChREBP-Mlx HNF4 ChORE DR-1 -144 -125 -169 L4 L3 (L4L3) region of the L-PK promoter F F RF RF RF + INT-747 RF + INT-747 *** ** * ** *** 25 *** *** *** 20 15 10 5 0 Low High Low High Low High Low High 35 30 *** ** 25 *** 20 Relative (L-PK/36B4)mRNA levels 15 10 5 0 Low High Low High Glc - - + + siRNA FXR E ** ** Relative luciferase activity Glc Low High High GW4064 - - + Figure 1. Caron S & Huaman Samanez C A ** ** 200 5 *** 4 150 3 Relative (L-PK/28S) mRNA levels 100 Plasma glucose (mg/dl) 2 50 1 0 0 B C Relative (L-PK/36B4) mRNA levels Glc - siRNA FXR + FXR Relative (L-PK/36B4) mRNA levels Actin 1.0 0.6 Glc D

  2. AB1 AB2 IP : FXR - - + - + GW4064 95 kDa WB : ChREBP 1 124 196 241 472 Full length FXR WB : FXR 59 kDa FXR fragments F1-105 F106-196 F197-284 F215-300 F301-384 F215-472 Input 20% GST GST-FXR 1 2 3 4 5 AF-1 DBD LBD 105 GW4064 - - + ChREBP 106 196 1 ChREBP 197 284 215 300 ChREBP 301 384 ChREBP 215 472 ChREBP ChREBP Figure 2. Caron S & Huaman Samanez C A High Glc Low - - + + GW4064 95 kDa ChREBP 67 kDa Lamin A/C 1 2 3 4 Input 20% GST GST-FXR B GW4064 - - + ChREBP Mlx HNF4 1 2 3 4 C 1 2 3 4 D

  3. HNF4 Relative L-PK promoter occupancy Glc Low High High GW4064 - - + FXR * Relative L-PK promoter occupancy Glc Low High High GW4064 - - + Figure 3. Caron S & Huaman Samanez C ChREBP *** ** Relative L-PK promoter occupancy Glc Low High High GW4064 - - +

  4. p300 CBP * ** * Vehicle Relative L-PK promoter occupancy GW4064 Relative L-PK promoter occupancy Glc Low High Glc Low High High High GW4064 - - GW4064 - - + + 40 35 Input 10% GST GST-SMRT 30 - - + Vehicle 25 GW4064 FXR 20 15 1 2 3 4 10 5 SMRT * Relative L-PK promoter occupancy Glc Low High High GW4064 - - + Figure 4. Caron S & Huaman Samanez C A B ** ** - *** + siRNA SMRT SMRT Relative (L-PK/36B4) mRNA levels Actin 1.0 0.4 Low High Low High Glc Si SMRT - - + + H3K9-Ac D C * RelativeL-PK promoter occupancy GW4064 Glc Low High High GW4064 - - + E F ** 14 * *** 12 10 *** 8 Relative (L-PK/36B4) mRNA levels 6 4 2 Glc Low High Low High - - TSA + +

  5. 2.5 2.0 Vehicle GW4064 1.5 1.0 0.5 0.0 Glc Glc Glc Low Low Low High High High High High High Low Low Low High High High High High High GW4064 GW4064 GW4064 - - - + + + + + + - - - + + + + + + Figure 5. Caron S & Huaman Samanez C ApoCIII FAS * *** * A 8 2.0 * 6 1.5 Relative mRNA levels 4 1.0 2 0.5 0 0.0 Glc Low High Low High TxNIP PNPLA3 * * * ** 20 15 Relative mRNA levels 10 5 0 Glc Low High Low High B FXR ChREBP 60 5 4 40 3 Relative TxNIP promoter occupancy 2 20 1 0 0 CBP p300 6 14 12 5 10 4 Relative TxNIP promoter occupancy 8 3 6 2 4 1 2 0 0 H3K9-Ac SMRT 10 8 8 6 6 Relative TxNIP promoter occupancy 4 4 2 2 0 0

  6. Vehicle GW4064 Figure 6. Caron S & Huaman Samanez C HK3 PGM1 * * 3.5 ** ** 3.5 3.0 3.0 2.5 2.5 Relative mRNA levels 2.0 2.0 1.5 1.5 1.0 1.0 0.5 0.5 0.0 0.0 Glc Glc Low High Low High PGAM1 TPI1 * * * 2.5 2.5 ** 2.0 2.0 Relative mRNA levels 1.5 1.5 1.0 1.0 0.5 0.5 0.0 0.0 Low High Glc Low High Glc ACSS1 LDHA * * *** 9 3.5 * 8 3.0 7 2.5 6 Relative mRNA levels 2.0 5 4 1.5 3 1.0 2 0.5 1 0.0 0 Glc Low High Glc High Low

  7. SMRT CBP CBP p300 p300 ChREBP Figure 7. Caron S & Huaman Samanez C A High glucose FXR HNF4 ChREBP Ac L-PK promoter histones ChORE DR1 -144 -125 -169 L4 L3 B High glucose + FXR activation HDAC FXR HNF4 Ac L-PK promoter ChORE histones DR1 -144 -125 -169 L4 L3

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