Basic Study
Copyright ©The Author(s) 2018.
World J Gastroenterol. Jan 14, 2018; 24(2): 195-210
Published online Jan 14, 2018. doi: 10.3748/wjg.v24.i2.195
Table 1 Effect of 8 wk of treatment with INT-767 on metabolic parameters, non-alcoholic fatty liver disease activity score/fibrosis stage, body weight/composition, and liver weight in ob/ob-NASH mice
Vehicle, (n = 10)INT-767, 3 mg/kg (n = 10)INT-767, 10 mg/kg (n = 10)
Baseline plasma ALT (U/L)577 ± 43.4552 ± 36.1498 ± 27.3
Terminal plasma ALT (U/L)670 ± 58.9478 ± 33.9250 ± 21.6bf
Baseline plasma AST (U/L)436 ± 36.7421 ± 16.7359 ± 15.6
Terminal plasma AST (U/L)552 ± 49.4447 ± 38.8257 ± 42.3ef
Baseline plasma TC (mmol/L)10.3 ± 0.810.3 ± 0.811.1 ± 0.3
Terminal plasma TC (mmol/L)10.7 ± 0.59.2 ± 0.37.2 ± 0.4ef
Baseline plasma TG (mmol/L)0.8 ± 0.00.8 ± 0.10.8 ± 0.1
Terminal plasma TG (mmol/L)0.7 ± 0.00.6 ± 0.00.6 ± 0.1
Terminal liver TC (mg/g tissue)32.9 ± 1.724.0 ± 1.1d18.0 ± 1.5f
Terminal liver TG (mg/g tissue)233 ± 12.3229 ± 15.4149 ± 14.0d
Fasting blood glucose (week 4, mmol/ L)7.6 ± 0.18.2 ± 0.28.0 ± 0.3
OGTT, glucose AUC (week 4, mmol/ L x min)1318 ± 611304 ± 381417 ± 78
Fed blood glucose (week 8, mmol/ L)7.1 ± 0.26.8 ± 0.27.3 ± 0.3
Fed plasma insulin (week 8, pmol/ L)567 ± 133482 ± 122799 ± 229
Baseline steatosis score3.0 ± 0.02.9 ± 0.12.9 ± 0.1
Terminal steatosis score3.0 ± 0.03.0 ± 0.01.8 ± 0.2f
Baseline inflammation score2.5 ± 0.13.0 ± 0.03.0 ± 0.0
Terminal inflammation score2.3 ± 0.12.2 ± 0.21.0 ± 0.1f
Baseline ballooning degeneration score0.6 ± 0.10.7 ± 0.10.8 ± 0.1
Terminal ballooning degeneration score0.9 ± 0.10.7 ± 0.10.2 ± 0.1f
Baseline NAFLD activity score (NAS)6.1 ± 0.26.3 ± 0.26.4 ± 0.2
Terminal NAFLD activity score (NAS)6.2 ± 0.25.9 ± 0.23.0 ± 0.3f
Baseline fibrosis stage2.7 ± 0.22.6 ± 0.12.6 ± 0.1
Terminal fibrosis stage2.7 ± 0.12.5 ± 0.11.6 ± 0.1f
Terminal steatosis (% area)41.1 ± 1.040.6 ± 1.624.8 ± 2.3f
Terminal fibrosis (% area)15.9 ± 0.913.6 ± 0.88.9 ± 0.6f
Baseline BW (g)49.8 ± 0.748.2 ± 1.049.4 ± 1.3
Terminal BW (g)54.6 ± 0.852.6 ± 0.851.3 ± 1.8
Body weight change (%, relative to day 0)109 ± 1.3107 ± 2.1103 ± 2.3
Baseline whole-body lean mass (g)14.0 ± 0.414.6 ± 0.314.4 ± 0.4
Terminal whole-body lean mass (g)17.3 ± 0.417.6 ± 0.517.2 ± 0.2
Baseline whole-body lean mass (% of BW)28.2 ± 0.630.3 ± 0.629.1 ± 0.6
Terminal whole-body lean mass (% of BW)31.9 ± 0.633.9 ± 0.933.6 ± 0.8
Baseline whole-body fat mass (g)18.5 ± 0.418.5 ± 0.719.5 ± 0.7
Terminal whole-body fat mass (g)22.5 ± 0.421.0 ± 0.719.3 ± 0.7e
Baseline whole-body fat mass (% of BW)37.2 ± 0.738.4 ± 1.239.4 ± 0.6
Terminal whole-body fat mass (% of BW)41.4 ± 0.540.4 ± 0.937.5 ± 0.7e
Terminal liver weight (g)5.4 ± 0.24.9 ± 0.14.1 ± 0.1f
Terminal liver weight (% of BW)9.8 ± 0.39.4 ± 0.28.0 ± 0.3d
Table 2 INT-767 and obeticholic acid improve liver histomorphology in ob/ob-NASH steatohepatitis mice with biopsy-confirmed liver pathology
TreatmentFibrosis stage
NAS
No improvementWith improvement% improving1No improvementWith improvement% improving1
Vehicle ( = 11)1100%1100%
OCA 10 mg/kg ( = 12)10217%8433%
OCA 30 mg/kg ( = 11)7436%a011100%a
INT-767 3.0 mg/kg ( = 12)1200%7542%a
INT-767 10 mg/kg ( = 11)2982%a011100%a
Table 3 INT-767 and obeticholic acid improve quantitative liver histopathology in ob/ob-NASH mice
TreatmentLipid (steatosis)Galectin-3 (inflammation)Collagen 1a1 (fibrosis)
% fractional area
Before treatmentAfter treatmentBefore treatmentAfter treatmentBefore treatmentAfter treatment
Vehicle (n = 11)33.0 ± 0.930.4 ± 0.95.7 ± 0.57.8 ± 0.51.2 ± 0.312.1 ± 0.4
OCA 10 mg/kg (n = 12)33.4 ± 0.831.8 ± 0.45.5 ± 0.35.0 ± 0.2a0.9 ± 0.19.0 ± 0.6a
OCA 30 mg/kg (n = 11)32.2 ± 1.122.7 ± 1.0a5.5 ± 0.44.0 ± 0.4a1.2 ± 0.28.0 ± 0.7a
INT-767 3.0 mg/kg (n = 12)33.0 ± 0.929.4 ± 1.3a5.6 ± 0.55.4 ± 0.2a1.2 ± 0.28.5 ± 0.6a
INT-767 10 mg/kg (n = 11)33.7 ± 0.812.5 ± 1.5a5.6 ± 0.32.9 ± 0.1a0.9 ± 0.25.0 ± 0.3a