Genes associated with farnesoid X receptor signaling in the liver significantly up- or downregulated after treatment with OCA 30 mg/kg or INT-787 30 mg/kg compared with vehicle.

Differences in expression levels of genes meeting the adjusted p p value. Vehicle, n = 10; OCA 30 mg/kg, n = 9; INT-787 30 mg/kg, n = 9.</p

Fig 5 -

Body weight (g) at baseline (A) and end of study (week 8) (B). Data are individual body weights; minimum, maximum, and median values; and interquartile range (Q1 and Q3). OCA indicates obeticholic acid. Vehicle, n = 9; OCA 45/30 mg/kg, n = 10; OCA 60/30 mg/kg, n = 11; INT-787 10 mg/kg, n = 11; INT-787 30 mg/kg, n = 10; INT-787 60 mg/kg, n = 9; INT-787 120 mg/kg, n = 11 for animals with body weight measurements at day 57.</p

Genes associated with lipid metabolism in the liver significantly up- or downregulated after treatment with OCA 30 mg/kg or INT-787 30 mg/kg compared with vehicle.

Differences in expression levels of genes meeting the adjusted p p value. Vehicle, n = 10; OCA 30 mg/kg, n = 9; INT-787 30 mg/kg, n = 9.</p

S1 Raw data -

The nuclear farnesoid X receptor (FXR), a master regulator of bile acid and metabolic homeostasis, is a key target for treatment of nonalcoholic steatohepatitis (NASH). This study compared efficacy of FXR agonists obeticholic acid (OCA) and INT-787 by liver histopathology, plasma biomarkers of liver damage, and hepatic gene expression profiles in the Amylin liver NASH (AMLN) diet–induced and biopsy-confirmed Lepob/ob mouse model of NASH. Lepob/ob mice were fed the AMLN diet for 12 weeks before liver biopsy and subsequent treatment with vehicle, OCA, or INT-787 for 8 weeks. Hepatic steatosis, inflammation, and fibrosis (liver lipids, galectin-3, and collagen 1a1 [Col1a1], respectively), as well as plasma alanine transaminase (ALT) and aspartate transaminase (AST) levels, were assessed. Hepatic gene expression was assessed in Lepob/ob mice that were fed the AMLN diet for 14 weeks then treated with vehicle, OCA, or INT-787 for 2 weeks. INT-787, which is equipotent to OCA but more hydrophilic, significantly reduced liver lipids, galectin-3, and Col1a1 compared with vehicle, and to a greater extent than OCA. INT-787 significantly reduced plasma ALT and AST levels, whereas OCA did not. INT-787 modulated a substantially greater number of genes associated with FXR signaling, lipid metabolism, and stellate cell activation relative to OCA in hepatic tissue. These findings demonstrate greater efficacy of INT-787 treatment compared with OCA in improving liver histopathology, decreasing liver enzyme levels, and enhancing gene regulation, suggesting superior clinical potential of INT-787 for the treatment of NASH and other chronic liver diseases.</div

Representative images of liver histopathologic assessments of steatosis (H&E staining), inflammation (galectin-3 staining), and fibrosis (Col1a1 staining).

Col1a1 indicates collagen type 1 alpha 1 chain; H&E, hematoxylin and eosin; OCA, obeticholic acid. Stains are magnified 20×, scale bar = 100 μm.</p

Fig 4 -

Levels of the plasma liver enzymes ALT (A) and AST (B) at termination. Data are individual plasma ALT and AST (U/L) values; minimum, maximum, and median values; and interquartile range (Q1 and Q3). *p p p p #p ##p ###p ####p < 0.0001 by 1-way analysis of variance with Bonferroni post hoc test. ALT indicates alanine transaminase; AST, aspartate transaminase; OCA, obeticholic acid. Vehicle, n = 10; OCA 45/30 mg/kg, n = 11; OCA 60/30 mg/kg, n = 11; INT-787 10 mg/kg, n = 11; INT-787 30 mg/kg, n = 10; INT-787 60 mg/kg, n = 9; INT-787 120 mg/kg, n = 11 for animals with plasma ALT and AST measurements at termination.</p

Change in body weight from baseline to week 8.

Data are expressed as mean ± SEM. OCA indicates obeticholic acid; SEM, standard error of the mean. (TIF)</p

Genes associated with stellate cell activation (fibrosis) in the liver significantly up- or downregulated after treatment with OCA 30 mg/kg or INT-787 30 mg/kg compared with vehicle.

Differences in expression levels of genes meeting the adjusted p p value. Vehicle, n = 10; OCA 30 mg/kg, n = 9; INT-787 30 mg/kg, n = 9.</p

Fig 1 -

Experimental design for disease progression analysis (A) and mRNA sequencing (B). ALT indicates alanine transaminase; AMLN, Amylin liver NASH; AST, aspartate transaminase; MRI, magnetic resonance imaging; NASH, nonalcoholic steatohepatitis; OCA, obeticholic acid; RNA, ribonucleic acid.</p

Fig 3 -

Levels of histopathology markers quantified by percentage fractional area for steatosis (A), inflammation (B), and fibrosis (C). Data are percentage of fractional area change from baseline with minimum, maximum, and median values and interquartile range (Q1 and Q3). *p p p #p ##p ###p ####p < 0.0001 by 1-way analysis of variance with Bonferroni post hoc test. Col1a1 indicates collagen type 1 alpha 1 chain; OCA indicates obeticholic acid. Vehicle, n = 10; OCA 45/30 mg/kg, n = 11; OCA 60/30 mg/kg, n = 11; INT-787 10 mg/kg, n = 11; INT-787 30 mg/kg, n = 10; INT-787 60 mg/kg, n = 10; INT-787 120 mg/kg, n = 11.</p