Research Article Details

Article ID: A13307
PMID: 30038487
Source: Drug Des Devel Ther
Title: Farnesoid X receptor agonist INT-767 attenuates liver steatosis and inflammation in rat model of nonalcoholic steatohepatitis.
Abstract: Introduction: Nonalcoholic steatohepatitis (NASH) is largely driven by the dysregulation of liver metabolism and inflammation. Bile acids and their receptor Farnesoid X receptor (FXR) play a critical role in the disease development. Here, we investigated whether INT-767, the newly-identified dual FXR/TGR5 agonist, can protect rat from liver injury during NASH. Materials and methods: NASH model was established by feeding the male SD rats with high-fat diet for 16 weeks. INT-767 was given by gavage to NASH rats from week 13 to week 16. At the end of 16 weeks, liver and serum were harvested, and bile acids, glucose and lipid metabolism, liver injury and histological features were evaluated. Results: INT-767 treatment significantly alleviates high-fat caused liver damage characterized with lipid accumulation and hepatic infiltration of immune cells. INT-767 robustly restores the lipid, glucose metabolism to normal level, attenuates insulin resistance through upregulating FXR level and reverting the dysregulation of its target genes in liver metabolism. Molecularly INT-767 also attenuates the pro-inflammatory response by suppression of TNF-α and NF-κB signaling pathway. Conclusion: INT-767 may be an attractive candidate for a potential novel strategy on the treatment of NASH.
DOI: 10.2147/DDDT.S170518

Strategy ID Therapy Strategy Synonyms Therapy Targets Therapy Drugs
S01 Improve insulin resistance insulin sensitizer; insulin resistance; glucose tolerance Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide Details
S02 Enhance lipid metabolism triglyceride-lowering; lipid tolerance; lipid metabolism 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; Details
S05 Anti-inflammatory inflammatory Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; Details

Target ID Target Name GENE Action Class UniProtKB ID Entry Name
T08 Tumor necrosis factor TNF inhibitor Cytokine P01375 TNFA_HUMAN Details
T17 Farnesoid X-activated receptor NR1H4 agonist Nuclear hormone receptor Q96RI1 NR1H4_HUMAN Details
T18 Acetyl-CoA carboxylase 1 ACACA inhibitor Enzyme Q13085 ACACA_HUMAN Details
T07 Bile acid receptor NR1H4 agonist Nuclear hormone receptor Q96RI1 NR1H4_HUMAN Details

Diseases ID DO ID Disease Name Definition Class
I05 9352 Type 2 diabetes mellitus A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus Details

Drug ID Drug Name Type DrugBank ID Targets Category Latest Progress
D184 INT-767 Chemical drug -- FXR agonist; TGR5 agonist Enhance lipid metabolism Under investigation Details
D328 Serine Chemical drug DB00133 SRR Improve insulin resistance Under clinical trials Details
D182 Insulin Biological drug DB00030 INSR agonist; CPE modulator&product of -- Under clinical trials Details