INT-767 is a potent dual agonist of the farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5), with EC50 values of 30nM and 630nM, respectively[1,2]. INT-767 reduces hepatic lipids, improves insulin resistance, and alleviates inflammation, and is commonly used in the treatment and research of non-alcoholic steatohepatitis (NASH) and other metabolic diseases[3,4].
In vitro, treatment of rabbit visceral fat preadipocytes (rPADs) with INT-767 (1μM) for 10 days significantly increased oxygen consumption (from 30.83 ± 3.15 to 69.44 ± 14.74 nmol O2/mL) while decreasing ATP production (from 13.89 ± 0.92 to 9.34 ± 0.59 relative light units (RLU)/cell number)[5].
In vivo, oral administration of INT-767 (10mg/kg; once daily) for 8 weeks in ob/ob mice with NASH reduced hepatic collagen content and lipid area[6]. Treatment of NASH rats with INT-767 (20mg/kg; once daily) by gavage for 4 weeks significantly improved insulin resistance, as indicated by a reduced homeostatic model assessment of insulin resistance index (HOMA-IR) and increased serum glucagon-like peptide-1 (GLP-1) levels [7].
References:
[1] BAGHDASARYAN A, CLAUDEL T, GUMHOLD J, et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/-(Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO output[J]. Hepatology, 2011, 54(4): 1303-1312.
[2] RIZZO G, PASSERI D, DE FRANCO F, et al. Functional characterization of the semisynthetic bile acid derivative INT-767, a dual farnesoid X receptor and TGR5 agonist[J]. Molecular Pharmacology, 2010, 78(4): 617-630.
[3] VIGNOZZI L, CELLAI I, FILIPPI S, et al. HP-01-006 The dual FXR/TGR5 agonist INT-767 counteracts nonalcoholic steatohepatitis and erectile dysfunction in a rabbit model of high fat diet-induced metabolic syndrome[J]. The Journal of Sexual Medicine, 2017, 14(Supplement 4a): e143-e144.
[4] WANG X X, LUO Y, WANG D, et al. A dual agonist of farnesoid X receptor (FXR) and the G protein–coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice[J]. Journal of Biological Chemistry, 2017, 292(29): 12018-12024.
[5] COMEGLIO P, CELLAI I, MELLO T, et al. INT-767 prevents NASH and promotes visceral fat brown adipogenesis and mitochondrial function[J]. Journal of Endocrinology, 2018, 238(2): 107-127.
[6] ROTH J D, FEIGH M, VEIDAL S S, et al. INT-767 improves histopathological features in a diet-induced ob/ob mouse model of biopsy-confirmed non-alcoholic steatohepatitis[J]. World Journal of Gastroenterology, 2018, 24(2): 195.
[7] HU Y B, LIU X Y, ZHAN W. Farnesoid X receptor agonist INT-767 attenuates liver steatosis and inflammation in rat model of nonalcoholic steatohepatitis[EB/OL]. Drug Des Dev Ther, 2018, 12: 2213-2221.
INT-767是一种强效的法尼醇X受体（FXR）和Takeda G蛋白偶联受体5（TGR5）双重激动剂，EC50值分别为30nM和630nM[1,2]。INT-767可减少肝脂、改善胰岛素抵抗和缓解炎症，通常用于非酒精性脂肪性肝炎（NASH）和其它代谢疾病的治疗和研究[3,4]。
在体外，INT-767（1μM）处理兔内脏脂肪前体细胞rPADs 10天，显著提高了氧消耗量（从30.83 ± 3.15增加至69.44 ± 14.74 nmol O2/mL），同时降低了ATP生成（从13.89 ± 0.92降至9.34 ± 0.59 相对光单位（RLU）/细胞数）[5]。
在体内，INT-767（10mg/kg; once daily）通过口服治疗NASH的ob/ob小鼠8周，降低了肝脏胶原蛋白含量和脂质面积[6]。INT-767（20mg/kg; once daily）通过灌胃治疗NASH大鼠4周，可显著改善胰岛素抵抗，胰岛素抵抗指数（HOMA-IR）降低，血清胰高血糖素样肽-1（GLP-1）水平升高[7]。