Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is one of two known DGAT enzymes that catalyze the final step in triglyceride synthesis. Inhibition of DGAT1 is a promising strategy for the treatment of obesity and type 2 diabetes. T863 is a potent and specific DGAT1 inhibitor with respect to oleoyl-CoA with IC50 values of 49 nM and 17 nM in the CPM fluorescent assay and the TLC assay, respectively. T863 showed a dose-dependent inhibition of the binding of radiolabeled oleoyl-CoA to DGAT1. T863 caused a dose-dependent inhibition of cellular triacylglycerol (TAG) formation in HEK293-DGAT1 cells with an IC50 of 122 nM. In an acute lipid challenge model using C57/BL6 mice, administration of the corn oil bolus resulted in a significant, 60% increase in serum triglyceride levels in vehicle-treated animals, while no increase was observed in mice treated with 10 mg/kg T863 indicating T863 inhibits acute lipid absorption. Administration of T863 (30 mg/kg for 15 days) to DIO (diet-induced obese) mice caused a reduction in body weight, which reached statistical significance by the 13th day of treatment. Moreover, T863-treated DIO mice showed a modest improvement in clearing glucose from peripheral circulation[3].
作用机制
T863 binds to the oleoyl-CoA binding site of DGAT1 bound with 1,2-DOG[3].
T863 细胞实验
Cell Line
Concentration
Treated Time
Description
References
SUM159 cells
10 µM
30 minutes
To study the effect of T863 on lipid droplet formation
Nat Commun. 2023 May 29;14(1):3100
Mouse embryonic fibroblasts (D1D2KO MEF)
15 µM
24 hours
To validate TgDGAT as a target for T863, showing severe morphological alterations and absence of lipid droplets.
To evaluate the effect of T863 on inhibiting DGAT1 activity at the cellular level, results showed that T863 dose-dependently inhibited TAG formation.
J Biol Chem. 2011 Dec 2;286(48):41838-41851
Rat hepatic stellate cells
20 µM
6 days
To study the effect of T863 on TAG metabolism in rat HSCs, results showed that T863 significantly reduced TAG levels, indicating that DGAT1 plays a key role in the rapid TAG synthesis during rat HSC activation.
J Lipid Res. 2016 Jul;57(7):1162-74
Hepatic stellate cells (HSCs)
20 µM
6 days
To investigate the role of DGAT1 in the formation of newly synthesized TAGs during HSC activation, results showed that T863 inhibited the formation of new TAGs, especially PUFA-enriched TAG species.
J Lipid Res. 2016 Jul;57(7):1162-74
3T3-L1 preadipocytes
50 µM
7 days
Significantly reduced lipid accumulation in 3T3-L1 adipocytes without affecting cell proliferation
Nutrients. 2024 Apr 2;16(7):1036.
T863 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
Diet-induced obese (DIO) mouse model
Oral
30 mg/kg
15 consecutive days (once daily for days 1–7, twice daily for days 8–14, and a single dose on the morning of day 15)
To evaluate the effects of T863 on body weight, insulin sensitivity, and serum lipids in DIO mice, results showed that T863 caused weight loss, improved insulin sensitivity, and reduced serum lipids.
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