Fatty acid metabolism dysregulated through elevated fatty acid synthesis (FASyn), impaired fatty acid oxidation (FAOxn), or both is a hallmark of various metabolic disorders. ACC (acetyl-CoA carboxylase) catalyzes the ATP-dependent carboxylation of acetyl-CoA to form malonyl-CoA, the rate-limiting and first committed reaction in FASyn. ND-630, a reversible and highly specific ACC inhibitor, inhibits hACC1 with an IC50 of 2.1 ± 0.2 nM and hACC2 with an IC50 of 6.1 ± 0.8 nM. When ND-630 and [14C]acetate were administered to Hep-G2 cells for 4 h, ND-630 inhibited FASyn with EC50 values of 66 nM in cells cultured in medium containing 10% serum and 8.7 nM when assessed in serum-free medium. When ND-630 and [14C]palmitate were administered to C2C12 cells for 6 h, ND-630 increased both the release of [14C]O2 and the production of [14C]acid-soluble material. ND-630 exhibited an aqueous solubility of 594 μM and human and rat plasma protein binding of 98.5% and 98.6%, respectively. When chow-fed male Sprague–Dawley rats were treated orally with ND-630 for 1 h, hepatic malonyl-CoA was dose-dependently reduced with an ED50 of 0.8 mg/kg. When chow-fed male Sprague–Dawley rats treated orally with ND-630 for 1 h were given an i.p. bolus of [14C]acetate, ND-630 reduced hepatic FASyn with an ED50 of 0.14 mg/kg. Moreover, ND-630 increased whole-body FAOxn, assessed as a reduction in respiratory quotient (RQ). As a consequence of FASyn inhibition and FAOxn stimulation, ND-630 dose-dependently reduced the hepatic steatosis produced by the HSD (high-sucrose diet) without altering either hepatic cholesterol or glycogen. ND-630 also dose-dependently reduced the elevated plasma triglycerides and free fatty acids produced by the HSD[1].
作用机制
ND-630 interacts within the acetyl-CoA carboxylase subunit phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit enzymatic activity[1].
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