Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation.

ABSTRACT: Small molecules selectively inducing peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α acetylation and inhibiting glucagon-dependent gluconeogenesis causing anti-diabetic effects have been identified. However, how these small molecules selectively suppress the conversion of gluconeogenic metabolites into glucose without interfering with lipogenesis is unknown. Here, we show that a small molecule SR18292 inhibits hepatic glucose production by increasing lactate and glucose oxidation. SR18292 increases phosphoenolpyruvate carboxykinase 1 (PCK1) acetylation, which reverses its gluconeogenic reaction and favors oxaloacetate (OAA) synthesis from phosphoenolpyruvate. PCK1 reverse catalytic reaction induced by SR18292 supplies OAA to tricarboxylic acid (TCA) cycle and is requi

SUBMITTER: Mutlu B 

PROVIDER: S-EPMC11500315 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature