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

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 required for increasing glucose and lactate oxidation and suppressing gluconeogenesis. Acetylation mimetic mutant PCK1 K91Q favors anaplerotic reaction and mimics the metabolic effects of SR18292 in hepatocytes. Liver-specific expression of PCK1 K91Q mutant ameliorates hyperglycemia in obese mice. Thus, SR18292 blocks gluconeogenesis by enhancing gluconeogenic substrate oxidation through PCK1 lysine acetylation, supporting the anti-diabetic effects of these small molecules. [Display omitted] • SR18292 increases oxidation of glucose and gluconeogenic substrates • SR18292-mediated gluconeogenic inhibition does not induce de novo lipogenesis • Small molecule SR18292 enhances PCK1 acetylation, leading to OAA synthesis from PEP • Acetyl-mimetic mutation at K91 of PCK1 recapitulates the effects of SR18292 Although suppression of liver glucose production reduces hyperglycemia in diabetes, this inhibition can promote de novo lipogenesis from gluconeogenic substrates, exacerbating hepatic steatosis and compromising clinical interventions. Mutlu et al. elucidate how the small molecule SR18292 represses hepatic gluconeogenesis without perturbation of lipogenesis. [ABSTRACT FROM AUTHOR]