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.

中文翻译：

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靶向选择性 PCK1 和 PGC-1α 赖氨酸乙酰化的小分子通过增加乳酸氧化来引起抗糖尿病作用


已经确定了选择性诱导过氧化物酶体增殖物激活受体-γ 共激活因子 （PGC）-1α 乙酰化和抑制胰高血糖素依赖性糖异生的小分子，从而产生抗糖尿病作用。然而，这些小分子如何在不干扰脂肪生成的情况下选择性地抑制糖异生代谢物向葡萄糖的转化尚不清楚。在这里，我们表明小分子SR18292通过增加乳酸和葡萄糖氧化来抑制肝脏葡萄糖的产生。SR18292 会增加磷酸烯醇式丙酮酸羧激酶 1 （PCK1） 乙酰化，从而逆转其糖异生反应，并有利于从磷酸烯醇式丙酮酸合成草酰乙酸 （OAA）。SR18292诱导的 PCK1 反向催化反应将 OAA 供应到三羧酸 （TCA） 循环，是增加葡萄糖和乳酸氧化以及抑制糖异生所必需的。乙酰化模拟突变体 PCK1 K91Q 有利于厌氧反应，并模拟SR18292在肝细胞中的代谢作用。PCK1 K91Q 突变体的肝脏特异性表达可改善肥胖小鼠的高血糖。因此，SR18292 通过 PCK1 赖氨酸乙酰化增强糖异生底物氧化来阻断糖异生，从而支持这些小分子的抗糖尿病作用。