Hypoketotic hypoglycaemia is a biochemical hallmark of glycogen storage disease type 1 (GSD1). This is due to inhibition of carnitine-palmitoyl transferase 1 by malonyl-CoA. This inhibits the influx of long-chain fatty acids into the mitochondrial matrix for fatty acid oxidation. This leads to reduced hepatic ketogenesis and impaired energy production in the liver and kidney. Hypoketotic hypoglycaemia may result in CNS symptoms due to energy depletion.

Recently, it was reported that enzymes involved in mitochondrial long-chain fatty acid oxidation are upregulated in PBMC from patients suffering from GSD1.

I suggest that administration of the prodrug bempedoic acid results in reduced production of malonyl-CoA by inhibiting the ATP-citrate lyase, thus releasing the block of mitochondrial long-chain fatty acid influx. These fatty acids could make use of the increased capacity of fatty acid oxidation as observed in PBMC recently. In the liver, ketogenesis is activated, and energy production is increased in both the liver and kidney. This could result in improved metabolic control and avoidance of cerebral energy depletion.

Bempedoic acid is approved as medication in adult patients with hypercholesterolaemia and mixed dyslipidaemia. Repurposing bempedoic acid for the use in GSD1 may improve metabolic control in GSD1.

低酮性低血糖是 1 型糖原累积病 (GSD1) 的生化标志。这是由于丙二酰辅酶 A 抑制肉毒碱棕榈酰转移酶 1 所致。这抑制了长链脂肪酸流入线粒体基质以进行脂肪酸氧化。这会导致肝脏生酮减少以及肝脏和肾脏的能量产生受损。低酮性低血糖可能因能量耗尽而导致中枢神经系统症状。

最近，据报道，GSD1 患者的 PBMC 中参与线粒体长链脂肪酸氧化的酶上调。

我建议给予前药 bempedoic 酸，通过抑制 ATP-柠檬酸裂合酶，导致丙二酰辅酶 A 的产生减少，从而释放线粒体长链脂肪酸流入的阻滞。最近在 PBMC 中观察到，这些脂肪酸可以利用脂肪酸氧化能力的增强。在肝脏中，生酮被激活，肝脏和肾脏的能量产生增加。这可能会改善代谢控制并避免脑能量消耗。

Bempedoic Acid 被批准作为治疗高胆固醇血症和混合性血脂异常的成人患者的药物。将 bempedoic 酸重新用于 GSD1 可能会改善 GSD1 的代谢控制。