Prevention of hypertriglyceridemia is one of the biomedical targets in Glycogen Storage Disease type Ia (GSD Ia) patients, yet it is unclear how hypoglycemia links to plasma triglyceride (TG) levels. We analyzed whole-body TG metabolism in normoglycemic (fed) and hypoglycemic (fasted) hepatocyte-specific glucose-6-phosphatase deficient (L-G6pc^−/−) mice. De novo fatty acid synthesis contributed substantially to hepatic TG accumulation in normoglycemic L-G6pc^−/− mice. In hypoglycemic conditions, enhanced adipose tissue lipolysis was the main driver of liver steatosis, supported by elevated free fatty acid concentrations in GSD Ia mice and GSD Ia patients. Plasma very-low-density lipoprotein (VLDL) levels were increased in GSD Ia patients and in normoglycemic L-G6pc^−/− mice, and further elevated in hypoglycemic L-G6pc^−/− mice. VLDL-TG secretion rates were doubled in normo- and hypoglycemic L-G6pc^−/− mice, while VLDL-TG catabolism was selectively inhibited in hypoglycemic L-G6pc^−/− mice. In conclusion, fasting-induced hypoglycemia in L-G6pc^−/− mice promotes adipose tissue lipolysis and arrests VLDL catabolism. This mechanism likely contributes to aggravated liver steatosis and dyslipidemia in GSD Ia patients with poor glycemic control and may explain clinical heterogeneity in hypertriglyceridemia between GSD Ia patients.

中文翻译：

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受损的极低密度脂蛋白分解代谢将低血糖与 Ia 型糖原贮积病中的高甘油三酯血症联系起来

预防高甘油三酯血症是 Ia 型糖原贮积病 (GSD Ia) 患者的生物医学目标之一，但尚不清楚低血糖如何与血浆甘油三酯 (TG) 水平相关。我们分析了正常血糖（进食）和低血糖（禁食）肝细胞特异性葡萄糖-6-磷酸酶缺乏（L- G6pc ^-/-）小鼠的全身 TG 代谢。脂肪酸从头合成对血糖正常的 L- G6pc中的肝脏 TG 积累有很大贡献^-/-老鼠。在低血糖情况下，增强的脂肪组织脂肪分解是肝脏脂肪变性的主要驱动因素，这得到 GSD Ia 小鼠和 GSD Ia 患者中游离脂肪酸浓度升高的支持。GSD Ia 患者和血糖正常的 L -G6pc ^-/-小鼠的血浆极低密度脂蛋白 (VLDL) 水平升高，而低血糖 L -G6pc ^-/-小鼠的血浆极低密度脂蛋白 (VLDL) 水平进一步升高。VLDL-TG 分​​泌率在正常和低血糖 L -G6pc ^{-/-小鼠中加倍，而 VLDL-TG 分​​解代谢在低血糖 L} -G6pc ^-/-小鼠中被选择性抑制。总之，空腹诱导的 L- G6pc低血糖^-/-小鼠促进脂肪组织脂肪分解并阻止 VLDL 分解代谢。这种机制可能导致血糖控制不佳的 GSD Ia 患者的肝脂肪变性和血脂异常加重，并可能解释 GSD Ia 患者之间高甘油三酯血症的临床异质性。