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低血糖症与糖原贮积病 Ia 型患者的高三酰甘油血症有关，这与极低密度脂蛋白代谢受损有关。

Impaired Very-Low-Density Lipoprotein catabolism links hypoglycemia to hypertriglyceridemia in Glycogen Storage Disease type Ia.

机构信息

Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Department of Metabolic Diseases, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

出版信息

J Inherit Metab Dis. 2021 Jul;44(4):879-892. doi: 10.1002/jimd.12380. Epub 2021 Apr 7.

DOI:10.1002/jimd.12380
PMID:33739445
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8360207/
Abstract

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.

摘要

预防高甘油三酯血症是糖原贮积病 Ia 型（GSD Ia）患者的生物医学治疗靶点之一，但低血糖与血浆甘油三酯（TG）水平之间的关系尚不清楚。我们分析了血糖正常（进食）和低血糖（禁食）时肝特异性葡萄糖-6-磷酸酶缺乏（L-G6pc）小鼠的全身 TG 代谢。在血糖正常的 L-G6pc 小鼠中，从头脂肪酸合成对肝 TG 积累有很大贡献。在低血糖状态下，脂肪组织脂解增强是肝脂肪变性的主要驱动因素，这得到了 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，低血糖的 L-G6pc 小鼠进一步升高。VLDL-TG 分泌率在血糖正常和低血糖的 L-G6pc 小鼠中增加了一倍，而 VLDL-TG 分解代谢在低血糖的 L-G6pc 小鼠中被选择性抑制。总之，L-G6pc 小鼠的禁食诱导性低血糖促进脂肪组织脂解，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 患者肝脂肪变性和血脂异常加重，并可能解释 GSD Ia 患者高甘油三酯血症的临床异质性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/911b/8360207/d004e982c260/JIMD-44-879-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/911b/8360207/e3194ada3989/JIMD-44-879-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/911b/8360207/eb84a8be3fbb/JIMD-44-879-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/911b/8360207/689343ba73c0/JIMD-44-879-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/911b/8360207/d004e982c260/JIMD-44-879-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/911b/8360207/e3194ada3989/JIMD-44-879-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/911b/8360207/eb84a8be3fbb/JIMD-44-879-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/911b/8360207/689343ba73c0/JIMD-44-879-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/911b/8360207/d004e982c260/JIMD-44-879-g003.jpg

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