■在我们最近使用[U-13C3]甘油的研究中,一小部分仓鼠显示出不寻常的甘油代谢特征:甘油的糖异生作用可忽略不计,甘油转化为1,3-丙二醇(1,3PDO)和3-羟基丙酸酯(3HP),在肝脏和血液中检测到。当前研究的目的是评估这些不寻常的甘油产物与肝脏中其他生化过程的关联。
■禁食仓鼠腹膜内接受对乙酰氨基酚(400mg/kg;n=16)或盐水(n=10)。等待2小时后,所有动物腹膜内接受[U-13C3]甘油。甘油注射后1小时收获肝脏和血液用于NMR分析和基因表达测定。
■在8只仓鼠(2只对照和6只仓鼠用对乙酰氨基酚处理)的肝脏和血浆中检测到源自[U-13C3]甘油的1,3PDO和3HP。这些动物的肝脏中的甘油代谢与常规代谢途径大不相同。[U-13C3]甘油被代谢为乙酰辅酶A,如在谷氨酸和β-羟基丁酸酯中检测到的下游产物所证明的那样,然而,丙酮酸和葡萄糖中的13C标记最小(p<0.001,每种代谢物中的13C标记差异).醛脱氢酶的表达在具有1,3PDO和3HP的仓鼠肝脏中增强(p<0.05)。
■仓鼠肝脏中1,3PDO和3HP的检测与甘油的非正统代谢有关,其特征在于3HP转化为乙酰辅酶A,然后通过TCA循环进行生酮和氧化代谢。需要额外的机理研究来确定这些仓鼠的一部分中异常甘油代谢的原因。
BACKGROUND: In our recent study using [U-13C3]glycerol, a small subset of hamsters showed an unusual profile of glycerol metabolism: negligible gluconeogenesis from glycerol plus conversion of glycerol to 1,3-propanediol (1,3PDO) and 3-hydroxypropionate (3HP) which were detected in the liver and blood. The purpose of the current study is to evaluate the association of these unusual glycerol products with other biochemical processes in the liver.
METHODS: Fasted hamsters received acetaminophen (400 mg/kg; n = 16) or saline (n = 10) intraperitoneally. After waiting 2 h, all the animals received [U-13C3]glycerol intraperitoneally. Liver and blood were harvested 1 h after the glycerol injection for NMR analysis and gene expression assays.
RESULTS: 1,3PDO and 3HP derived from [U-13C3]glycerol were detected in the liver and plasma of eight hamsters (two controls and six hamsters with acetaminophen treatment). Glycerol metabolism in the liver of these animals differed substantially from conventional metabolic pathways. [U-13C3]glycerol was metabolized to acetyl-CoA as evidenced with downstream products detected in glutamate and β-hydroxybutyrate, yet 13C labeling in pyruvate and glucose was minimal (p < 0.001, 13C labeling difference in each metabolite). Expression of aldehyde dehydrogenases was enhanced in hamster livers with 1,3PDO and 3HP (p < 0.05).
CONCLUSIONS: Detection of 1,3PDO and 3HP in the hamster liver was associated with unorthodox metabolism of glycerol characterized by conversion of 3HP to acetyl-CoA followed by ketogenesis and oxidative metabolism through the TCA cycle. Additional mechanistic studies are needed to determine the causes of unusual glycerol metabolism in a subset of these hamsters.