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The development of gluconeogenesis in rat liver: experiments in vivo
Insights
Gluconeogenesis, the process of creating glucose, is blocked in fetal rat liver due to a reduced cellular environment and impaired conversion of oxaloacetate to phosphoenolpyruvate. This contrasts with newborn rats, where gluconeogenesis is functional.
Area of Science:
- Biochemistry
- Developmental Biology
- Metabolic Regulation
Background:
- Gluconeogenesis is a vital metabolic pathway for glucose synthesis.
- The regulation of gluconeogenesis differs significantly between fetal and newborn stages.
- Cellular redox state plays a crucial role in metabolic pathway activity.
Purpose of the Study:
- To investigate the developmental differences in gluconeogenesis between fetal and newborn rat liver.
- To identify the specific blocks in gluconeogenesis in fetal liver.
- To elucidate the role of cellular redox state in fetal liver metabolism.
Main Methods:
- Substrate-loading experiments with lactate, pyruvate, and aspartate in fetal and newborn rats.
- Tracer studies using [(14)C]-labeled substrates.
- Measurement of hepatic phosphoenolpyruvate concentration.
- Analysis of lactate/pyruvate ratios and malate formation.
Main Results:
- Fetal rat liver showed no increase in phosphoenolpyruvate concentration upon substrate injection, unlike newborn rats.
- Radioactive incorporation into liver glucose was observed only in newborn rats.
- Fetal liver exhibited a highly reduced cytosolic environment, indicated by high lactate/pyruvate ratios and increased malate formation.
- A block in gluconeogenesis at the oxaloacetate to phosphoenolpyruvate conversion step was identified in fetal liver.
Conclusions:
- Gluconeogenesis is significantly impaired in fetal rat liver compared to newborn rats.
- A highly reduced cytosolic environment in fetal liver hinders gluconeogenesis.
- The conversion of oxaloacetate to phosphoenolpyruvate is a key regulatory step affected during fetal development.
Abstract:
1. The injection of substrate amounts of lactate into newborn rats produced an increase in the concentration of phosphoenolpyruvate in liver. Similar experiments with foetal rats showed no increase in phosphoenolpyruvate concentration although pyruvate formation was observed. 2. The administration of pyruvate to foetal rats was also without effect on the hepatic phosphoenolpyruvate concentration, although a 20-fold increase in this was observed when pyruvate was injected into newborn animals. 3. Analogous experiments with aspartate produced qualitatively similar differences between foetal and newborn rats. 4. When [(14)C]-lactate, -pyruvate or -aspartate was injected into foetal or newborn rats incorporation of radioactivity into liver glucose was observed only in the newborn animals. 5. Lactate/pyruvate ratios of 213 in foetal liver and 13.5 in the livers of newborn rats indicated a relatively reduced environment in the cytosol of foetal liver. This difference in redox state was illustrated experimentally by a greater conversion of pyruvate into lactate and an increased formation of malate in foetal liver. 6. Although both the substrate-loading and tracer experiments indicated a block in gluconeogenesis in foetal liver at the stage of conversion of oxaloacetate into phosphoenolpyruvate, gluconeogenesis was also hindered by a highly reduced environment.