Glyceroneogenesis and the Source of Glycerol for Hepatic Triacylglycerol Synthesis in Humans
Glyceroneogenesis,i.e. the synthesis of the glycerol moiety of triacylglycerol from pyruvate, has been suggested to be quantitatively important in both the liver and adipose tissue during fasting. However, the actual contribution of glyceroneogenesis to triacylglycerol synthesis has not been quantified in vivo in human studies. In the present study we have measured the contribution of glycerol and pyruvate to in vivo synthesis of hepatic triacylglycerol in nonpregnant and pregnant women after an overnight fast.
After a 16-h fast, ∼6.1% of the plasma triacylglycerol pool was derived from plasma glycerol, whereas 10 to 60% was derived from pyruvate in nonpregnant women and pregnant women early in gestation. Our data suggest that glyceroneogenesis from pyruvate is quantitatively a major contributor to plasma triacylglycerol synthesis and may be important for the regulation of very low density lipoprotein triacylglycerol production.
Our data also suggest that 3-glycerol phosphate is in rapid equilibrium with the triosephosphate pool, resulting in rapid labeling of the triose pool by the administered tracer glycerol. Because the rate of flux of triosephosphate to glucose during fasting far exceeds that to triacylglycerol, more glycerol ends up in glucose than in triacylglycerol.
Alternatively, there may be two distinct pools of 3-glycerol phosphate in the liver, one involved in generating triosephosphate from glycerol and the other involved in glyceride-glycerol synthesis.
The synthesis of triacylglycerol in the liver, adipose tissue, and skeletal muscle following a meal is an important metabolic pathway for the deposition of fat and in the maintenance of energy homeostasis in all vertebrates. Even after an overnight fast in adult humans, and following a brief fast in newborn infants, a substantial re-esterification of fatty acids has been documented using isotopic tracer methods (1-3). The source of glycerol for the esterification of fatty acids in various tissues has generally been considered to be plasma glucose or glycerol; however direct evidence for such an inference has not been documented.
Triacylglycerol synthesis requires both fatty acids and a source of 3-glycerol phosphate. During fasting, the source of 3-glycerol phosphate can either be plasma glucose via glycolysis or glycerol released from the hydrolysis of triacylglycerol. In the adipose tissue in particular, the glycerol released from the hydrolysis of triacylglycerol cannot be re-utilized for the esterification of fatty acids because of absence of glycerol kinase. It has been proposed that during fasting adipose tissue generates the 3-glycerol phosphate required for triacylglycerol synthesis, either from glucose via glycolysis or, alternatively, from pyruvate via an abbreviated or truncated version of gluconeogenesis, termed glyceroneogenesis (4-7). The key enzyme in this pathway is the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (PEPCK;1 EC 220.127.116.11). The transcription of the gene for PEPCK is stimulated by cAMP during periods of fasting (8, 9), resulting in an increase in enzyme activity in both adipose tissue and liver. In isolated epididymal adipose tissue from the rat, the rate of re-esterification of free fatty acids was greatly increased by the provision of a glyceroneogenic precursor such as pyruvate (10). In addition, hepatic glyceroneogenesis has been shown to account for ∼89% of glyceride-glycerol in the triacylglycerol synthesized by rats fed a high protein diet (11).
There has not been a quantitative analysis of the relative rates of glyceride-glycerol synthesis from its precursors, plasma glycerol, pyruvate, or glucose in humans. In the present study we have quantified the relative contribution of plasma glycerol and pyruvate (plus lactate, alanine, etc.) to glyceride-glycerol in nonpregnant and pregnant women during fasting. Pregnant women were studied because of the higher concentration of plasma triacylglycerol during pregnancy, particularly in the third trimester. Our data show that the source of glyceride-glycerol following a brief fast is predominantly pyruvate. Because the synthesis of glucose and glyceride-glycerol from plasma glycerol share common enzymatic reactions, our data also suggest a functional separation of the pathways of glycerol entry into the liver and the 3-glycerol phosphate precursor pool for triacylglycerol synthesis.
When doing LC, our metabolisms are essentially the same as the fasted state. More than half of the triglycerides that are broken down to free fatty acids are re-esterified to triglycerides even in the fasted state. Where do we get the G3P? Glyceroneogenesis. And there's that pesky PEPCK again.
This blows one of Taubes' central theories out of the water!