Glyceroneogenesis and the Source of Glycerol for Hepatic Triacylglycerol Synthesis in Humans

Abstract

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. Five nonpregnant women were administered [ 13 C 3 ]glycerol tracer as prime constant rate infusion, and the appearance of tracer in plasma glucose and triacylglycerol was quantified using gas chromatography-mass spectrometry. The contribution of pyruvate to hepatic triacylglycerol was quantified in nonpregnant and pregnant women using the deuterium labeling of body water method. The appearance of [ 2 H] in hydrogens on C 1 and C 3 of triacylglycerol was measured following periodate oxidation of the glycerol isolated from hydrolyzed triacylglycerol. After a 16-h fast, ϳ6.1% 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.

Acute and selective regulation of glyceroneogenesis and cytosolic phosphoenolpyruvate carboxykinase in adipose tissue by thiazolidinediones in type 2 diabetes

“…As a consequence, we observed a large decrease in plasma NEFA concentration in agreement with the role that glyceroneogenesis is playing in G3P synthesis required for fatty acid esterification after a high-fat or high-protein carbohydrate-free diet and for reesterification during fasting [36,37]. According to the minor role of glycerol phosphorylation in this process, we could not detect any variation in glycerol release whether rats were treated with rosiglitazone or not, in agreement with our previous studies, in which either a very mild decrease or no variation in glycerol release was observed [18]. We can thus easily attribute the improvement in plasma dyslipidaemia to the early induction of fatty acid reesterification linked to glyceroneogenesis in response to thiazolidinediones.…”

“…Lactate is the most probable physiological substrate for G3P synthesis because of the large amount of this metabolite in plasma during fasting [17]. This pathway occurs also in liver, in addition to gluconeogenesis [18]. Recent data identified glyceroneogenesis as a thiazolidinedione target in cultured rat adipocytes and adipose tissue, which was the result of induction of its key enzyme, the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C) [19].…”

Pck1 Gene Silencing in the Liver Improves Glycemia Control, Insulin Sensitivity, and Dyslipidemia in db/db Mice

“…PEPCK-C silencing resulted in reduced plasma TAG, together with an important elevation of hepatic lipids, mainly nonsterified fatty acids. An important but not sufficiently appreciated role for PEPCK-C in the liver is glyceroneogenesis: the provision of glycerol-3-phosphate to sustain fatty acid re-esterification for triglyceride synthesis (29,30). Therefore, PEPCK-C silencing could induce a significant reduction in fatty acid re-esterification activity.…”

ATF-2 Regulates Fat Metabolism inDrosophila

“…Some reports described the important role of glyceroneogenesis to control the fat store. For instance, in fasting pregnant women, up to 60% of plasma glyceride-glycerol (the glycerol portion of triglyceride) was generated by glyceroneogenesis, primarily in the liver (Kalhan et al, 2001). Similarly, more than 80% of the glyceride-glycerol in epididymal fat of rats fed a high-protein diet is produced by adipocyte glyceroneogenesis (Botion et al, 1998).…”