Biosynthesis of Triacylglycerols:- Adipose Tissue Generates Glycerol 3-phosphate by Glyceroneogenesis
Glyceroneogenesis is a shortened version of gluconeogenesis, from pyruvate to DHAP (see Fig. 14–16), followed by conversion of the DHAP to glycerol 3 phosphate by cytosolic NAD-linked glycerol 3-phosphate dehydrogenase (Fig. 21–21). Glycerol 3-phosphate is subsequently used in triacylglycerol synthesis. Glyceroneogenesis was discovered in the 1960s by Lea Reshef, Richard Hanson, and John Ballard, and simultaneously by Eleazar Shafrir and his coworkers, who were intrigued by the presence of two gluconeogenic enzymes, pyruvate carboxylase and phosphoenolpyruvate (PEP) carboxykinase, in adipose tissue, where glucose is not synthesized. After a long period of inattention, interest in this pathway has been renewed by the demonstration of a link between glyceroneogenesis and late-onset (type 2) diabetes, as we shall see.
Glyceroneogenesis has multiple roles. In adipose tis sue, glyceroneogenesis coupled with reesterification of free fatty acids controls the rate of fatty acid release to the blood. In brown adipose tissue, the same pathway may control the rate at which free fatty acids are delivered to mitochondria for use in thermogenesis (see Fig. 19–30). And in fasting humans, glyceroneogenesis in the liver alone supports the synthesis of enough glycerol 3-phosphate to account for up to 65% of fatty acids reesterified to triacylglycerol. Flux through the triacylglycerol cycle between liver and adipose tissue is controlled to a large degree by the activity of PEP carboxykinase, which limits the rate of both gluconeogenesis and glyceroneogenesis. Glucocorticoid hormones such as cortisol (a biological steroid derived from cholesterol; see Fig. 21–46) and dexamethasone (a synthetic glucocorticoid) regulate the levels of PEP carboxykinase reciprocally in the liver and adipose tissue. Acting through the glucocorticoid receptor, these steroid hormones increase the expression of the gene encoding PEP carboxykinase in the liver, thus increasing gluconeogenesis and glyceroneogenesis (Fig. 21–22).
FIGURE 21–21 Glyceroneogenesis. The pathway is essentially an ab breviated version of gluconeogenesis, from pyruvate to dihydroxyacetone phosphate (DHAP), followed by conversion of DHAP to glycerol 3-phosphate, which is used for the synthesis of triacylglycerol.
Stimulation of glyceroneogenesis leads to an in crease in the synthesis of triacylglycerol molecules in the liver and their release into the blood. At the same time, glucocorticoids suppress the expression of the gene encoding PEP carboxykinase in adipose tissue. This results in a decrease in glyceroneogenesis in adipose tissue; recycling of fatty acids declines as a result, and more free fatty acids are released into the blood. Thus, glyceroneogenesis is regulated reciprocally in the liver and adipose tissue, affecting lipid metabolism in opposite ways: a lower rate of glyceroneogenesis in adipose tissue leads to more fatty acid release (rather than recycling), whereas a higher rate in the liver leads to more synthesis and export of triacylglycerols. The net result is an increase in flux through the triacylglycerol cycle. When the glucocorticoids are no longer present, flux through the cycle declines as the expression of PEP carboxykinase increases in adipose tissue and decreases in the liver.
The recent attention given to glyceroneogenesis has arisen in part from the connection between this pathway and diabetes. High levels of free fatty acids in the blood interfere with glucose utilization in muscle and promote the insulin resistance that leads to type 2 diabetes. A new class of drugs called thiazolidinediones have been shown to reduce the levels of fatty acids circulating in the blood and increase sensitivity to
insulin. Thiazolidinediones bind to and activate a nuclear hormone receptor called peroxisome proliferator activated receptor (PPARγ), leading to the induction in adipose tissue of PEP carboxykinase (Fig. 21–22); a higher activity of PEP carboxykinase then leads to increased synthesis of the precursors of glyceroneogenesis. The therapeutic effect of thiazolidinediones is thus due, at least in part, to the increase in glyceroneogenesis, which in turn increases the resynthesis of triacyl glycerol in adipose tissue and reduces the release of free fatty acid from adipose tissue into the blood.
FIGURE 21–22 Regulation of glyceroneogenesis. (a) Glucocorticoid hormones stimulate glyceroneogenesis and gluconeogenesis in the liver, while suppressing glyceroneogenesis in the adipose tissue (by reciprocal regulation of the gene expressing PEP carboxykinase (PEPCK) in the two tissues); this increases the flux through the triacylglycerol cycle. The glycerol freed by the breakdown of triacylglycerol in adipose tissue is released to the blood and trans ported to the liver, where it is primarily converted to glucose, although some is converted to glycerol 3-phosphate by glycerol kinase. (b) A class of drugs called thiazolidinediones are now used to treat type 2 diabetes. In this disease, high levels of free fatty acids in the blood interfere with glucose utilization in muscle and promote insulin resistance. Thiazolidinediones activate a nuclear receptor called peroxisome proliferator-activated receptor γ (PPARγ), which induces the activity of PEP carboxykinase. Therapeutically, thiazolidinediones increase the rate of glyceroneogenesis, thus increasing the resynthesis of triacylglycerol in adipose tissue and reducing the amount of free fatty acid in the blood.
