Hormone-sensitive triacylglycerol

Chylomicrons deliver tiiacylglycerols to tissues, where lipoprotein lipase releases free fatty acids for entry into cells. Triacylglycerols stored in adipose tissue are mobilized by a hormone-sensitive triacylglycerol lipase. The released fatty acids bind to serum albumin and are carried in the blood to the heart, skeletal muscle, and other tissues that use fatty acids for fuel. 

The major source of free fatty acids in the blood is from the breakdown of triacylglycerol stores in adipose tissue which is regulated by the action of hormone-sensitive triacylglycerol lipase (see Topic K4). Fatty acid breakdown and fatty acid synthesis are coordinately controlled so as to prevent a futile cycle (see Topic K3). 

Regulation The concentration of free fatty acids in the blood is controlled by the rate at which hormone-sensitive triacylglycerol lipase hydrolyzes the triacylglycerols stored in adipose tissue. Glucagon, epinephrine and norepinephrine cause an increase in the intracellular level of cAMP which allosterically activates cAMP-dependent protein kinase. The kinase in turn phosphorylates hormone-sensitive lipase, activating it, and leading to the release of fatty acids into the blood. Insulin has the opposite effect it decreases the level of cAMP which leads to the dephosphorylation and inactivation of hormone-sensitive lipase. 

The breakdown of fatty acids in (3-oxidation (see Topic K2) is controlled mainly by the concentration of free fatty acids in the blood, which is, in turn, controlled by the hydrolysis rate of triacylglycerols in adipose tissue by hormone-sensitive triacylglycerol lipase. This enzyme is regulated by phosphorylation and dephosphorylation (Fig. 5) in response to hormonally controlled levels of the intracellular second messenger cAMP (see Topic E5). The catabolic hormones glucagon, epinephrine and norepinephrine bind to receptor proteins on the cell surface and increase the levels of cAMP in adipose cells through activation of adenylate cyclase (see Topic E5). The cAMP allosterically activates... 

Fig. 5. Summary of the control of hormone-sensitive triacylglycerol lipase.

Proteins phosphorylated by cAPK include glycogen phosphorylase b kinase (activates), PFK-2 (inactivates), acetyl CoA carboxylase (inactivates), hormone-sensitive triacylglycerol lipase... 

Increased lipid synthesis/inhibi-tion of lipolysis Activation of lipoprotein lipase (LPL)/induc-tion of fatty acid synthase (FAS)/inactivation of hormone sensitive lipase (HSL) Facilitated uptake of fatty acids by LPL-dependent hydrolysis of triacylglycerol from circulating lipoproteins. Increased lipid synthesis through Akt-mediated FAS-expression. Inhibition of lipolysis by preventing cAMP-dependent activation of HSL (insulin-dependent activation of phosphodiesterases )... 

Figure 25-7. Metabolism of adipose tissue. Hormone-sensitive lipase is activated by ACTH, TSH, glucagon, epinephrine, norepinephrine, and vasopressin and inhibited by insulin, prostaglandin E, and nicotinic acid. Details of the formation of glycerol 3-phosphate from intermediates of glycolysis are shown in Figure 24-2. (PPP, pentose phosphate pathway TG, triacylglycerol FFA, free fatty acids VLDL, very low density lipoprotein.)...

Otfier fiormones accelerate tfie release of free fatty acids from adipose tissue and raise tfie plasma free fatty acid concentration by increasing the rate of lipolysis of the triacylglycerol stores (Figure 25—8). These include epinephrine, norepinephrine, glucagon, adrenocorticotropic hormone (ACTH), a- and P-melanocyte-stimulat-ing hormones (MSH), thyroid-stimulating hormone (TSH), growth hormone (GH), and vasopressin. Many of these activate the hormone-sensitive hpase. For an optimal effect, most of these lipolytic processes require the presence of glucocorticoids and thyroid hormones. These hormones act in a facilitatory or permissive capacity with respect to other lipolytic endocrine factors. 

Adipose tissue Storage and breakdown of triacylglyc-erol Esterification of fatty acids and lipolysis lipogenesis Glucose, lipoprotein triacylglycerol Free fatty acids, glycerol Lipoprotein lipase, hormone-sensitive lipase... 

The physiological pathway for oxidation of fatty acids in organs or tissues starts with the enzyme triacylglycerol lipase within adipose tissue, that is, the hormone-sensitive lipase. This enzyme, plus the other two lipases, results in complete hydrolysis of the triacylglycerol to fatty acids, which are transported to various tissues that take them up and oxidise them by P-oxidation to acetyl-CoA. This provides a further example of a metabolic pathway that spans more than one tissue (Figure 7.13) (Box 7.1). 

Two conditions in which the rate of ketone body formation is increased are hypoglycaemia and prolonged starvation in adults or short-term starvation in children. What is the mechanism for increasing the rate Although there are several fates for fatty acids in the liver, triacylglycerol, phospholipid and cholesterol formation and oxidation via the Krebs cycle, the dominant pathway is ketone body formation (Figure 7.20). Three factor regulate the rate of ketone body formation (i) hormone sensitive lipase activ-... 

The initial step to release fatty acids is triacylglycerol hydrolysis catalyzed by hormone-sensitive (HS) lipase. 

Hormone-sensitive lipase PMRRSV Triacylglycerol mobilization and fatty acid oxidation... 

Decreased triacylglycerol degradation Elevated insulin favors the dephosphorylated (inactive) state of hormone-sensitive lipase (see p. 187). Triacylglycerol degradation is thus inhibited in the well-fed state. 

Increased degradation of triacylglycerols The activation of hormone-sensitive lipase (see p. 187) and subsequent hydrolysis of stored triacylglycerol are enhanced by the elevated catecholamines epinephrine and, particularly, norepinephrine. These compounds, which are released from the sympathetic nerve endings in adipose tissue, are physiologically important activators of hormone-sensitive lipase (Figure 24.13, ) ... 

Fatty acids are carried to tissues for use in synthesis of triacylglycerols, phospholipids, and other membrane lipids. The mobilization of fatty acids from triacylglycerol stores and from cholesterol esters depends upon hormone-sensitive lipase (p. 635).53b/ 53c This enzyme is activated by cAMP-dependent phos-... 

The anabolic hormone insulin has the opposite effect to glucagon and epinephrine. It stimulates the formation of triacylglycerols through decreasing the level of cAMP, which promotes the dephosphorylation and inactivation of hormone-sensitive lipase (Fig. 5). Insulin also stimulates the dephosphorylation of acetyl CoA carboxylase, thereby activating fatty acid synthesis (see Topic K3). Thus fatty acid synthesis and degradation are coordinately controlled so as to prevent a futile cycle. 

Extracellular epinephrine (adrenaline) (from the adrenal medulla) activates /33-adrenergic receptors on fat cells to induce the breakdown of triacylglycerols to free fatty acids and glycerol. The intracellular enzyme involved in this process, hormone-sensitive lipase, is activated by protein kinase A. What are the key elements of the signal transduction cascade ... 

The hydrolysis of triacylglycerol to monoacylglycerol and fatty acids by hormone-sensitive lipase can be stimulated by epinephrine, norepinephrine, adrenal steroids, glucagon, and the hypophysial hormones, luteotropin (prolactin or luteinizing hormone), )3- and a-lipotropins, somatotropin, thyrotropin, and vasopressin. 

The release of fatty acids from adipose tissue is regulated by the rate of hydrolysis of triacylglycerol and the rate of esterification of acyl-CoA with glycerol 3-phosphate. The rate of hydrolysis is stimulated by hormones that bind to cell-surface receptors and stimulate adenylate cyclase (which catalyzes the production of cAMP from ATP). Hormone-sensitive lipase (Sec. 13.4) can exist in two forms, one of which exhibits very low activity and a second which is phosphorylated and has high activity. Before hormonal stimulation of adenylate cyclase, the low-activity lipase predominates in the fat cell. Stimulation of protein kinase by an increase in cAMP concentration leads to phosphorylation of the low-activity lipase. An increase in the rate of hydrolysis of triacylglycerol and the release of fatty acids from the fat cell follows. This leads to a greater utilization of fatty acids by tissues such as heart, skeletal muscle, and liver. 

In response to energy demands, the fatty acids of stored triacylglycerols must be mobilised for use by peripheral tissues. This release is controUed by a complex series of interrelated cascades that result in the activation of hormone-sensitive lipase. In adipocytes this stimulus can come from glucagon, adrenaline (epinephrine) or 8-corticotropin. These hormones bind cell-surface receptors that are coupled to the activation of adenyl cyclase the resultant increase in intracellular cAMP leads to activation of cAMP-dependent protein kinase, which in turn phosphorylates and activates hormone-sensitive lipase (Figure 5.5). 

Hormone-sensitive lipase hydrolyses fatty acids from carbon atoms 1 or 3 of triacylglycerols. The resulting diacylglycerols are substrates for either hormone-sensitive lipase or the noninducible enzyme diacylglycerol lipase. Finally, monoacylglycerols are snbstrates for monoa-cylglycerol lipase. 

Figure 5.5 Hormone-induced fatty add mobilisation in adipocytes. Through hormone-induced rises in intracellular cAMP levels, phosphorylation (activation) of hormone-sensitive lipase initiates the mobilisation of fatty acids from triacylglycerol.

Figure 22.6. Mobilization of Triacylglycerols. Triacylglycerols in adipose tissue are converted into free fatty acids and glycerol for release into the bloodstream in response to hormonal signals. A hormone-sensitive lipase initiates the process.

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