Hormone-sensitive lipase, adipose tissue, regulation

As well as stimulating glycogenolysis, a rise in blood glucagon concentration increases triglyceride breakdown in liver and white adipose tissue. This occurs via activation of hormone-sensitive lipase that is regulated by phosphorylation via cAMP-dependentprotein kinase, which makes it fully active. 

The regulation of fat metabolism is relatively simple. During fasting, the rising glucagon levels inactivate fatty acid synthesis at the level of acetyl-CoA carboxylase and induce the lipolysis of triglycerides in the adipose tissue by stimulation of a hormone-sensitive lipase. This hormone-sensitive lipase is activated by glucagon and epinephrine (via a cAMP mechanism). This releases fatty acids into the blood. These are transported to the various tissues, where they are used. 

Figure 7.10 Hormones that regulate the activity of the hormone-sensitive lipase in adipose tissue. Each hormone binds to a receptor on the outside of the plasma membrane and changes the activity of the lipase within the adipocyte, via a messenger molecule (Chapter 12). A hormone - independent lipase is also present with provides a low rate of release of fatty acid when the former is inactive.

Figure 7.14 Regulation of rate of fatty acid oxidation in tissues. Arrows indicate direction of change (i) Changes in the concentrations of various hormones control the activity of hormone-sensitive lipase in adipose tissue (see Figure 7.10). (ii) Changes in the blood level of fatty acid govern the uptake and oxidation of fatty acid, (iii) The activity of the enzyme CPT-I is controlled by changes in the intracellular level of malonyl-CoA, the formation of which is controlled by the hormones insulin and glucagon. Insulin increases malonyl-CoA concentration, glucagon decrease it. Three factors are important TAG-lipase, plasma fatty acid concentration and the intracellular malonyl-CoA concentration.

Many enzymes are regulated by covalent modification, most frequently by the addition or removal of phosphate groups from specific serine, threonine, or tyrosine residues of the enzyme. In the fed state, most of the enzymes regulated by covalent modification are in Ihe dephosphorylated form and are active (see Figure 24.2). Three exceptions are glycogen phosphorylase (see p. 129), fructose bis-phosphate phosphatase-2 (see p. 98), and hormone-sensitive lipase of adipose tissue (see p. 187), which are inactive in their dephosphorylated state. 

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 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. 

K.N. Frayn, S.W. Coppack, B.A. Fielding, and S.M. Humphreys, Coordinated regulation of hormone-sensitive lipase and lipoprotein lipase in human adipose tissue in vivo implications for the control of fat storage and fat mobilization, Adv. Enzyme Regul., 1995, 35, 163—178. 

P. Belfrage, and E. Degerman, Regulation of hormone-sensitive lipase activity in adipose tissue, Methods Enzymol.,... 

Figure 6. The roles and regulation of lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) in adipose tissue. GLUT 4, glucose transporter.

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). 

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. 36.10. Regulation of hormone-sensitive hpase (HSL) in adipose tissue. During fasting, the glucagon/insuhn ratio rises, causing cAMP levels to be elevated. Protein kinase A is activated and phosphorylates HSL, activating this enzyme. HSL-P initiates the mobilization of adipose triacylglycerol by removing a fatly acid (FA). Other lipases then act, producing fatty acids and glycerol. Insulin stimulates the phosphatase that inactivates HSL in the fed state.

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