Adipose tissue, hormone sensitive lipase

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.)...

J.K. Huttunen and D. Steinberg, Activation and phosphorylation of purified adipose tissue hormone-sensitive lipase by cyclic AMP-dependent protein kinase, Biochim. Biophys. Acta, 1971, 239, 411-427. 

In Type I diabetes mellitus, there is a severe deficiency (or total absence) of insulin due to an autoimmune attack on the cells that produce insulin, pancreatic j8-cells. The absence of insulin produces a deficiency in adipose tissue lipoprotein lipase. This causes sluggish catabolism of VLDL and leads to hypertriglyceridemia. Another mechanism by which insulin deficiency promotes increased VLDL levels is the failure to inhibit the activity of adipose tissue hormone-sensitive lipase. This enzyme hydrolyzes cytoplasmic triglyceride droplets. The fatty acids then go to the liver, where they are re-esterified to form triglycerides. These triglycerides are exported on VLDL particles. Since adipose tissue-derived fatty acids are an important substrate for hepatic VLDL triglycerides, the failure to suppress adipose tissue lipolysis is an important contributor to the enhanced rate of VLDL triglyceride secretion. 

The hypertriglyceridemia of Type II diabetes, unlike that which is found with Type I diabetes, is not due to excessive adipocyte lipolysis. This is because only a small level of insulin action is required to suppress excessive adipose tissue hormone-sensitive lipase activity. In Type II diabetes, there is insufficient adipose tissue lipoprotein lipase and excessive hepatic triglyceride synthesis. Thus, inefficient VLDL triglyceride catabolism and excessive VLDL triglyceride secretion both contribute to the excess VLDL in Type II diabetes. 

Severson, D. L., Khoo, J. C., and Steinberg, D., 1977, Role of phosphoprotein phosphatases in reversible deactivation of chicken adipose tissue hormone-sensitive lipase, /. Biol. Chem. 252 1484. 

A principal action of insufin in adipose tissue is to inhibit the activity of hormone-sensitive lipase, reducing the release not only of free fatty acids but of glycerol as well. Adipose tissue is much more sensitive to insulin than are many other tissues, which points to adipose tissue as a major site of insufin action in vivo. 

In adipose tissue, the effect of the decrease in insulin and increase in glucagon results in inhibition of lipo-genesis, inactivation of lipoprotein lipase, and activation of hormone-sensitive lipase (Chapter 25). This leads to release of increased amounts of glycerol (a substrate for gluconeogenesis in the liver) and free fatty acids, which are used by skeletal muscle and liver as their preferred metabolic fuels, so sparing glucose. 

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 glycerol produced by the action of hormone-sensitive lipase in the adipose tissue cannot be utilized by adipose tissue itself. Adipose cells lack the enzyme glycerol kinase, which is necessary to convert glycerol to glycerol phosphate. 

The major hormone-sensitive control point for the mobilization of fat and the (f-oxidation pathway is the effect of phosphorylation on the activity of the hormone-sensitive lipase of the adipose tissue. The major direct control point for (f oxidation is the inhibition of carnitine acyl-... 

Adipose Adipose tissue is the primary storage facility for fat. Fat is stored in these tissues as an intracellular droplet of insoluble triglyceride. A hormone-sensitive lipase mobilizes triglyceride stores by hydrolysis to free fatty acids. 

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. 

Adipose tissue releases fat by activation of the hormone-sensitive lipase. The glycerol released by adipose tissue can provide some glucose equivalents to the liver. Adipose tissue itself can t use glycerol—it s missing glycerol kinase to make glycerol 3-phosphate. 

In adipose tissue, insulin stimulation suppresses triglyceride hydrolysis (to free fatty acids and glycerol) by activating cAMP phosphodiesterase (cAMP PDE). Cyclic AMP, (3, 5 cAMP), is required to stimulate hormone sensitive lipase (HSL), the enzyme which hydrolyses triglyceride within adipocytes PDE converts active 3, 5 cAMP to inactive 5 AMP thus preventing the stimulation of HSL. The net effect of insulin on lipid metabolism is to promote storage. 

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.

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). 

Figure 7.13 Physiological pathway for fatty acid oxidation. The pathway starts with the hormone-sensitive lipase in adipose tissue (the flux-generating step) and ends with the formation of acetyl-CoA in the various tissues. Acetyl-CoA is the substrate for the flux-generating enzyme, citrate synthase, for the Krebs cycle (Chapter 9). Heart, kidney and skeletal muscle are the major tissues for fatty acid oxidation but other tissues also oxidise them.

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.

In adipose tissue, the increased concentration of cyclic AMP activates the hormone-sensitive lipase to increase the rate of Upolysis and hence fatty acid release from adipose tissue. This increases the plasma level of fatty acids and hence their oxidation by muscle (see Chapter 7). 

The increased levels of catecholamines and glucocorticoids, the increased sympathetic activity and the decreased level of insulin increase the activity of hormone-sensitive lipase in adipose tissue that is responsible for the increased rate of lipolysis. Also important are the proinflammatory cytokines, TNFa, interleukins 1 and 6. The significance of fat as a fuel in trauma explains why the cytokines have a... 

Which one of the following is characteristic of low insulin levels A. Increased glycogen synthesis B. Decreased gluconeogenesis from lactate C. Decreased glycogenolysis D. Increased formation of 3-hydroxybutyrate E. Decreased action of hormone-sensitive lipase Correct answer = D. 3-hydroxybutyrate—a ketone body—synthesis is enhanced in the liver by taw insulin levels, which favor activation of hormone-sensitive lipase and release of fatty acids from adipose tissue. Glycogen synthesis is decreased, whereas gluconeogenesis is increased. 

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. 

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, ) ... 

E. a decreased activity of hormone-sensitive lipase in adipose tissue. 

Correct answer = C. Free fatty acids bound to albumin are increased as a result of an increased activity of hormone-sensitive lipase in adipose tissue. Hepatic ketogenesis is stimu lated by elevated levels of glucagon. The forma tion of acetyl CoA is inc reased. 

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