Hormone sensitivity

Stimulation of glycogen breakdown involves consumption of molecules of ATP at three different steps in the hormone-sensitive adenylyl cyclase cascade (Figure 15.19). Note that the cascade mechanism is a means of chemical amplification, because the binding of just a few molecules of epinephrine or glucagon results in the synthesis of many molecules of cyclic / MP, which, through the action of c/ MP-dependent protein kinase, can activate many more molecules of phosphorylase kinase and even more molecules of phosphorylase. For example, an extracellular level of 10 to 10 M epinephrine prompts the for-... 

Lipolysis 1 Hormone sensitive lipase (HSL) l Adrenergic stimulation of lipolysis Adipocytes... 

Tumors derived from hormone sensitive tissues may remain hormone dependent and are then amenable to therapeutic approaches with hormonal agents. These include hormones with opposing (apoptotic) action, hormone antagonists, and agents that inhibit hormone synthesis. 

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 )... 

Use synthetic nonapeptidc agonist analog of gonadorelin (LH-RH), gonad stimulating principle for treatment ol hormone sensitive prostatic carcinoma and endometriosis... 

The Provision of Glycerol 3-Phosphate Regulates Esterification Lipolysis Is Controlled by Hormone-Sensitive Lipase (Figure 25-7)... 

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.)...

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. 

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. 

Holm C et al Molecular mechanisms regulating hormone sensitive lipase and lipolysis. Annu Rev Nutr 2000 20 365. 

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... 

A gene (erstEl) encoding a thermostable esterase was isolated from Escherichia coli cells that had been transformed by DNA libraries with metagenomes from environmental samples isolated from thermal habitats. The enzyme belonged to the hormone-sensitive lipase family, could be overexpressed in E. coli, was active between 30 and 95°C, and used 4-nitrophenyl esters with chain lengths of C4-C16 (Rhee et al. 2005). 

Rhee J-K, D-G Ahn, Y-G Kim, J-W Oh (2005) New thermophilic and thermostable esterase with sequence similarity to the hormone-sensitive lipase family cloned from a metagenomic library. Appl Environ Microbiol 71 817-825. 

J Llopis, GEN Kass, SK Duddy, GA Moore, S Orrenius. (1991). Mobilization of hormone sensitive calcium pool increases hepatocyte tight junctional permeability in the perfused rat liver. FEBS Lett 280 84-86. 

Shen, W.-E., Sridhar, K., Bernlohr, D.A. and Kraemer, F.B. (1999) Interaction of rat hormone-sensitive lipase with adipocyte lipid-binding protein. Proceedings of the National Academy of Sciences USA 96, 5528—5532. 

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. 

Fatty acyl-CoA in, acetyl-CoA and NADH, FADH2 out From triglycerides through hormone-sensitive lipase... 

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 birds, both neural aromatase and 5a-reductase are induced by testosterone, and this regulation provides a way by which androgens can regulate CNS hormone sensitivity without regulating receptor number [ 1 ]. 

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 9.11 Lipid mobilization by hormone sensitive lipase (HSL)...

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