Hormonal Control of Metabolism - Assignment Example

Hormonal control of metabolism (triacyglycerol metabolism a) How does the glucose level inside adipose cells regulate the release of the fatty acids into blood? The triacylglycerols stored in adipose tissue are an enormous reservoir of metabolic fuel. Adipose tissue is specialized for the esterification of fatty acids and for their release from triacylglycerols. In human beings, the liver is the major site of fatty acid synthesis. These fatty acids are esterified in the liver to glycerol phosphate to form triacylglycerol and are transported to the adipose tissue in lipoprotein particles, such as very low density lipoproteins. Triacylglycerols are not taken up by adipocytes; rather, they are first hydrolyzed by an extracellular lipoprotein lipase for uptake. This lipase is stimulated by processes initiated by insulin. After the fatty acids enter the cell, the principal task of adipose tissue is to activate these fatty acids and transfer the resulting CoA derivatives to glycerol in the form of glycerol 3-phosphate. This essential intermediate in lipid biosynthesis comes from the reduction of the glycolytic intermediate dihydroxyacetone phosphate. Thus, adipose cells need glucose for the synthesis of triacylglycerols (Figure 1). Figure 1: Synthesis and Degradation of Triacylglycerols by Adipose Tissue Triacylglycerols are hydrolyzed to fatty acids and glycerol by intracellular lipases. The release of the first fatty acid from a triacylglycerol, the rate-limiting step, is catalyzed by a hormone-sensitive lipase that is reversibly phosphorylated. The hormone epinephrine stimulates the formation of cyclic AMP, the intracellular messenger in the amplifying cascade, which activates a protein kinasea recurring theme in hormone action. Triacylglycerols in adipose cells are continually being hydrolyzed and resynthesized. Glycerol derived from their hydrolysis is exported to the liver. Most of the fatty acids formed on hydrolysis are reesterified if glycerol 3-phosphate is abundant. In contrast, they are released into the plasma if glycerol 3-phosphate is scarce because of a paucity of glucose. Thus, the glucose level inside adipose cells is a major factor in determining whether fatty acids are released into the blood (Berg et al., 2002). b) What would be the consequence of the deficiency of hexokinase in adipose tissue on fatty acid metabolism? Hexokinase (glycolysis) is necessary to synthesize glycerol from glyceraldehydes 3-phosphate, which is then used to make triacylglycerols in adipose tissue. Deficiency in hexokinase would hinder triacylglycerol synthesis. c) What effect does insulin have on the release and storage of fatty acids? The blood is the carrier of triacylglycerols in the form of VLDLs and chylomicrons, fatty acids bound to albumin, amino acids, lactate, ketone bodies and glucose. The pancreas is the primary organ involved in sensing the organisms dietary and energetic states via glucose concentrations in the blood. In response to low blood glucose, glucagon is secreted, whereas, in response to elevated blood glucose insulin is secreted. Insulin, has the opposite effect to glucagon and epinephrine leading to increased glycogen and triacylglyceride synthesis. One of the many effects of insulin is to lower cAMP levels which lead to increased dephosphorylation through the enhanced activity of protein phosphatases such as PP-1. With respect to fatty acid metabolism this yields dephosphorylated and inactive hormone sensitive lipase. Insulin also stimulates certain phosphorylation events. This occurs through activation of several cAMP-independent kinases. Insulin stimulated phosphorylation of ACC activates this enzyme (King and Marchesini, 2003). 2. a) How are free fatty acid transported in blood? Utilization of dietary lipids requires that they first be absorbed through the intestine. As these molecules are oils they would be essentially insoluble in the aqueous intestinal environment. Solubilization (emulsification) of dietary lipid is accomplished via bile salts that are synthesized in the liver and secreted from the gallbladder. The emulsified fats can then be degraded by pancreatic lipases (lipase and phospholipase A2). These enzymes, secreted into the intestine from the pancreas, generate free fatty acids and a mixture of mono- and diacylglycerols from dietary triacylglycerols. Pancreatic lipase degrades triacylglycerols at the 1 and 3 positions sequentially to generate 1,2-diacylglycerols and 2-acylglycerols. Phospholipids are degraded at the 2 position by pancreatic phospholipase A2 releasing a free fatty acid and the lysophospholipid. Following absorption of the products of pancreatic lipase by the intestinal mucosal cells, the resynthesis of triacylglycerols occurs. The triacylglycerols are then solubilized in lipoprotein complexes (complexes of lipid and protein) called chylomicrons. A chylomicron contains lipid droplets surrounded by the more polar lipids and finally a layer of proteins. Triacylglycerols synthesized in the liver are packaged into VLDLs and released into the blood directly. Chylomicrons from the intestine are then released into the blood via the lymph system for delivery to the various tissues for storage or production of energy through oxidation. The triacylglycerol components of VLDLs and chylomicrons are hydrolyzed to free fatty acids and glycerol in the capillaries of adipose tissue and skeletal muscle by the action of lipoprotein lipase. The free fatty acids are then absorbed by the cells and the glycerol is returned via the blood to the liver (and kidneys). The glycerol is then converted to the glycolytic intermediate DHAP (King, 2006). b) What is the role of protein kinase A in lipolysis? Perilipin (Peri) A is a phosphoprotein located at the surface of intracellular lipid droplets in adipocytes. Activation of cyclic AMP-dependent protein kinase (PKA) results in the phosphorylation of Peri A and hormone-sensitive lipase (HSL), the predominant lipase in adipocytes, with concurrent stimulation of adipocyte lipolysis. [11] Adipose tissue contains hormone-sensitive lipase that is activated by PKA-dependent phosphorylation leading to increased fatty acid release to the blood. This leads to increased fatty acid oxidation in other tissues such as muscle and liver. In the liver the net result (due to increased acetyl-CoA levels) is the production of ketone bodies. The increased fatty acid availability in response to glucagon or epinephrine is assured of being completely oxidized since PKA also phosphorylates (and as a result inhibits) ACC, thus inhibiting fatty acid synthesis (King and Marchesini, 2003). 3) Why a very restricted diet with a low intake of carbohydrates interfere with complete oxidation of fatty acids and results in the formation of ketone bodies instead? When there is a low carbohydrate intake, other hormones such as glucagon are stimulated, releasing glucose from muscle tissue and the liver into the bloodstream to restore it to normal concentrations. When insulin is low concentrations, the body turns to the oxidation of fatty acids for its primary fuel source instead of the desired glucose (Hoang, 2003). Adipose tissue contains hormone-sensitive lipase, that is activated by PKA-dependent phosphorylation leading to increased fatty acid release to the blood. This leads to increased fatty acid oxidation in other tissues such as muscle and liver. In the liver the net result (due to increased acetyl-CoA levels) is the production of ketone bodies. This would occur under conditions where insufficient carbohydrate stores and gluconeogenic precursors were available in liver for increased glucose production. The increased fatty acid availability in response to glucagon or epinephrine is assured of being completely oxidized since PKA also phosphorylates (and as a result inhibits) ACC, thus inhibiting fatty acid synthesis (King and Marchesini, 2003). 4) What effect would deficiency of carnitine have on the fatty acid metabolism? Carnitine is a naturally occurring hydrophilic amino acid derivative, produced endogenously in the kidneys and liver and derived from meat and dairy products in the diet. It plays an essential role in the transfer of long-chain fatty acids into the mitochondria for beta-oxidation. Carnitine binds acyl residues and helps in their elimination, decreasing the number of acyl residues conjugated with coenzyme A (CoA) and increasing the ratio between free and acylated CoA. Carnitine deficiency is a metabolic state in which carnitine concentrations in plasma and tissues are less than the levels required for normal function of the organism. Biologic effects of low carnitine levels may not be clinically significant until they reach less than 10-20% of normal. Carnitine deficiency may be primary or secondary. Primary carnitine deficiency is caused by a deficiency in the plasma membrane carnitine transporter, with urinary carnitine wasting causing systemic carnitine depletion. Intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the mitochondrial matrix. Consequently, long-chain fatty acids are not available for beta-oxidation and energy production, and the production of ketone bodies (which are used by the brain) also is impaired. Regulation of the intramitochondrial free CoA also is affected, with accumulation of acyl-CoA esters in the mitochondria. This, in turn, affects the pathways of intermediary metabolism that require CoA (eg, Krebs cycle, pyruvate oxidation, amino acid metabolism, mitochondrial and peroxisomal beta oxidation). The 3 areas of involvement include (1) the cardiac muscle, which is affected by progressive cardiomyopathy (by far, the most common form of presentation), (2) the central nervous system, which is affected by encephalopathy caused by hypoketotic hypoglycemia, and (3) the skeletal muscle, which is affected be myopathy. Muscle carnitine deficiency (restricted to muscle) is characterized by depletion of carnitine levels in muscle with normal serum concentrations. Evidence indicates that the causal factor is a defect in the muscle carnitine transporter. In secondary carnitine deficiency, which is caused by other metabolic disorders (eg, fatty acid oxidation disorders, organic acidemias), carnitine depletion may be secondary to the formation of acylcarnitine adducts and the inhibition of carnitine transport in renal cells by acylcarnitines. In disorders of fatty acid oxidation, excessive lipid accumulation occurs in muscle, heart, and liver, with cardiac and skeletal myopathy and hepatomegaly. Long-chain acylcarnitines also are toxic and may have an arrhythmogenic effect, causing sudden cardiac death (Scaglia, 2004). References Berg, J.M., Tymoczko, J.L. and Stryer, L. (2002) Biochemistry. Fifth edition. W. H. Freeman and Company. Hoang, M. (2003) Low Carbohydrate diets– Fab or Fad? [online]. Available from: . [18 March 2006]. King, M.W. and Marchesini, S. (2003). Lipid Metabolism. [online]. Available from: . [19 March 2006]. King, M.W. (2006). Mobilization of Fat Stores. [online]. Available from: . [18 March 2006]. Scaglia, F. (2004) Carnitine Deficiency. [online]. Available from: . [20 March 2006]. Read More

Insulin, has the opposite effect to glucagon and epinephrine leading to increased glycogen and triacylglyceride synthesis. One of the many effects of insulin is to lower cAMP levels which lead to increased dephosphorylation through the enhanced activity of protein phosphatases such as PP-1. With respect to fatty acid metabolism this yields dephosphorylated and inactive hormone sensitive lipase. Insulin also stimulates certain phosphorylation events. This occurs through activation of several cAMP-independent kinases.

Insulin stimulated phosphorylation of ACC activates this enzyme (King and Marchesini, 2003). 2. a) How are free fatty acid transported in blood? Utilization of dietary lipids requires that they first be absorbed through the intestine. As these molecules are oils they would be essentially insoluble in the aqueous intestinal environment. Solubilization (emulsification) of dietary lipid is accomplished via bile salts that are synthesized in the liver and secreted from the gallbladder. The emulsified fats can then be degraded by pancreatic lipases (lipase and phospholipase A2).

These enzymes, secreted into the intestine from the pancreas, generate free fatty acids and a mixture of mono- and diacylglycerols from dietary triacylglycerols. Pancreatic lipase degrades triacylglycerols at the 1 and 3 positions sequentially to generate 1,2-diacylglycerols and 2-acylglycerols. Phospholipids are degraded at the 2 position by pancreatic phospholipase A2 releasing a free fatty acid and the lysophospholipid. Following absorption of the products of pancreatic lipase by the intestinal mucosal cells, the resynthesis of triacylglycerols occurs.

The triacylglycerols are then solubilized in lipoprotein complexes (complexes of lipid and protein) called chylomicrons. A chylomicron contains lipid droplets surrounded by the more polar lipids and finally a layer of proteins. Triacylglycerols synthesized in the liver are packaged into VLDLs and released into the blood directly. Chylomicrons from the intestine are then released into the blood via the lymph system for delivery to the various tissues for storage or production of energy through oxidation.

The triacylglycerol components of VLDLs and chylomicrons are hydrolyzed to free fatty acids and glycerol in the capillaries of adipose tissue and skeletal muscle by the action of lipoprotein lipase. The free fatty acids are then absorbed by the cells and the glycerol is returned via the blood to the liver (and kidneys). The glycerol is then converted to the glycolytic intermediate DHAP (King, 2006). b) What is the role of protein kinase A in lipolysis? Perilipin (Peri) A is a phosphoprotein located at the surface of intracellular lipid droplets in adipocytes.

Activation of cyclic AMP-dependent protein kinase (PKA) results in the phosphorylation of Peri A and hormone-sensitive lipase (HSL), the predominant lipase in adipocytes, with concurrent stimulation of adipocyte lipolysis. [11] Adipose tissue contains hormone-sensitive lipase that is activated by PKA-dependent phosphorylation leading to increased fatty acid release to the blood. This leads to increased fatty acid oxidation in other tissues such as muscle and liver. In the liver the net result (due to increased acetyl-CoA levels) is the production of ketone bodies.

The increased fatty acid availability in response to glucagon or epinephrine is assured of being completely oxidized since PKA also phosphorylates (and as a result inhibits) ACC, thus inhibiting fatty acid synthesis (King and Marchesini, 2003). 3) Why a very restricted diet with a low intake of carbohydrates interfere with complete oxidation of fatty acids and results in the formation of ketone bodies instead? When there is a low carbohydrate intake, other hormones such as glucagon are stimulated, releasing glucose from muscle tissue and the liver into the bloodstream to restore it to normal concentrations.

When insulin is low concentrations, the body turns to the oxidation of fatty acids for its primary fuel source instead of the desired glucose (Hoang, 2003).

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