Regulation of Oxidation of Fatty Acids

Regulation of Oxidation of Fatty Acids

•  Hormones regulate lipolysis, in adipose tissue.More free fatty acids are available for the βoxidation. 
•  Insulin inhibits lipolysis. 
•  Acylcarnitine transferase-1 is inhibited by malonyl CoA , one of the intermediates of fattyacid synthesis. 
•  High level of NADHH inhibits acyl CoA dehydrogenase.
•  Increased concentration of acetyl CoA inhibits Thiolase. 
•  When the animal is well fed by carbohydrate, fatty acid oxidation is lowered. 

The metabolism of Ketone Bodies 

When the level of acetyl CoA from β-oxidation increases in excess of that required for entry into the citric acid cycle, It undergoes ketogenesis in the mitochondria of liver (ketone body synthesis). The three compounds viz., acetoacetate, β-hydroxybutyrate, and acetone are collectively known as ketone bodies. The synthesis of ketone bodies takes place during severe starvation or severe diabetes mellitus. During such conditions, the body totally depends on the metabolism of stored triacylglycerols to fulfill its energy demand. In the synthesis, two molecules of acetyl CoA condense together to form acetoacetyl CoA, a reaction catalyzed by thoilase. Another molecule of acetyl CoA reacts with the acetoacetyl CoA to form 3-Hydroxy-3-methyl glutaryl CoA (HMGCoA). This step is the rate limiting step and the reaction is catalyzed by HMGCoA synthase enzyme. Note that this compound is also an intermediate in the synthesis of cholesterol in the liver cell cytosol but the mitochondrial HMGCoA goes to ketone body synthesis.

The HMGCoA formed in the hepatocytes mitochondria by the action of the enzyme HMGCoA lyase is changed to acetoacetate. The acetoacetate, when its concentration is very high in blood is spontaneously decarboxylated to acetone. Acteoacetate can be converted to β-hydroxy butyrate by a dehydrogenase enzyme. It is a reversible reaction. See the figure The odor of acetone may be detected in the breath of a person who has a high level of acetoacetate, like diabetic patients. During starvation and severe diabetes mellitus peripheral tissues fully depend on ketone bodies. Even tissues like the heart and brain depend mainly on ketone bodies during such conditions to meet their energy demand.

Fig 4.8. Synthesis of ketone bodies. 

Regulation of Ketone Body Synthesis 

It is regulated by 

• Rate of β-oxidation 

• Availablity of substrates to enter TCA cycle 

• Mobilization of carbohydrate stores 

Utilization of Ketone Bodies 

Ketone bodies are produced in the Liver and they are utilized in extrahepatic tissues. Liver does not contain the enzyme required for activation of ketone bodies Aceto acetate is activated by two processes for its utilization. 

1. Aceto acetate + ATP + CoA → Acetoacetyl CoA + AMP. The enzyme is Synthethase 

2. Aceteo acetate + Succinyl CoA → Aceto acetyl CoA + Succinate. The enzyme is Thiophorase(Absent in Liver) 

Aceto acetyl CoA is broken down to two molecules of Acetyl CoA, which enters TCA cycle for the production of energy. Aceto acetate and β-hydroxy butyrate are the normal substrates for respiration and important sources of energy .Renal cortex and heart muscle use acetoacetate in preference to glucose .Brain switches over to utilization of ketone bodies for energy during starvation and in uncontrolled diabetes. Acetone is exhaled out .It does not produce energy. Normal level of ketone bodies in blood is 1mg %.In ketonemia, the level increases. Excretion of ketone bodies increases in urine, called ketonuria. If the patient suffers from both the signs, it is called ketosis. 

Causes of Ketosis: 

1. Prolonged starvation, depletion of carbohydrate stores results in increased fatty acid oxidation and ketosis.

2. Lactating mothers develop ketosis, if the carbohydrate demands are not met with. 

3. Diabetic patients with uncontrolled blood glucose, invariably suffer from ketosis, ketoacidosis. 

Ketosis usually associated with sustained high levels of free fatty acids in blood. Lipolysis and ketogenesis are regulated by hormones. 

In Diabetes, there is lack of insulin, which brings about lipolysis and decreased utilization of glucose. Lipoysis increases free fatty acids in blood, which are oxidized to meet energy requirements. This causes increased production of acetyl CoA, NADH, ATP which in turn inhibits TCA cycle. Acetyl CoA requires oxalo acetate to enter TCA cycle .Since oxaloacetate is not forming from glucose, acetyl CoA can’t enter the cycle. It is diverted to ketone bodies synthesis. Similarly in starvation, due to hypoglycemia, there is less insulin, lipolysis increases and ketogenesis increases .Oxaloacetate is also diverted to gluconeogenesis, which further depletes TCA cycle .So acetyl CoA can only be converted to ketone bodies.

The Biosynthesis of Fatty Acids 

Apart from diet fatty acids can be synthesized in the body. Denovo synthesis of fatty acids take place in cytosol of liver, lactating mammary gland, adipose tissue and renal cortex. Main site for TG, fatty acid synthesis is adipose tissue. 

* Acetyl CoA is converted to Malonyl CoA by acetyl CoA carboxylase. 

* Malonyl CoA and acetyl CoA are attached to acyl carrier protein (ACP). 

* Malonyl ACP acetyl ACP get condensed to ketoacyl ACP, by condensing enzyme. 

* Ketoacyl ACP gets reduced to hydroxyl acyl ACPby a reductase. It requires NADPHH. 

* It loses one molecule of water, forms 2-enoyl acyl ACP. Enzyme is dehydratase. 

* It undergoes reduction and forms Butyryl ACP.NADPHH and reductase are needed for the reaction.  

The formation of malonyl CoA is the committed step in fatty acid synthesis 

For the synthesis, all the enzymes are required in the form of fatty acid Synthase complex. 

1. Ketoacyl Synthase (condensing enzyme). 

2. Ketoacyl reductase 

3. Dehydratase 

4. Enoyl acyl ACP reductase 

5. Thioesterase. 

Acetyl CoA + 7 malonyl CoA + 14NADPHH = Palmitoyl CoA + 7CoA +7CO2 +14 NADP +7H2O. The main sources of NADPH for fatty acid synthesis are the pentose shunt but the malic enzyme reaction has also a small contribution. The formation of malonyl CoA is the committed step in fatty acid synthesis For the synthesis, all the enzymes are required in the form of fatty acid Synthase complex. Stochiometry of the reaction Acetyl CoA + 7malonyl CoA + 14NADPH + 7H+ → Palmitate + 7CO2 + 14NADP+ + 8CoA + 6H2O Hence the overall stoichiometry for the synthesis is: 8Acetyl CoA + 7ATP + 14NADPH → Palmitate + 14NADP+ + 8CoA + 6H2O + 7ADP + 7Pi

Regulation o Fatty Acid Synthesis: 

• High carbohydrate diet increases synthesis. 

• Palmitoyl CoA inhibits synthesis 

• Fasting decreases acetyl carboxylase, decreases fatty acid synthesis. 

• Insulin stimulates fatty acid synthesis.  

Biosynthesis of Triacylglycerols 

1. Major pathway: 2.Activate fatty acids are attached to glycerophosphate to form phosphatidic acid ,by acyl transferase.It is converted to diglyceride by the removal of phosphate group by phosphatase.Another fatty acid is attached to the diglyceride to form triglyceride.The synthesis takes place in adipose tissue and Liver. 

2. Minor pathway: Monoglyceride is acylated to form diglyceride .It is later converted to triglyceride by addition of one more fatty acid.The process is seen during absorption of Lipids.