Oxidation of Lipids V

Suaib Luqman

  1. Objectives
  • v To understand the Ketosis and ketone bodies formation
  • v How cholesterol is dilapidated
  • v What is the fate of phospholipids, sphingomyelin degradation
  1. Concept Map

3. Description

 

 

 

 

Ketone bodies and the Ketosis Phenomenon

 

 

In the normal animal fatty acid degradation and synthesis proceed without significant accumulation of intermediates. Under some circumstances certain products accumulate in the blood which is traditionally but inaccurately termed “ketone bodies”. These are acetoacetic acid, β-hydroxybutyric acid and acetone. All these products stem from acetoacetyl CoA, a normal intermediate in the oxidation of fatty acid. Moreover it is readily formed by the reversal of the thiolase reaction.

 

2 Acetyl CoA   Acetoacetyl Coa + CoA

 

 

The major fate of acetoacetyl CoA in liver is conversion to β-hydroxy-β-methylglutaryl CoA, an important intermediate in the biogenesis of cholesterol and steroids and in the degradation of leucine.

 

The two carbon fragments (acetyl-Co A) derived from β-oxidation may then enter the citric acid cycle for complete oxidation or they may recombine (condense) to form acetoacetyl-Co A (active acetoacetate) and other ketones. The production of ketone bodies under normal conditions is minimal rather acetyl-CoA condenses with oxaloacetate and enters the citric acid cycle for complete oxidation. Acetoacetyl-CoA is readily converted in the liver to free acetoacetic acid because this organ only contains deacylase. The free acetoacetic acid then diffuses into the blood and is carried to the peripheral tissues where it may then be oxidized. This is depicted in the figure below.

 

Pathways of Ketogenesis in Liver

 

Although the parent compound of the ketone bodies, acetoacetyl CoA, is a normal intermediate in both fatty acid degradation and cholesterol synthesis, certain facets of its metabolism merit special mention, particularly because of its importance in ketosis. In figure some of the primary interrelationships of lipid metabolism are shown. The key factors would appear to be the central role of acetyl CoA and β -hydroxy-β-methylglutaryl CoA. In the case of acetyl CoA, the three major fates are oxidation cia the citric acid cycle, formation of acetoacetyl CoA, and synthesis of fatty acids, primarily via the malonyl CoA pathway. The release of acetoacetate by liver is a continuing normal process. The total ketone body concentration in blood, expressed as β -hydroxybutyrate, is normally 1mg per 100 mL and the average total daily excretion in the urine is approximately 20mg. This is because of efficient mechanism for removal of acetoacetic acid by peripheral tissues, especially muscle which can derive a sizable fraction of its total energy requirement from this nutrient. In order to be utilized acetoacetic acid must first be reconverted into its CoA derivative by transfer of a CoA residue from succinyl CoA by the action of a specific thiophorase. The acetoaceyl Coa thus formed may then be cleaved by thiolase yielding two molecules of acetyl CoA which then enter the citric acid cycle.

 

Ketone Bodies Synthesis in Liver and its Use in Peripheral Tissues

 

 

An elevation of the concentration of ketone bodies in the blood above normal levels is called ketonemia. If the blood level exceeds the renal threshold and appreciable amounts of ketone bodies appear in the urine, ketonuria is said to exist. Of the ketone bodies, acetone alone has a significant vapour pressure, and whenever a marked degree of ketonemia and ketonuria exist, the odor of acetone is likely to be detected in the exhaled air. This triad of ketonemia, ketonuria and acetone odor of the breath is commonly termed ketosis.

 

Causes of Ketosis

 

A diminution in the quantity of carbohydrate catabolised may cause ketosis. Perhaps the most readily understood condition is starvation. When no food is allowed, the organism rapidly consumes its own stores of glycogen in the liver, and thereafter it survives largely upon energy derived from its depot lipid. A starvation result in a lipemia which reflects migration of excessive quantities of lipid from the depots to the liver, and this in turn produces a fatty liver. The degradation of fatty acids in the liver proceeds at greater than usual rate. As a consequence, there is a pleothora of acetoacetyl Coa, which results in an excess of acetoacetate and its products, acetone and β-hydroxybutyrate. Ketone incident to starvation is most frequently encountered clinically in gastrointestinal disturbances in infancy or pregnancy.

 

Cholesterol Degradation

 

 

Direct degradation of cholesterol does not occur because of the ring structure, therefore its elimination is the possible way to regulate it yet before elimination it is converted to bile acids and bile salts which are excreted through feces. Little cholesterol is modified by bacteria before excretion in the intestine. A large portion of the cholesterol in lymph and in blood plasma is found in chylomicra.

Structure of cholesterol and its ester

 

Since the dispersed fate of these fat droplets is due chiefly to their content in phosphatide, it is not surprising that the ratio of phosphatide to cholesterol in the blood remains fairly constant. Of the cholesterol in plasma, roughly to thirds exists esterified with fatty acids. The maintenance of this ratio is a function of liver, and decreases in this value due to lowering of cholesterol ester concentration are seen in liver disease. The liver serves both as the chief synthetic source and the chief agent for disposal of plasma cholesterol, a portion of that removed from the blood appearing in the bile.

Though sparingly soluble in water, cholesterol readily dissolves in aqueos bile salt solutions, probably because of the formation of choleric acids, soecific coordination compounds of bile acids and sterols. In the gall bladder, both water and bile salts are reabsorbed by the action of the cholecystic mucosa and if this process continues excessively, cholesterol crystals separate from the bile. Either biliary stasis or inflammatory disease of the gall bladder can lead to this situation. Concretions made of chiefly of cholesterol crystals are among the common calculi of the biliary duct, the disease being termed cholelithiasis. Such calculi in the gall bladder may be undetected (silent), but if they descend the biliary tract and particularly if they occlude the common bile duct, a variety of clinically important events ensue. Cholesterol enters the intestinal tract by direct excretion across the intestinal mucosa as well as via the bile. In the lumen of the gut a portion is reduced microbially to coprosterol via the following steps and thereby excluded from reabsorption.

Catabolism of Cholesterol à Conversion to bile acids

Only a fraction of the cholesterol metabolized daily is excreted as sterols in the faeces. Virtually none appears in the urine. It emerges that cholesterol serves as precursors for a variety of biologically important structurally related steroids.

 

 

 

Approximately 80% of the cholesterol metabolized is transformed by liver tissues into various bile acids. Experimental evidence indicates that hydroxylation of cholesterol is more or less completed before the degradation of the side chain is finished

Degradation of Phospholipids

 

 

Phosphoglyceride degradation occurs by the action of phospholipase. Phospholipases serve as messenger for example IP3 and DAG or arachidonic acid which is acted by COX and LOX to generate a variety of signaling molecules. Phospholipase A1 and A2 cleave fatty acids from membrane bound phospholipids that can be replaced by different fatty acid through the catalysis of fatty acyl CoA transferase. This mode is one of the route to create unique lung surfactant, DPCC [Dipalmitoylphosphatidylcholine].

 

Degradation of Sphingomyelin

 

It is degradaed by sphingomyelinase which is a lysosomal enzyme catalyzing a hydrolytic removal of phosphorylcholine leaving behind ceramide. Ceramide is degraded by ceramidase into sphingosine and free fatty acid. Both the sphingosine and ceramide regulate signal transduction pathways and thus influences Protein kinase C promoting apoptosis. Niemann-Pick disease is caused by the defect in catalyzing sphingomyelin and it is an autosomal recessive disease. The enzyme responsible is sphingomyelinase (a type of phospholipase C). Infants with lysosomal storage disease containing sphingomyelin in the central nervous system die early

 

Bile acids and Bile salts

 

Bile consists of a watery mixture of inorganic and organic molecules. The organic part consists of mainly phosphatidylcholine and bile salts (conjugated form of bile acids). Bile salts are the only means for cholesterol degradation both as a solubilizer of cholesterol in bile as well as metabolic product of cholesterol.

 

  1. Summary

 

In this lecture we learnt about:

  • The formation of ketone bodies and ketosis phenomenon.
  • How cholesterol is broken down.
  • The fate of phospholipid, sphingomyelin and bile acid/salts. Catabolism.

 

Weblinks

 

 

 

Books

 

  1. Lehninger Principles of Biochemistry by David L. Nelson, ‎Albert L. Lehninger, ‎Michael M. Cox. 2008. https://books.google.co.in/books?isbn=071677108X
  2. Ketone Bodies—Advances in Research and Application: 2012 https://books.google.co.in/books?isbn=1481604082
  3. Biochemical and clinical aspects of ketone body. Hans-Dieter Söling, ‎Claus-Dieter Seufert, ‎Kurt George Matthew Mayer Alberti. 1978. https://books.google.co.in/books?id=R_VqAAAAMAAJ
  4. The Ketosis Diet: Ketogenic Diet Tips Made Simple by Amy Zulpa. 2014. https://books.google.co.in/books?isbn=1680324144
  5. The Ketogenic Diet: A Complete Guide for the Dieter by Lyle McDonald, ‎Elzi Volk. 1998. Page 32. https://books.google.co.in/books?isbn=0967145600