Ketogenesis

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1. Ketogenesis Ketolysis
2. Ketosis (ketoacidosis)
3. Metabolism of Cholesterol

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Ketogenesis

• It is the formation of ketone bodies in the liver
  mitochondria.
• Ketone bodies are
• CH3-CO-CH2-COOH Acetoacetic acid
• CH3-CHOH-CH2-COOH ß-hydroxybutyric acid
• CH3-CO-CH3 Acetone (non-metabolized
• 
  
  product)

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• Ketone bodies are formed from acetyl CoA
  resulting from ß oxidation of FA in excess of
  optimal function of Kreb's cycle.
• Under normal fed state
• the hepatic production of acetoacetate and ß
  hydroxybutyrate is minimal and the concentration
  of these compounds in the blood is very low (does
  not exceed 1 mg or lt0.2 mM).
• Most acetyl CoA fatty acid or pyruvate oxidation
  enter the citric acid cycle only if fat and
  carbohydrates degrdation are balanced.

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Steps synthesis of Ketone bodies

1. Two molecules of acetyl CoA react with each other
   in the presence of thiolase enzyme to form
   acetoacetyl CoA.

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• Condensation of acetoacetyl CoA with
• acetyl CoA to form HMG CoA
• (3 or ß hydroxyl- 3or ß methyl glutaryl CoA)
• catalyzed by HMG CoA synthetase,

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1. HMG-CoA lyase enzyme catalyzes the cleavage of
   HMG-CoA to acetoacetate and acetyl CoA.

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• Acetoacetate produces ß-hydroxybutyrate in
• a reaction catalyzed by ß-hydroxybutyrate
  
• dehydrogenase in the present NADH.

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• Both acetoacetate and ß-hydroxybutyrate can be
  transported across the mitochondrial membrane and
  the plasma membrane of the liver cells,
• enter to the blood stream to be used as a
  fuel by other cells of the body.

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1. In the blood stream, small amounts of
   acetoacetate are spontaneously (non-
   enzymatically) decarboxyated to acetone.

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• Acetone is volatile and can not be detected in
  the blood.
• The odor of acetone may be detected in the breath
  and also in the urine of a person who has high
  level of ketone bodies in the blood.
• e.g. in severe diabetic ketoacidosis, while
  under normal conditions, acetone formation is
  negligible.

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• Regulation of Ketone body synthesis
• HMG COA synthase is the regulatory enzyme
• Induced by increased fatty acids in the blood.
• It is inhibited by high level of CoASH, thus when
  fatty acids flows to the liver, CoASH used for
  its activation and for thiolase.
• Thus, CoASH levels are reduced and HMG CoA
  synthase is active and vice versa.

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Importance of Ketogenesis

• Ketogenesis becomes of great significant during
  starvation when carbohydrate store are depleted
  and oxidation of fats becomes a major source of
  energy to the body.
• The brain normally uses glucose as the only fuel.
  After the diet has been changed to lower blood
  glucose for 3 days, the brain gets 25 of its
  energy from ketone bodies. After about 40 days,
  this goes up to 70, but can not utilize FA.

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Ketolysis

• Ketolysis is the complete oxidation of ketone
  bodies to C02 and water.
• Site
• Mitochondria of extrahepatic tissues due to
  high activity of the enzymes acetoacetate
  thiokinase and thiophorase, but not in the liver
  due to deficiency of these enzymes

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• During glucose is in short supply (starvation) or
  in insulin deficiency, the mitochondria of
  Cardiac (70 of its energy) ,skeletal muscles and
  kidney can use free fatty acids as a source of
  energy.
• However, during prolonged starvation when supply
  of glucose is limited, the brain may utilize
  ketone bodies as the major fuel.

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Mechanism

• ß-hydroxy butyrate is dehydrogenated forming
  acetoacetate, the reaction is catalyzed by
  ß-hdyroxybutyrate dehydrogenase.

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• Activation of acetoacetate to acetoacetyl CoA
  occurs by one of two pathways 
• One mechanism involves succinyl CoA and the
  enzyme succinyl CoA acetoacetate CoA transferase
  (CoA transferase).
• Other mechanism involves the activation of
  acetoacetate with ATP in presence of CoA SH
  catalyzed by thiokinase (Acetoacetyl CoA
  synthetase).

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• Acetoacetyl CoA is split to acetyl CoA by
  thioalse and oxidized via citric acid cycle to
  C02 and H20.

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• Utilization of acetone by tissues is very slow,
  it may be converted to propandiol which becomes
  oxidized to pyruvate, or splits to acetate and
  formate.
• Importance of ketolysis
• Ketolysis completes the oxidation of FA which
  started in the liver. It is a major source of
  energy to extrahepatic tissues during starvation.

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Energetics production from degradation of ketone
bodies in peripheral tissue

• Acetoacetate is oxidized into 2 acety1 CoA ,
  
• which enter the citric acid cycle.
• Activation of acetoacetate consumes 1 ATP , and
  the total amount of ATP from metabolism of 2
  acety1 CoA is
• 24 1 23 ATP
• 2. Conversion of ß- hydroxybutyrate back into
  acetoacetate generates 1 NADH , which produces an
  additional 3ATP total ATP produce 26ATP) (24
  3) 1 26 ATP
• after entering the electron transport
  chain .

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• 3. The liver cannot use ketones for fuel because
  it lacks the enzyme succiny CoA acetoacetate CoA
  transferase (thiophorase),
• which is necessary to convert acetoacetate
  into 2 acety1 CoA.

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Ketosis (ketoacidosis)

• It is the accumulation of the ketone bodies in
  the blood (Ketonemia) and their appearance in the
  urine (ketonuria)
• together with acetone odour in the breath and
  acetone can be detected in urine.

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Mechanism

• Ketosis can occur in any condition characterized
  by inhibited carbohydrate utilization and at the
  same time increased fatty acid oxidation.
• This condition associated with decreased insulin
  relative to the anti insulin hormones, leading to
  increased lipolysis and release of FFA from
  adipose tissue as well as decreased oxidation of
  glucose by the liver.

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• This increases the uptake and oxidation of FA by
  the liver forming excess acetyl COA.
• The decreased glucose oxidation decreases the
  availability of oxalacetic (because it will be
  directed for gluconeogenesis)
• and so the excessive amounts of active
  acetate will be directed for ketone bodies
  formation.

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• Causes of ketosis
• Diabetes mellitus.
• Starvation.
• Unbalanced diet i.e. high fat, low carbohydrate
  diet.
• Renal glucosuria.

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• Effects of ketosis
• Increased ketone bodies in blood is
  neutralized by the alkali reserve (blood
  buffers), this lead to metabolic acidosis.
• If ketone bodies are far high than the capacity
  of alkali reserve they will result in acidemia -
  uncompensated acidosis with a decrease in blood
  PH which is a serious that results in death if
  not treated.

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Metabolism of Cholesterol

• Cholesterol is the most important animal sterols
  which is the precursor of all other steroid in
  the body e.g. corticosteroids, sex hormones, bile
  acids and vitamin D.
• Cholesterol biosynthesis
• Cholesterol is derived about equally from the
  diet or manufactured de novo in cells of humans
  especially in liver , intestine, and adrenal
  cortex .
• Acetyl CoA is the source of all carbon atoms in
  cholesterol.
• All tissues containing nucleated cells are
  capable of synthesizing cholesterol.

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• The liver is the main source of plasma
  cholesterol but intestine also participates. The
  liver is the principle organ which removes
  cholesterol from blood.
• The enzymes involved in cholesterol biosynthesis
  are present in cytosol and microcosms of the
  cell.

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Synthesis of cholesterol

• Cholesterol is synthesized from cytosolic acetyl
  CoA which is transported from mitochondria via
  the citrate transport system.
• It starts by the
• condensation of three
• molecules of acetyl CoA
• with the formation of
• HMG CoA.

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• 3. HMG CoA reduced to mevalonic acid (C6) is a
  reaction requiring NADPHH and enzyme HMG CoA
  reductase.
• Two molecules of NADPH are consumed in the
  reaction.

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• Mevalonic is dehydrated and decarboxyalted to
  isoprenoid units.
• 5 Molecules of isopentenyl pyrophosphate are
  converted to squalene (30 C with liberation of
  phosphate then by cyclization and demethylation
  (-3 CH3 ) cholesterol (27 carbon).

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Control of cholesterol biosynthesis

• 1. Control of HMG CoA enzyme
• HMG CoA reductase is the key enzyme, which exists
  in phosphorylated inactive and dephosphorylated
  active form.
• HMG CoA reductase is activated by insulin and by
  feeding carbohydrate.
• HMG CoA reductase is inhibited by glucagon,
  therefore its activity decrease during
  starvation, as starvation directing acetyl CoA to
  the formation of ketone bodies.

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• Cholesterol feeding inhibits liver HMG CoA
  reductase.
• Bile salts inhibit the intestinal HMG CoA
  reductase.
• 2- A second point of control is the cyclization
  of squaline to lanosterol.

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Blood Cholesterol

• Plasma cholesterol is in a dynamic state,
  entering the blood complexed with lipoproteins
  and leaving the blood as tissues remove
  cholesterol from lipoproteins or degrade them
  intracellularly.
• Cholesterol occurs in plasma lipoproteins in 2
  forms
• free cholesterol (30) and esterified form
  with long chain fatty acids (70).
• It is the free cholesterols that exchanges
  between different lipoproteins and plasma
  membranes of cells.

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• Total cholesterol in plasma is normally between
  140-300 mg/dl, 2/3 of this is esterified with
  long chain FA (linoleic).
• Cholesterol esters are continually hydrolysed in
  liver and resynthesized in plasma.
• Cholesterol is present in all the lipoproteins
  but in fasting more than 60 is carried in p
  lipoproteins (LDL).

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Blood lipids

• Plasma lipids are usually measured after 12 hours
  fasting. The total plasma lipids ranges from
  400-700 mg/dl (mean value 470 mg/dl). The
  different types of plasma lipids are as follows