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KETONE BODIES
METABOLISM
BYDr KHALED SALEH ALGARIRI
IMS – MSUJanuary 2015
OBJECTIVES
What are Ketone Bodies ?
How they are produced and Utilized ?
How ketone body metabolism is regulated ?
When and why excess amount of ketone bodies are produced ?
What is Ketosis and Ketoacidosis ?
Biochemical basis for diabetic and starvation ketosis and
ketoacidosis.
INTRODUCTION
When there is a adequate balance between .Lipid and carbohydrate metabolism, most of theacetyl CoA produced from the B-oxidationpathway is further processed through the citricacid cycle.
The first step of the citric acid cycle involves the
reaction between oxaloacetate and acetylCoA. Sufficient oxaloacetate must bepresent for the acetyl CoA to react with.
Certain body conditions upset the lipid-carbohydrate balance required for acetyl CoA generated by fatty acids to be processed by the citric acid cycle. These condition include
dietary intake high in fat and low in carbohydrates
Diabetic condition where the body cannot adequately processed glucose even though it is present
Prolonged fasting condition, including starvation, where glycogen supplies are exhausted.
Under these conditions, the problem of adequate oxaloacetate supplies arises, which is compounded by the body’s using oxaloacetate that is present to produce glucose through gluconeogenesis.
Ketone body is one of the three substances ( acetoacetate, B- hydroxybutyrate and acetone) produced from acetyl CoA when an excess of acetyl CoA from fatty acid dergadation accumulates because of triacylglycerol- carbohydrate metabolic inbalances. The structural formulas for the three ketone bodies, two of which are C4 molecules and the other a C3 molecule.
Triglyceride
Fatty Acids
Glycerol
Albumin
adipose
tissue
Fatty Acids
liver
Fatty Acids
Fatty Acids albumin
Acetyl Co A
b-
oxidation
Energy for the Brain and
Extrahepatic tissues
TCA Cycle
Hormone Sensitive Lipase
GlucagonEpinephrineGlucocorticoids
+
1
3
2
Fatty Acids
mitochondria
KetoneBodies
Ketone bodies are synthesized only in liver
KETOGENESIS
Ketogenesis takes place in liver using Acetyl co A as a substrate or a precursor molecule.Enzymes responsible for ketone body formation are associated mainly with the mitochondria
• step 1: first condensation:• Ketogenesis begins as two acetyl CoA molecules combine to
produce acetoacetate CoA, a reversal af the step of the B-oxidation.
• Step 2: second condensation:• Acetoacetyl CoA then reacts with a third acetyl CoA and water
to produced 3-hydroxy-3-methlglutary CoA and CoA-SH
• Step 3: Chain cleavage.
HMG-CoA is then cleaved to acetyl CoA and Acetoacetate.
• Step 4: Reduction:
Acetoacetate is reduced to B-hydroxybutyrate. The reducing agent is NADH.
KETOGENESIS
The ratio of [3 Hydroxybutyrate] / [Acetoacetate] in
blood varies from 1:1 to 10:1
Acetone is volatile – Expelled out through Lungs
Acetoacetate and 3 Hydroxybutyrate are excreted
through urine
Liver is not able to utilize ketone bodies due to the
absence of the enzyme required to activate acetoacetate
Extrahepatic tissues contain the enzyme required to
activate acetoacetate (They are able to utilize ketone
bodies)
KETOGENESIS
β-Hydroxybutyrate
Succinyl CoA
CoA transferase
CoA-SH
Thiolase
KETOLYSIS
NADHNAD+
The liver has acetoacetate available to supply to other organs because it lacks the particular CoA transferase and that is the reason that “Ketone bodies are synthesized in the liver but utilized in the peripheral tissues”.
β-Hydroxybutyratedehydrogenase
The liver extracts about 30% of the free fatty acids passing through it
The factors regulating mobilization of free fatty acids from adipose tissue are important in controlling oxidation of fatty acids
Increased Mobilization of fatty acid
Increased Ketogenesis
REGULATION OF KETOGENESIS
Regulated at three crucial steps
1) Lipolysis in Adipose tissue
Ketogenesis does not occur unless there is an increase in the level of circulating free fatty acids that arise from lipolysis of triacylglycerol in adipose tissue.
When glucose levels fall, lipolysis induced by glucagon secretion causes increased hepatic ketogenesis due to increased substrate (free fatty acids) delivery from adipose tissue.
Conversely, insulin, released in the well-fed state, inhibits ketogenesis via the triggering dephosphorylation and inactivation of adipose tissue hormone sensitive lipase (HSL).
2) Fate of fatty acid-free fatty acids are either oxidized to CO2 or ketone bodies or esterified to triacylglycerol and phospholipids.
There is regulation of entry of fatty acids into the oxidative pathway by carnitine Acyl transferase-I (CAT-I)
Malonyl-CoA, the initial intermediate in fatty acid biosynthesis formed by acetyl-CoA carboxylase in the fed state, is a potent inhibitor of CAT-I .
Under these conditions, free fatty acids enter the liver cell in low concentrations and are nearly all esterified to acylglycerols and transported out of the liver in very low density lipoproteins (VLDL).
Carnitine Acyl Transferase-I (CAT-I)
[INSULIN] / [GLUCAGON]
Triglycerol
Fatty Acid
AcetylCoACarboxylase
Citrate
Oxaloacetate
Pyruvate
Oxaloacetate
Glucose
Acetyl CoA
Malonyl CoA
Pyruvate
Citrate
CAT - I
_
[INSULIN] / [GLUCAGON]
3) Fate of Acetyl Co A The acetyl-CoA formed in beta-oxidation is oxidized
in the citric acid cycle, or it enters the pathway of ketogenesis to form ketone bodies.
As the level of serum free fatty acids is raised, proportionately more free fatty acids are converted to ketone bodies and less are oxidized via the citric acid cycle to CO2.
Entry of acetyl CoA into the citric acid cycle depends on the availability of Oxaloacetate for the formation of citrate, but the concentration of Oxaloacetate is lowered if carbohydrate is unavailable or improperly utilized.
Ketosis is a disorder of excessive production of ketone bodies
The concentration of total ketone bodies in blood of well fed mammals does not exceed 0.2mmol/L
Loss via urine is usually less than 1 mg/24h in humans
Blood level of ketone bodies increased –Ketonemia
Excretion of ketone bodies in urine increased -Ketonuria
KETOSIS/ KETONEMIA & KETONURIA
CLINICAL SIGNIFICANCE of KETOACIDOSIS
Ketone bodies (acetoacetic acid & 3-OH Butyric acid ) are acidic in nature
Hydrogen ions are neutralized by bicarbonate (HCO3-) of the
blood. Bicarbonate (HCO3-) level of the blood decreases
and results metabolic acidosis.
When ketone bodies are released in large quantities the normal pH-buffering mechanisms are overloaded ; the reduced pH, in combination with a number of other metabolic abnormalities results in KETOACIDOSIS.
In severe ketoacidosis, cells begin to lose ability to use ketone bodies also.
CLINICAL FEATURES OF KETOSIS
Acidosis
Smell of acetone in patient's breath.
Osmotic diuresis induced by ketonuria may lead to dehydration
Sodium loss (The ketone bodies are excreted in urine as their sodium salt)
Dehydration
Coma
seen when there is excess fatty acid
oxidation by the liver
KETOACIDOSIS
Excess fatty acid oxidation by the liver – when
there is excess mobilization of the fatty acids
from adipose tissue
Excess mobilization of fat from adipose tissue
when (Insulin : Glucagon)
1.Uncontrolled Diabetes Mellitus:
Diabetic ketoacidosis
2. Prolonged Starvation:
Starvation Ketoacidosis
STARVATION INDUCED KETOSIS
Prolonged fasting may result From an inability to obtain food
from the desire to lose weight rapidly, or in clinical situations in which an individual cannot eat because of trauma, surgery, neoplasms, burns etc.
In the absence of food the plasma levels of glucose, amino acids and triacylglycerols fall,
triggering a decline in insulin secretion and an increase in glucagon release.
The decreased insulin to glucagon ratio, makes this period of nutritional deprivation a catabolic state, characterized by degradation of glycogen, triacylglycerol and protein.
This sets in to motion an exchange of substrates between liver, adipose tissue, muscle and brain that is guided by two priorities-
(i) the need to maintain glucose level to sustain the energy metabolism of brain ,red blood cells and other glucose requiring cells and
(ii) to supply energy to other tissues by mobilizing fatty acids from adipose tissues and converting them to ketone bodies to supply energy to other cells of the body.
STARVATION INDUCED KETOSIS
After about 3 days of starving liver forms lot of ketone bodies
• Brain fulfils 1/3 of its energy needs from Acetoacetate.
• Heart also uses Ketone bodies
After several weeks of starvation ketone bodies become major fuel of brain (brain derives 60-75% of energy from ketone bodies under conditions of prolonged starvation)
Now only 40gm glucose / day is needed by brain compared to 120 gm/day on 1st day of starvation
DIABETIC KETOACIDOSIS
Diabetic Ketoacidosis (DKA) is a state of inadequate insulin levels resulting in high blood sugar and accumulation of organic acids and ketones in the blood.
It happens predominantly in type 1 diabetes mellitus,
But can also occur in type 2 diabetes mellitus under certain circumstances.
This may be due to intercurrent illness (pneumonia, influenza, gastroenteritis, a urinary tract infection), pregnancy, inadequate insulin administration (e.g. defective insulin pen device), myocardial infarction (heart attack), stroke or the use of cocaine.
STARVATION KETOACIDOSIS
Excess mobilization of fatty acids
Hyperglucagonemia alters hepatic metabolism tofavour ketone body formation, through activation of the
enzyme carnitine palmitoyltransferase I(CPT-I).
Excess b-oxidation of fatty acids in the hepatocytes
Excess ketone body formation
[INSULIN] / [GLUCAGON]
Blood glucose level is decreased
DIABETIC KETOACIDOSIS
The decreased ratio of insulin to Glucagon promotesGluconeogenesis, glycogenolysis, and Ketone bodyformation in the liver, as well as increases in substrate deliveryfr from fat and muscle (free fatty acids, amino acids) to the liver
Hyperglucagonemia alters hepatic metabolism tofavor ketone body formation, through activation of the enzyme carnitine palmitoyltransferase -I.
Excess b-oxidation of fatty acids in the hepatocytes
Excess ketone body formation
DKA results from relative or absolute insulin deficiency combined with counter regulatory hormone excess( Glucagon, cortisol, and
growth hormone). [Insulin/Glucagon]
Diabetic Ketoacidosis may be diagnosed when the combination of hyperglycemia (high blood sugars), ketones on urinalysis and acidosis are demonstrated.
DIABETIC KETOACIDOSIS
MANAGEMENT OF KETOACIDOSIS
Treatment is to give insulin and glucose
1- When glucose and insulin are given intravenously, potassium is trapped within the cells
2-Fatal hypokalemia can occur
3-Clinician should always monitor the electrolytes
Administration of bicarbonate, and maintenance of electrolyte and fluid balance