Ketone body metabolism

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

_


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


Blood glucose level is decreased


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.


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

Health & Medicine

Ketone body metabolism