Post on 27-Jun-2015
description
04/13/2023 Dr. Ashok Kumar J; IMS; MSU 1
Ketone Body Metabolism
Dr. Ashok Kumar JInternational Medical School
Management and Science UniversityMalaysia
04/13/2023 Dr. Ashok Kumar J; IMS; MSU 2
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.
04/13/2023
Under certain conditions
1.When glucose is not available to the cells of the body (starvation)
2.When glucose cannot be utilized by the cells of the body ( Diabetes mellitus)
Fatty acids are catabolized to provide
energy
Dr. Ashok Kumar J; IMS; MSU
Catabolism of fatty acids
3
04/13/2023
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
GlucagonEpinephrineGlucocortic-oids
+
1
3
2Fatty Acids
mitochondria
Dr. Ashok Kumar J; IMS; MSU
Ketone Bodies
4
04/13/2023 Dr. Ashok Kumar J; IMS; MSU
High rate of Fatty Acid Oxidation in
Liver
Produce considerable amount of
Acetoacetate, 3-hydroxybutyrate
Acetoacetate continuously under go decarboxylation to form acetone
•Acetoacetate•3 Hydroxy butyrate•Acetone Are called ketone bodies
Ketone Bodies
5
04/13/2023
CH3-C
O S-CoACH3-C
O S-CoA
CH3-C -
O
CH2-C
O
S-CoAAcetoacetyl CoA
Acetyl CoA Acetyl CoA
Thiolase HS-CoA
Ketone Body Synthesis (Ketogenesis)
Dr. Ashok Kumar J; IMS; MSU 6
04/13/2023
CH3-C -
O
CH2-C
O S-CoA
CH3-C
O S-CoA
CH3-CO
S-CoA
CH3-C -
OH
CH2 -C
O S-CoA
CH2-CO- O
HMG CoA Synthase
HS-CoA
HMG CoA Lyase
CH3-C
O
CH2-CO- O -
acetoacetate
HMG CoA
Acetoacetyl CoAAcetyl CoA
Acetyl CoA
Dr. Ashok Kumar J; IMS; MSU 7
Ketone Body Synthesis (Ketogenesis)
04/13/2023 Dr. Ashok Kumar J; IMS; MSU
CH3- C
O
CH2- CO- O
acetoacetate
NAD+
NADH + H+
CH3- CH
OH -CH2- C
O- O
3-Hydroxy butyrate
CH3- CH
O -CH3
Acetone
CO2
Ketone Bodies
3-Hydroxy butyrateDehydrogenase
8
Ketone Body Synthesis (Ketogenesis) continued……..
Spontaneously
04/13/2023
• 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
Dr. Ashok Kumar J; IMS; MSU 9
Ketone Bodies
04/13/2023 Dr. Ashok Kumar J; IMS; MSU
Ketone bodies are produced in Liver
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)
10
04/13/2023 Dr. Ashok Kumar J; IMS; MSU
Utilization of ketone bodies
CH3- C
O
CH2- CO- O
acetoacetate
NAD+
NADH + H+
CH3- CH
OH -CH2- C
O- O
3-Hydroxy butyrate
3-Hydroxy butyrateDehydrogenase
CH3- C
O
CH2- C
O S-CoA
Acetoacetyl CoA
Succinyl CoA – acetoacetate CoA transferase ( Thiophorase)
CH3-C
O S-CoA2
CoA-SH
Thiolase
11
04/13/2023 Dr. Ashok Kumar J; IMS; MSU 12
Acetyl CoA enters TCA cycle - Oxidized further to derive energy
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
04/13/2023 Dr. Ashok Kumar J; IMS; MSU
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
1Regulated at three crucial steps
13
04/13/2023CPT-I (CAT –I) gateway into the mitochondria
[INSULIN] / [GLUCAGON]
AcylCoATriglycerol
Fatty Acid
AcylCoA AcetylCoA
Carboxylase
Citrate
Oxaloacetate
βOxidationPyruvate
Oxaloacetate
Glucose
Acetyl CoA
Malonyl CoA
Pyruvate
AcetylCoA
Citrate
CPT - I _
Dr. Ashok Kumar J; IMS; MSU
AcetylCoA
[INSULIN] / [GLUCAGON] 2
14
04/13/2023 Dr. Ashok Kumar J; IMS; MSU
Fall in the concentration of Oxaloacetate particularly with in the mitochondria
Impair the ability of TCA cycle to use acetyl CoA
Divert it towards ketogenesis
Increase in [NADH] /[NAD] ratioAffect the equilibrium between
malate and oxaloacetate
15
3 Regulation
Oxaloacetate Is diverted for Gluconeogenesis
04/13/2023
Ketosis & Ketoacidosis
Dr. Ashok Kumar J; IMS; MSU 16
04/13/2023
• 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
Dr. Ashok Kumar J; IMS; MSU
Ketonemia; Ketonuria
17
04/13/2023
Ketonemia + Ketonuria = Ketosis
Dr. Ashok Kumar J; IMS; MSU
Ketosis ; 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 –
metabolic acidosis
Metabolic acidosis is due to accumulation of ketone bodies so it is called ketoacidosis
18
04/13/2023 Dr. Ashok Kumar J; IMS; MSU 19
Salient Features of Ketosis …..
• Acidosis• Kussmaul's respiration• 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
04/13/2023
seen when there is excess fatty acid oxidation by the liver
Dr. Ashok Kumar J; IMS; MSU
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 20
04/13/2023 Dr. Ashok Kumar J; IMS; MSU
Diabetic Ketoacidosis
Excess mobilization of fatty acids
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
Relative or absolute deficiency of insulin combined with counter regulatory hormone excess
[INSULIN] / [GLUCAGON]
21
04/13/2023 Dr. Ashok Kumar J; IMS; MSU
Starvation Ketoacidosis
Excess mobilization of fatty acids
Hyperglucagonemia alters hepatic metabolism tofavour ketone body formation, through activation of the
enzyme carnitine palmitoyltransferase I.
Excess b-oxidation of fatty acids in the hepatocytes
Excess ketone body formation
[INSULIN] / [GLUCAGON]
Blood glucose level is decreased
22
04/13/2023 Dr. Ashok Kumar J; IMS; MSU 23
Test for Ketone bodiesRothera’s test : • Urine taken in a test tube• Saturated with ammonium sulphate• drops of freshly prepared sodium nitroprusside is added and
mixed• Liquor ammonia through the sides of the test tube • Appearance of a purple ring at the junction indicates presence
of ketone bodies
Gerhadt's test for acetoacetic acid: To 5 ml of urine, add dilute ferric chloride solution drop by dropA red color indicates the presence of acetoacetic acidNot a sensitive test Salicylates will give a false positive test
04/13/2023 Dr. Ashok Kumar J; IMS; MSU 24
Management of Ketoacidosis
• Treatment is to give insulin and glucose When glucose and insulin are given intravenously, potassium is
trapped within the cellsFatal hypokalemia can occurClinician should always monitor the electrolytes
• Administration of bicarbonate, and maintenance of electrolyte and fluid balance
04/13/2023 Dr. Ashok Kumar J; IMS; MSU 25
Thank You
Any questions………….. ?
drashokkumarj@gmail.comSMS - 0183246771