Ketogenesis & Ketolysis

Slides:



Advertisements
Similar presentations
Review session for exam-III
Advertisements

Lipid Metabolism Remember fats?? Triacylglycerols - major form of energy storage in animals Your energy reserves: ~0.5% carbs (glycogen + glucose) ~15%
Lipids Metabolism. Fatty acids TAG Complete oxidation of fatty acids to CO2 & H2O: 9 Kcal/gram of fat Fatty acids: are stored in adipose tissue, in the.
 It can be divided into 3 processes: 1)Biosynthesis of glycerol. 2)Biosynthesis of fatty acids. 3)Biosynthesis of the triacylglycerol.  It occurs in.
THE KETONE BODIES: FROM PROVIDERS OF ENERGY FOR LIFE TO FATAL KILLERS By Prof Morsi Arab University of Alexandria, Egypt.
LIPOLYSIS: FAT OXIDATION & KETONES BIOC DR. TISCHLER LECTURE 33.
Synthesis of Triglycerides
Lipogenesis Fats not only obtained from the diet but also obtained from lipogenesis in the body. Lipogenesis means synthesis of fats from CHO and proteins.
Introduction  lipids are a good source of energy as 1 gm supplies 9.1 calories, which is over double that supplied by carbohydrates or protein.  Dietary.
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings  High-energy phosphate groups are transferred directly from phosphorylated substrates.
Integration of Metabolism. Cellular Locations for Metabolism Citric Acid Cycle, Oxidative Phosphorelation, Fatty Acid Oxidation - Mitochondria Glycolysis.
1 Metabolic Pathways for Lipids. Ketogenesis and Ketone Bodies. Fatty Acid Synthesis.
Chapter 16 (Part 2) Fatty acid Catabolism (  -oxidation)
Overview of catabolic pathways. Chapter 16 - Lipid Metabolism Triacylglycerols and glycogen are the two major forms of stored energy in vertebrates Glycogen.
Substrates for lipid synthesis Phosphatidate is a precursor of storage and membrane lipids Formed by the addition of two fatty acids to glycerol 3-phosphate.
Metabolism Chapter 24 Biology Metabolism overview 1. Metabolism: – Anabolic and Catabolic Reactions 2. Cell respiration -catabolic reaction 3. Metabolic.
Absorptive (fed) state
Section 7. Lipid Metabolism
Fat Metabolism I’m not fat, I’ve just got a lot of potential energy!
KETONE BODY METABOLISM Dr.Siddiqui Abdulmoeed Associate Professor of Biochemistry College of Medicine Al-jouf University.
Hormonal regulation of carbohydrate metabolism
Integration of Metabolism
Generation and Storage of Energy
LIPID METABOLISM: CHOLESTEROL METABOLISM. Functions of Cholesterol a precursor of steroid hormones (progesterone, testosterone, estradiol, cortisol, etc.)
Cholesterol Metabolism Cardiovascular Block. Overview Introduction Cholesterol structure Cholesteryl esters Cholesterol synthesis Rate limiting step Regulation.
Fatty acid oxidation 3 steps to break down fatty acids to make energy 1.Fatty acid must be activated: bond to coenzyme A 2.Fatty acid must be transported.
Cholesterol Metabolism
Cholesterol metabolism: INTRODUCTION  Cholesterol is a sterol, present in cell membrane, brain and lipoprotein  It is a precursor for all steroids 
Chapter 23 Fatty Acid Metabolism Denniston Topping Caret 6 th Edition Copyright  The McGraw-Hill Companies, Inc. Permission required for reproduction.
Lipid metabolism Pavla Balínová. Lipids Lipids dissolve well in organic solvents but they are insoluble in water. Biological roles of lipids: ● lipids.
NS 315 Unit 4: Carbohydrate Metabolism Jeanette Andrade MS,RD,LDN,CDE Kaplan University.
Oxidation of Fatty Acids. BIOMEDICAL IMPORTANCE Oxidation in – Mitochondria Biosynthesis in – Cytosol Utilizes NAD + and FAD as coenzymes generates ATP.
Ketone bodies Liver mitochondria have the capacity to convert acetyl CoA derived from fatty acid oxidation into ketone bodies which are: 1- Acetoacetic.
ECDA SEPT LIPOGENESIS  Fatty acids are formed by the action of fatty acid synthase from acetyl-CoA and malonyl-CoA (a 3- carbon compound) precursors.
Fatty Acid Metabolism. Why are fatty acids important to cells? fuel molecules stored as triacylglycerols building blocks phospholipids glycolipids precursors.
Fatty acid catabolism 1.Digestion, Mobilization, and Transport of Fatty acids  Oxidation 3. Ketone Bodies.
Ketone body formation and utilisation  Acetoacetate,  -hydroxy butyrate and acetone are collectively called as ketone bodies.  The process of formation.
Lipogenesis. Metabolism of cholesterol.
Lipogenesis Fats not only obtained from the diet but also obtained from lipogenesis in the body. Lipogenesis means synthesis of neutral fats (TAG) from.
Cholesterol metabolism Structure of cholesterol OH is polar part The ring is non polar part Cholesterol ester (CE) is completely non polar.
Regulation of Cellular respiration and Related pathways.
23-1 Principles and Applications of Inorganic, Organic, and Biological Chemistry Denniston,Topping, and Caret 4 th ed Chapter 23 Copyright © The McGraw-Hill.
Lipogenesis Fats not only obtained from the diet but also obtained from lipogenesis in the body. Lipogenesis means synthesis of neutral fats (TAG) from.
Biochemistry: A Short Course Second Edition Tymoczko Berg Stryer CHAPTER 27 Fatty Acid Degradation.
Ketone bodies During high rates of fatty acid oxidation, primarily in the liver, large amounts of acetyl-CoA are generated. These exceed the capacity of.
1 Chapter 17: Oxidation of Fatty Acids keystone concepts The insolubility of triglycerides in dietary lipids and adipose tissue must be accommodated Fatty.
Cholesterol Metabolism.  The chemical and biochemical aspects of cholesterol regarding structure, distribution and biological functions in human body.
LECTURE 4 Oxidation of fatty acids Regulation of Lipid Breakdown
* Lipid Biosynthesis - These are endergonic and reductive reactions, use ATP as source of energy and reduced electron carrier usually NADPH as reductant.
Integration of Metabolism Lecturer of Biochemistry
Cell Metabolism. BIG PICTURE BIG PICTURE The sun provides the energy that powers all life The sun provides the energy that powers all life Animals depend.
Organ and metabolism HENDRA WIJAYA.
3. CITRIC ACID CYCLE. The citric acid cycle (Kreb’s cycle, Tricarboxylic acid cycle) is a series of reactions in mitochondria that bring about the catabolism.
NS 315 Unit 4: Carbohydrate Metabolism
OXIDATION OF FATTY ACIDS
Ketogenesis (Biosynthesis of ketone bodies)
Metabolism of ketonе bodies
Respiratory chain well developed.
Ketone Bodies.
Fatty acid synthesis (Lipogenesis & Lipolysis)
Cholesterol is a soft fatty substance that is produced in the body and also obtained from food substances such as dairy products, eggs (egg yolk is rich.
Cholesterol Synthesis, Transport, & Excretion
How Cells Obtain Energy from Food
Ketone bodies metabolism (Ketogenesis & Ketolysis)
Chapter Twenty-One Lipid Metabolism.
Dr. Diala Abu-Hassan, DDS, PhD
Chapter Twenty-One Lipid Metabolism.
Cholesterol Metabolism
UNIT 4.2 METABOLISM OF FAT.
Lipid metabolism part2 Dr .Basima S. Ahmed Jaff.
Presentation transcript:

Ketogenesis & Ketolysis Ketosis (ketoacidosis) Metabolism of Cholesterol

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 β-hydroxybutyric acid CH3-CO-CH3 Acetone (non-metabolized product)

Ketone bodies are formed from acetyl CoA resulting from β oxidation of FA in excess of optimal function of Kreb's cycle. Under normal fed state: the hepatic production of acetoacetate and β hydroxybutyrate is minimal and the concentration of these compounds in the blood is very low (does not exceed 1 mg% or <0.2 mM). Most acetyl CoA fatty acid or pyruvate oxidation enter the citric acid cycle only if fat and carbohydrates degrdation are balanced.

Steps synthesis of Ketone bodies: Two molecules of acetyl CoA react with each other in the presence of thiolase enzyme to form acetoacetyl CoA.

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

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

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

Both acetoacetate and β-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.

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

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.

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.

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.

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

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.

Mechanism: β-hydroxy butyrate is dehydrogenated forming acetoacetate, the reaction is catalyzed by β-hdyroxybutyrate dehydrogenase.

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).

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

Importance of ketolysis: 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.

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 β- 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 .

which is necessary to convert acetoacetate into 2 acety1 CoA. 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.

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.

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.

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.

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

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.

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.

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.

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.

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

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).

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.

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.

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.

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).

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: