Metabolism of Lipids chapter 4

An overview of Lipid Metabolism:

 Metabolism of Lipids chapter 4

There are multiple types of lipids, including

 Triglyceride (TAG): It is a glycerol attached to mixture of

saturated and unsaturated fatty acids.

 Phospholipids: are typically composed of two fatty acids linked

to a glycerol and are attached to a polar molecule, like choline,

via a phosphate group.

Triacylglycerol (TAG) and phospholipids, are generated from glucose-

derived glycerol and mitochondrial-derived fatty acids.

 Metabolism of Lipids chapter 4

Fatty acid synthesis takes place in the cytosol, where mitochondrial

citrate serves as the precursor to eventually generate palmitate, which

can be modified to other fatty acids.

Fatty acid β-oxidation occurs in the mitochondrial matrix. Fatty acids

are transported into the matrix through carnitine acyltransferase I

(CPTI) located in the outer mitochondrial membrane, along with

carnitine acyltransferase II (CPTII) and carnitine-acylcarnitine

translocase, located in the inner mitochondrial membrane.

Fatty acid synthesis is coupled to NADPH → NADP +, whereas fatty

acid oxidation generates acetyl-CoA, NADH, and FADH 2 to produce

ATP through oxidative phosphorylation.

Fatty acid synthesis is regulated by acetyl-CoA carboxylase (ACC),

which is activated by citrate and inhibited by the fatty acid palmitate.

Fatty acid β-oxidation is regulated by malonyl-CoA, which inhibits

carnitine acyltransferase (CPTI) activity, thereby preventing fatty acid

import into the mitochondrial matrix for β-oxidation.

Lipids can modify proteins to alter their function. Notable

modifications are N-myristoylation, S- or N-palmitoylation, and S-

prenylation.
 Metabolism of Lipids chapter 4

Lipids, such as eicosanoids, phosphoinositides, and sphingolipids, serve

as signaling molecules.

The cholesterol biosynthetic pathway initiates in the cytosol and is

controlled by the enzyme 3-hydroxy-3-methylglutaryl CoA reductase

(HMG-CoA reductase), the target of statins (class of cholesterol-

lowering drugs).
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Steps in the β-Oxidation of Fatty Acids

Activation of Fatty Acids:. Fatty acids are activated to form fatty acyl CoA

molecules via a two-step process. This happens when the fatty acids enter the

cytosol and react with coenzyme A (CoA). Fatty acid activation occurs in the

endoplasmic reticulum and requires ATP (adenosine triphosphate). The

activation is catalyzed by acyl-CoA synthetase.

The fatty acyl-CoA cannot cross the membrane by diffusion and therefore

must be transported into the mitochondrial matrix using a carrier molecule

known as carnitine.

Oxidation of the fatty acyl-CoA occurs in the mitochondrial matrix via a

sequence of four reactions known collectively as β-oxidation.

Metabolism of Lipids chapter 4
 Metabolism of Lipids chapter 4

1. The first step in the catabolism of fatty acids is the formation of an

alkene in an oxidation reaction catalyzed by acyl-CoA dehydrogenase.

The coenzyme FAD is reduced by accepting two hydrogen atoms and

their electrons forming FADH2, which moves into the electron transport

chain.

2. Next, the trans-alkene is hydrated to form a secondary alcohol in a

reaction catalyzed by enoyl-CoA hydratase.

3. The secondary alcohol is then oxidized to a ketone by β-hydroxyacyl-

CoA dehydrogenase, with NAD+ acting as the oxidizing agent. The

reoxidation of each molecule of NADH to NAD + by the electron

transport chain furnishes 2.5–3 molecules of ATP.

4. The final reaction is cleavage of the β-ketoacyl-CoA by a molecule of

coenzyme A. The products are acetyl-CoA and a fatty acyl-CoA that

has been shortened by two carbon atoms. The reaction is catalyzed

by thiolase.

 The shortened fatty acyl-CoA is then degraded by repetitions of

these four steps, each time releasing a molecule of acetyl-CoA.

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Energetics of fatty acid oxidation:

The overall equation for the β-oxidation of palmitoyl-CoA (16 carbon atoms)

is as follows:

1 mol of ATP is split to AMP and 2Pi −2 ATP

8 mol of acetyl-CoA formed (8 × 12) 96 ATP

7 mol of FADH2 formed (7 × 2) 14 ATP

7 mol of NADH formed (7 × 3) 21 ATP

Total 129 ATP

The fate of the acetyl-CoA obtained from fatty acid oxidation depends on the

needs of an organism. It may -

 enter the citric acid cycle and be oxidized to produce energy

 Metabolism of Lipids chapter 4

 be used for the formation of water-soluble derivatives known as ketone

bodies
 serve as the starting material for the synthesis of fatty acids

Ketogenesis Pathway

Our body normally derives energy from stored carbohydrate by the process of

glycogenolysis (glycogen → glucose) or from non-carbohydrate sources such

as lactate by the process of gluconeogenesis.

Ketogenesis occurs continuously in a healthy individual, but under certain

conditions, when there is an increased concentration of fatty acids or

carbohydrate reserves are decreased, ketogenesis happens at a higher rate:

 Under low blood glucose level, e.g. during fasting or starvation

 On exhaustion of carbohydrate reserve, e.g. glycogen

 When there is insufficient insulin, e.g. Type-1 diabetes

All the main body parts such as the brain, skeletal muscles, heart, etc. can

utilise the energy formed by ketogenesis.

Insufficient gluconeogenesis results in hypoglycemia and excessive

production of ketone bodies resulting in a fatal condition called ketoacidosis.

Metabolism of Lipids chapter 4
Metabolism of Lipids chapter 4
 Metabolism of Lipids chapter 4

Ketogenesis Steps

The ketogenesis process occurs primarily in the mitochondria of liver cells.

Below are the steps in the process of ketogenesis:

1. Transfer of fatty acids in mitochondria with the help of carnitine.

2. 𝛽-oxidation of fatty acid to form acetyl CoA

3. 2 acetyl CoA form acetoacetyl CoA by the enzyme thiolase

4. 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) is synthesized which is

catalyzed by HMG-CoA synthase

5. HMG-CoA is broken down to acetoacetate and acetyl-CoA by the

action of HMG-CoA lyase

Acetoacetate thus produced forms other ketone bodies, acetone by

decarboxylation and D-3-hydroxybutyrate by reduction

Regulation of Ketogenesis
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Ketogenesis can be upregulated by hormones such as glucagon, cortisol,

thyroid hormones, and catecholamines by causing a more significant

breakdown of free fatty acids, thus increasing the amount available to be used

in the ketogenic pathway. However, insulin is the primary hormonal regulator

of this process.

Insulin regulates many key enzymes in the ketogenic pathway, and a state of

low insulin triggers the process. A low insulin state leads to:

 Increased free fatty acids (FFAs)

o Due to decreased inhibition of hormone-sensitive lipase

 Increased uptake of FFAs into the mitochondria

o Due to decreased activation of acetyl-CoA carboxylase,

decreasing malonyl CoA, which disinhibits Carnitine

Palmitoyltransferase 1 (CPT1)

 Increased production of ketone bodies

o Due to increased HMG-CoA activity

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Ketone bodies
 They are produced in liver cells by the breakdown of fatty acids.
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 Fatty acids undergo 𝛽-oxidation in the liver mitochondria to generate a

high amount of energy and form three compounds, that are known as

“ketone bodies”.

 The two main ketone bodies are acetoacetate (AcAc) and 3-beta-

hydroxybutyrate (3HB), while acetone is the third, and least abundant,

ketone body.

 These ketone bodies are water-soluble and lipid molecules having a

carbonyl group attached to two -R groups.

 Ketones are always present in the blood and their levels increase during

periods of caloric restriction of various scenarios: low food intake

(fasting), carbohydrate restrictive diets, starvation, prolonged intense

exercise, alcoholism, or during untreated (or inadequately treated) type

1 diabetes mellitus.

 They are released into the blood after glycogen stores in the liver have

been depleted. (Glycogen stores typically are depleted within the first

24 hours of fasting).

Overproduction of Ketone Bodies:

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In normal individuals, there is a constant production of ketone bodies by

the liver and their utilization by extrahepatic tissues. The concentration of

ketone bodies in blood is maintained around 1 mg/dL.

What are the symptoms of high ketones?

Early symptoms are similar to the symptoms of high blood sugar and include:

 Frequent urination

 Feeling extremely thirsty

 Dry mouth and dehydration

 Dry skin

 Headache

Ketoacidosis
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It is a metabolic state caused by uncontrolled production of ketone

bodies that cause a metabolic acidosis.

Causes:

Ketoacidosis is caused by the uncontrolled production of ketone bodies. The

most common cause of ketoacidosis is diabetic ketoacidosis but can also be

caused by alcohol, medications, toxins, and rarely, starvation.

Usually the production of ketones is carefully controlled by several

hormones, most importantly insulin. If the mechanisms that control ketone

production fail, ketone levels may become dramatically elevated. This is

called diabetic ketoacidosis and is characterized

by hyperglycemia, dehydration and metabolic acidosis.

Symptoms:

The most common symptoms include nausea, vomiting, abdominal pain, and

weakness.

β-Oxidation of Unsaturated Fatty Acids

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Let us consider an example of monounsaturated fatty acid such as oleic

acid and a polyunsaturated fatty acid such as linolenic acid.

 Monounsaturated fatty acid such as oleic acid is an 18 carbon chain

length fatty acid with a cis double bond present between the ninth and

the tenth carbons.

 Polyunsaturated fatty acid such as linolenic acid is an 18 carbon chain

length fatty acid with 2 cis double bonds between 9th and 10th carbons

& 12th and 13th carbons.

Just like the saturated fatty acids cross the mitochondrial membrane with the

help of carnitine shuttle, unsaturated fatty acids also reach the mitochondrial

matrix as fatty acyl-CoA.

Metabolism of Lipids chapter 4