Lipid.pdf2

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Lipid MetabolismBy Dr. Gamil Abdalla

1. Course outlines

1-Lipid digestion and absorption and their errors

2. Fate of absorbed lipids 3. Lipolysis and Lipogenesis 4. Fatty acid oxidation and synthesis 5. Ketogenesis and ketolysis 6. Cholesterol and Lipiprotein metabolis 7. Fatty liver

– Lipid familyTriglycerides (fats & oils)



– Phospholipids – Sterols (cholesterol) – cholesterol esters are digested by esterase to fatty

acids and cholesterol which absorbed as such

• • • As storage and transport form of metabolic fuel

• To keep the body temperature • Source for essential FA and oil soluble vitamins • To protect important organs

• Challenges

– Lipids are not water soluble – Triglycerides too large to be absorbed

• Digestive solution – Triglycerides mix with bile and pancreatic secretions

• Emulsification and digestion



• Minor digestion of triacylglycerols in

1. Mouth by lingual lipase 2. Stomach by gastric lipase (in infants only). • Major digestion of all lipids in the lumen of the duodenum/

jejunum by Pancreatic lipases

•

Produced in liver, stored in gallbladder

•Alkaline solution composed of:

–Bile salts

–Cholesterol

–Lecithin

–Bilirubin

•Responsible for fat emulsification

----------------------------------------------------

Mixed micelle formed by bile salts,

triacylglycerols and pancreatic lipase.

• Bile salts emulsify lipids



• Pancreatic lipase acts on triglycerides – Triglycerides

2 monoglyceride + 2 fatty acids • Pancreatic colipase

– Activated by trypsin – Interacts with triglyceride and pancreatic lipase

• Improves activity of pancreatic lipase

• Secreted from pancreas as procolipase

– Activated (cleaved) by trypsin

• Anchors lipase to the micel – One colipase to one lipase(i.e., 1:1 ratio)



•Produces small lipid spheres

– Greater surface area • Lipases attack TG at 1 and 3 positions

1 2

3 4





• Pancreatic insufficiency (chronic pancreatitis and

cystic fibrosis)

• Acidity of duodenal content (zollinger-Ellison syndrome)

• Deficiency of bile salts (ileal resection) • Bacterial over growth

• Decrease intestinal cells for absorption

• Failure of synthesis of apoproteins (abetalipoproteinemia)

1. Steatorhoea stool fat > 5 gm per day 2. Chyluria (milky urine)

Abnormal connections between lymphatics and urinary system.

1. Storage

2. Energy production 3. Gluconeogenesis



4. Synthesis of

• Cellular structures • Biological active compounds eg. Prostaglandins

• Mainly as triacylglycerols (triglycerides) in adipose cells

• Constitute 84% of stored energy



A- Definition: - Lipolysis is the hydrolysis of triacylglycerols in adipose tissue

into glycerol and fatty acids. Triglycerides Glycerol + 3 free fatty acids

B- Steps: - Lipolysis is carried out by a number of lipase enzymes, which

are present in adipose tissue. These are: 1. Hormone sensitive triacylglycerol lipase.

2. Diacylglycerol lipase. 3. Monoacylglycerol lipase.

I- Lipolysis





Place: liver, kidney, intestine

•NoteIn muscle cells and adipocytes, the activity of glycerol kinase

is low, so these tissues cannot use glycerol as fuel.



• TG lipase is the rate-limiting enzyme in the TG

degradation in adipose tissue. It is also named HSL becauseit is regulated by some hormones.

Effect of hormones on lipolysis

• Lipolytic Hormones:

epinephrine norepinephrine adrenocorticotropic hormone (ACTH)

• Hormone sensitive lipase (HSL)



thyroid stimulating hormone (TSH)

Glucagon etc. • Antilipolytic Hormones: insulin

• - In conditions where the need for energy is increased e.g.:

• 1- Starvation.

• 2- Diabetes mellitus. • 3- Low carbohydrate diet.

•Beta oxidation (major catabolic pathway and never occurs in the

brain)

• Alpha oxidation

• Omega oxidation

• Cleavage of fatty acids to acetate in tissues

• Occurs in the mitochondria of liver, kidney and heart

• Never occur in the brain • Fatty acid catabolism can be subdivided into 3 stages.

•Stage 1 Activation of FasAcyl-CoA Synthetase (Thiokinase), which locates in the

cytoplasm, catalyzes the activation of long chain fatty acids.



1. Irreversible

2. Consume 2 ~P 3. Site: cytosol

• Carrier: carnitine



• Carnitine carries long-chain activated fatty acids into

the mitochondrial matrix

t into Mitochondrial Matrix2.Transpor

Stage 3: β-oxidation of FAs β-oxidation means β-C reaction.

Four steps in one round



step 1: Dehydrogenate step 2: Hydration step 3: Dehydrogenate step 4: Thiolytic cleavage

Step 1. Dehydrogenate



Step 4. Thiolytic cleavage



one cycle of the β-oxidation:

fatty acyl-CoA + FAD + NAD+

+ HS-CoA →fatty acyl-CoA (2 C

less) + FADH2 + NADH + H+

+ acetyl-CoA

The β-oxidation pathway is cyclic

Summary

The product of the

β-oxidation is in theform of FADH

2, NADH,

acetyl CoA, only after Krebs cycle andoxidative

phosphorylation, canATP be produced.



-Oxidation of M ristic C14

-Oxidation of Myristic (C14) Acid



Cycles of -Oxidation

The length of a fatty acid

• Determines the number of oxidations and the

total number of acetyl CoA groups

Carbons in Acetyl CoA -Oxidation Cycles

Fatty Acid (C/2) (C/2 –1)

12 6 5

14 7 6

16 8 7

18 9 8

ATP production for Myristic(14 carbons):

Activation of myristic acid -2 ATP

7 Acetyl CoA

7 acetyl CoA x 12 ATP/acetyl CoA 84 ATP

6 Oxidation cycles

6 NADH x 3ATP/NADH 18 ATP

6 FADH2

x 2ATP/FADH2 12 ATP

Total 102 ATP



Oxidation of Special Cases

monounsaturated fatt acids

Odd Carbon Fatty Acids(13C)



SUMMARY OF ENERGY



• This types of oxidation occurs in α position and

characterized by: 1- It is mechanism mainly for branched chain fatty acid,

which is methylated at β position. 2- It is specific for oxidation of phytanic acid. 3- It is minor pathway for fatty acid oxidation. 4- It occurs mainly in brain and nervous tissues.

PALMITIC ACID (16 C)

STEARIC ACID (18 C)

II- α-Oxidation:



• In α-oxidation, there is one carbon atom removed at a

time from α position. • It dose not require CoASH and dose not generate high

energy phosphate.

Refsum’s disease:

This is inherited deficiency of enzymes responsible for α-

oxidation of phytanic acid. This leads to accumulation of phytanic acid in serum and nervous tissue and produce

nervous damage e.g. deafness and blindness.

1. It is oxidation of terminal CH3 group of

fatty acid.

2-It produces dicarboxylic fatty acids.

By β-oxidation, they are converted to

adipic acid (6 carbons) and suberic acid

(8 carbons).

2-It is a minor pathway forfatty acid oxidation and

used for oxidation of long chain fatty acids.

ω-Oxidation



Formation and Utilization

• Ketone bodies are:

• water-soluble fuels • Normally exported by the liver

• overproduced during fasting or in untreated diabetes

mellitus.

Ketone Bodies



The formation of ketone bodies (Ketogenesis)

Location: hepatic mitochondria Material: acetyl CoA Rate-limiting enzyme: HMG-CoA synthase

Utilization of ketone bodies (ketolysis)

Occurs at extrahepatic tissues



Occurs at extrahepatic tissues due to

Lack of succinyl-CoA transsulfurase and

Acetoacetate thiokinase in the liver.

• Ketone bodies are water soluble, they are convenient to

transport in blood, and readily taken up by non-hepatic

tissues

☻ In the early stages of fasting, the use of ketone bodies

by heart, skeletal muscle conserves glucose for support of central nervous system.

☻ With more prolonged starvation, brain can take up

more ketone bodies to spare glucose consumption

• High concentration of ketone bodies can induce ketonemia

and ketonuria, and even ketosis and acidosis

When carbohydrate catabolism is blocked by a disease of

diabetes mellitus or defect of sugar source, the blood

concentration of ketone bodies may increase,the patient may

suffer from ketosis and acidosis

The significance of ketone bodies



Ketosis consists of ketonemia, ketonuria

and smell of acetone in breath

• Severe diabetes mellitus

• Starvation • Hyperemesis (vomiting) in early pregnancy

Causes for ketosis



CH3COCH2CO2H pKa = 3.6

Acetoacetic Acid

CH3CHCH2CO2H pKa = 4.7b-Hydroxybutyric acid

Concentration of acetoacetic acid can result in metabolic

acidosis affinity of Hb for O2 coma death

Definition:- A

- Lipogenesis is the synthesis of triacylglycerol from fatty acids(acyl CoA) and glycerol (glycerol-3-phosphate). B- Steps: 1- Activation of fatty acids into acyl CoA:

Metabolic Acidosis in

Untreated Diabetes Mellitus

Lipogenesis



2- Synthesis of glycerol-3- phosphate:

3-Formation of TAG



After meal, lipogenesis is stimulated: - Insulin is secreted which stimulates glycolysis. Glycolysis supplies

dihydroxyacetone phosphate that converted into glycerol-3-phosphate in

adipose tissue, so lipogenesis is stimulated. During fasting lipogenesis is inhibited: - Anti-insulin hormones are secreted. These inhibit lipogenesis and

stimulate lipolysis

......

Regulation of lipogenesis

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