Lipid Metabolism

By 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

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

I- Lipolysis
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.

Place: liver, kidney, intestine

Note

In muscle cells and adipocytes, the activity of glycerol kinase is low, so these tissues cannot use glycerol as fuel.

 Hormone sensitive lipase (HSL)

TG lipase is the rate-limiting enzyme in the TG degradation in adipose tissue. It is also named HSL because it is regulated by some hormones.

Effect of hormones on lipolysis

Lipolytic Hormones: epinephrine norepinephrine adrenocorticotropic hormone (ACTH)

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 Fas

Acyl-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

2.Transport into Mitochondrial Matrix

Stage 3: -oxidation of FAs

-oxidation means -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

The -oxidation pathway is cyclic

Summary
one cycle of the -oxidation: fatty acyl-CoA + FAD + NAD+ + HS-CoA fatty acyl-CoA (2 C less) + FADH2 + NADH + H+ + acetyl-CoA

The product of the -oxidation is in the form of FADH2, NADH, acetyl CoA, only after Krebs cycle and oxidative phosphorylation, can ATP be produced.

-Oxidation of Myristic(C14)
Acid

-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 Fatty Acid (C/2) 12 6 14 7 16 8 18 9

-Oxidation Cycles
(C/2 1) 5 6 7 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 6 FADH2 x 2ATP/FADH2

Total

18 ATP 12 ATP 102 ATP

Oxidation of Special Cases (monounsaturated fatty acids)

Odd Carbon Fatty Acids(13C)

SUMMARY OF ENERGY YIELD

PALMITIC ACID (16 C)

STEARIC ACID (18 C)

II- -Oxidation:
This types of oxidation occurs in position and characterized by: 1- It is mechanism mainly for branched chain fatty acid, which is methylated at 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.

 In -oxidation, there is one carbon atom removed at a time from position. It dose not require CoASH and dose not generate high energy phosphate.

Refsums disease: This is inherited deficiency of enzymes responsible for 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.

-Oxidation

1. It is oxidation of terminal CH3 group of fatty acid. 2-It produces dicarboxylic fatty acids. By -oxidation, they are converted to adipic acid (6 carbons) and suberic acid (8 carbons). 2-It is a minor pathway for fatty acid oxidation and used for oxidation of long chain fatty acids.

Ketone Bodies
Formation and Utilization
Ketone bodies are: water-soluble fuels Normally exported by the liver overproduced during fasting or in untreated diabetes mellitus.

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.

The significance of ketone bodies

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

Ketosis consists of ketonemia, ketonuria and smell of acetone in breath

Causes for ketosis

Severe diabetes mellitus Starvation Hyperemesis (vomiting) in early pregnancy

Metabolic Acidosis in Untreated Diabetes Mellitus

CH3COCH2CO2H pKa = 3.6
Acetoacetic Acid

CH3CHCH2CO2H pKa = 4.7

b-Hydroxybutyric acid Concentration of acetoacetic acid can result in metabolic acidosis affinity of Hb for O2 coma death

Lipogenesis
A- Definition: - 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:

2- Synthesis of glycerol-3- phosphate:

3-Formation of TAG

Regulation of lipogenesis
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

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