LIPID METABOLISM

Dr. Vijay Marakala, MBBS, MD.

Assistant professor BIOCHEMISTRY SIMS & RC

LIPID METABOLISM

Catabolism of FA

Oxidation

Anabolism of FA De-novo

synthesis

Ketone body metabolism

Cholesterol metabolism

Lipoprotein metabolism

Triacylglycerol

Fatty acids

Acetyl CoA

TCA

CO2

Diet

Cholesterol

Ketone bodies

Steroids

CH, AA

Overview of lipid metabolism

FATTY ACID METABOLISM» Fatty acids are stored as Triacylglycerol

» Constitute 84% of stored energy+ Protein - 15%+ Carbohydrate (glucose or glycogen) - <1%

» Fatty acids mobilized from Triacylglycerol are oxidized to meet the energy needs of a cell

UTILIZATION OF FATTY ACIDS AS A FUEL3 stages Mobilization of FA

from TG into tissues

Activation and transportation of FA into mitochondria

Degradation of FA by oxidation into

acetyl-CoA

Mobilization of FA from TG into tissues

(Adrenalin, Glucagon, ACTH)

Mobilization of FA from TG

into tissues

Mobilization of FA from TG into

tissues

9FATE OF GLYCEROL

OH

OH

OH

Glycerol

In Liver:

DihydroxyacetonePhosphate

Pyruvate

Glucose

Glycolysis

Gluconeogenesis

OXIDATION OF FATTY ACIDS

» Saturated FA - β-oxidation - Peroxisomal FA oxidation - α-oxidation - ω-oxidation» Unsaturated FA - Modified β-oxidation pathway

β- OXIDATION - DEFINITION

β Oxidation of fatty acid is oxidation of fatty acid at the β carbon atom with successive

removal of two carbon atoms as acetyl CoA

Long assay

β- OXIDATION - STEPS

1• Activation of fatty acids in the cytosol

2• Transport of activated fatty acids in to

mitochondria

3• β-Oxidation proper in the mitochondria

β- OXIDATION- OVERVIEW

ACTIVATION OF FATTY ACIDS

Occurs in outer mitochondrial membrane for long chain fatty acids

Fatty Acid Acyl-CoA

Transport of activated fatty acids in to mitochondria

CAT-I

CAT-II

Overall process of β-oxidation

CH3-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CO-S-CoA16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1

αβω

8-Acetyl-CoA

7 Cycles of β –oxidation withSuccessive removal of 2 carbon units

7NADH+H+

7FADH2

Palmitoyl-CoA

Acetyl-CoA

SEQUENCE OF REACTIONS OF β-OXIDATION

Oxidation by FAD

Hydration

Oxidation by NAD

Thiolysis

oxidation

oxidation

hydration

thiolysis

C16

7 rounds

Acyl-CoA

Trans enoyl-CoA

3-Hydroxy acyl-CoA

3-Ketoacyl-CoA

Acyl-CoA Shortened by 2 carbon atoms

Acetyl-CoA

ENERGETICS OF COMPLETE OXIDATION OF PALMITIC ACID

Oxidation 7 cycles

7 FADH2 x 2ATP/FADH2 14 (10.5)

7 NADH + H+ x 3ATP/NADH 21 (17.5)

From 8 acetyl CoA

Each acetyl CoA provides 12 ATP by TCA cycle 96 (80)

Total ATP produced from one palmitic acid 131 (108)

Total ATP used for activation 2

NET YIELD OF ATP 129 (106)

REGULATION OF β-OXIDATION

AVAILABILITY OF FATTY ACIDS

Hormones GlucagonEpinephrineInsulin

SYNTHESIS OF FATTY ACIDS

Inhibition of carnitine acyl transferase I by malonyl CoA

SIGNIFICANCE OF β OXIDATION

Provision of energy

• 20-30% of energy requirement of the cell

• Major pathway

Ketone bodies

• Diabetes• Starvation

Synthesis of biomolecules from

acetyl CoA

• Acetylcholine • Cholesterol

β-OXIDATION OF ODD CHAIN FATTY ACIDS

Oxidized by β–oxidation in the same way as that of even number, except the propionyl-CoA and acetyl-CoA are the end products

CH3-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CO-S-CoA 11 10 9 8 7 6 5 4 3 2 1

αβ

β-OXIDATION OF ODD CHAIN FATTY ACIDS

β-OXIDATION OF ODD CHAIN

FATTY ACIDS

D

L

β-OXIDATION OF UNSATURATED FATTY ACIDS

• Requires additional enzymes• Isomerase and reductase

Presence of double bonds

β-OXIDATION IN PEROXISOMES

α-OXIDATION

• Minor pathway• Involves oxdn of fatty acids at α carbon atom• One carbon is removed from the carboxyl

end and released as CO2• Occurs in endoplasmic reticulum• Phytanic acid oxidation

α-OXIDATION

ω-OXIDATION

It is a minor pathwayTakes place in microsomes Involves oxidation of last

carbon atom ( ω carbon)More common with

medium chain fatty acids

Impaired Oxidation of Fatty Acids Gives Rise to Diseases Often

Associated With Hypoglycemia

DISORDERS OF FA OXIDATION

Disorders

Carnitine deficiency

Jamaican vomiting sickness

Refsum’s disease

Zellweger’s syndrome

DISORDERS OF FA OXIDATION

Can occur particularly in the newborn—and especially in preterm infants

Carnitine deficiency

Features • Muscle cramps, muscle

weakness

DISORDERS OF FA OXIDATION

• Caused by eating the unripe fruit of the akee tree, which contains a toxin, hypoglycin, that inactivates medium and short chain acyl-CoA dehydrogenase, inhibiting β-oxidation and causing hypoglycemia.

Jamaican vomiting sickness

DISORDERS OF FA OXIDATION

Is a rare neurologic disorder due to a defect that causes the accumulation of phytanic acid, which is found in plant foodstuffs and blocks β-oxidation.

Refsum’s disease

Features • Cerebral ataxia• Periphaeral neuropathy• Retinitis pigmentosa

DISORDERS OF FA OXIDATION

Occurs in individuals with a rare inherited absence of peroxisomes in all tissues.

Zellweger’s syndrome