���LIPID METABOLISM

Introduction

• Lipids occur in most tissues of the body but are abundantly present in fat depots (under skin, in omentum, around kidneys).
• Lipids are stored in fat cells known as “adipocytes” in the form of lipid droplets.
• A lipid droplet has triacylglycerol and cholesteryl esters as core, surrounded by single layer of phospholipids and special proteins known as perilipins at the surface.

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Conti…

• Lipids are water insoluble biomolecules and therefore, in blood these occur in the form of complexes which are water miscible due to;
• Electrically charged phospholipids
• Specific proteins

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• Plasma lipids are carried in two forms;
• Free fatty acids (unesterified fatty acids)

These are the metabolically most active plasma lipids, since these circulate in combination with plasma albumin in the blood

• Lipoprotein (Chylomicrons, VLDL, IDL, LDL, HDL)

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Sources of fat for energy metabolism

There are 3 sources of fatty acids for energy metabolism in humans and animals;

1. Dietary triacylglycerol's from meals
2. Triacylglycerol's synthesized in the liver during times when internal energy sources are abundant
3. Triacylglycerol's stored in adipocytes as lipid droplets (Depot fats)

FATE OF DIETARY TRIACYLGLYCEROLS

SECTION 1

Emulsification by bile salt

Bile acid: hydrophilic part is outer and hydrophobic inner

Fats: the hydrophilic part of fats is attached to hydrophobic sides of bile acid and hydrophobic tails of fats are in the inner of micelle

MOBILIZATION OF DEPOT FATS

SECTION 2

DEPOT FATS(reserve fats)

• Fats stored in the adipose tissues are known as depot fats.

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• Lipids in the form of triglycerides are stored in fat depots.

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• Depot fats are majorly neutral fats.

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• After prolonged starvation, the neutral fat content of tissues is decreased greatly since neutral fat serves as reserve.

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• These are important since;
• These are condensed source of energy (1gram of fat = 9.1KCal).
• Pose no osmotic problem being water insoluble

Mobilization of depot fats stepwise

• Binding of epinephrine or glucagon from blood stream to the receptor molecules found on the cell membrane of adipocytes.
• Adenylate cyclase converts the ATP in cAMP
• cAMP binds to protein kinase and cause its activation
• Protein kinase causes phosphorylation of the perilipins
• Entry of hormone sensitive triglyceride lipases into fat droplet and cleavage of the lipids into their components (e.g. triacylglycerol lipase activation leads to breakdown of fats into its fatty acid and glycerol components)

Hydrolysis of TAG by triacylglycerol lipase in adipocytes

Lipase

Lipase

Lipase

Fate of fatty acid from depot fat

• Free fatty acids are picked up by the serum albumin and circulate in the bloodstream.
• Once in cytosol, fatty acid undergo two different pathways;
• If the fatty acids are long chain (more than 12-C), these are acted upon by acyl-CoA synthetase in the endoplasmic reticulum to form long chain fatty acyl-CoA which is transported by carnitine into inner mitochondria for oxidation.
• Short and medium chain fatty acids (<10C respectively) easily pass through inner mitochondrial membrane and are changed to their acyl-CoA derivatives by the Acyl-CoA synthetase in mitochondrial matrix.

Conti…

• Fatty acids may undergo oxidation at;
• Alpha carbon
• Beta carbon (quantitatively most important pathway)
• Omega carbon

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The product of oxidation is Acetyl-CoA which is fed directly into the Krebs cycle. Ultimate product of oxidation is carbon dioxide and ATP which are used for energy by the muscle cells.

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Site of oxidation in the cell: Fatty acids are oxidized majorly in mitochondria of tissues and to a smaller extent by alpha and beta oxidation in peroxisomes and omega oxidation in endoplasmic reticulum.

Fate of glycerol

• Adipose tissues (adipocytes) do not contain the enzyme “glycerol kinase” required for the utilization of glycerol.
• Therefore, it is liberated into blood stream and hence transported to liver.
• In liver, glycerol is converted to glycogen or glucose (gluconeogenesis).

OXIDATION OF FATTY ACIDS

BETA OXIDATION

• Majorly occur in mitochondria of the tissues and upto smaller extent in the peroxisomes

1. Beta oxidation of saturated fatty acids (even numbers)

• Occurs in mitochondria
• Step 1: Conversion of fatty acid to fatty acyl CoA by fatty acyl CoA synthetase or fatty acyl thiokinase
• Step 2: Dehydrogenation of fatty acyl CoA to the alpha-beta unsaturated fatty acyl CoA
• Step 3: Hydroxylation of alpha-beta unsaturated fatty acyl CoA to form beta- hydroxy fatty acyl CoA
• Step 4: Dehydrogenation of beta- hydroxy fatty acyl CoA to beta-keto fatty acyl CoA
• Step 5: Thiolysis of beta-keto fatty acyl CoA to acetyl CoA and lower fatty acyl CoA

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Example of saturated fatty acid oxidation

Since palmitic acid contain C>12, So, it cannot pass inner mitochondrial membrane as such; needs a transporter.

Step 0: Transport of long chain fatty acid into inner mitochondria (rate limiting step for long chain fatty acids)

Palmitoyl CoA + Carnitine Palmitoyl-carnitine + CoA (Cytosol)

CAT-I

Palmitoyl-Carnitine Palmitoyl-CoA + Carnitine (Mitochondrial matrix)

CAT-II

Carnitine importance

• Transportation of long chain fatty acid from cytosol to mitochondrial matrix.
• Transport of excessive acetyl CoA produced in mitochondria to cytosol.
• Its deficiency leads to;
• Lipid accumulation
• Ketoacidosis
• Muscular weakness
• Hypoglycemia

Inhibitor of carnitine shuttle mechanism

Malonyl CoA is inhibitor of the carnitine shuttle mechanism. It is produced during fatty acid synthesis in the cytosol. So, during synthesis of fatty acids, their beta oxidation is automatically prevented.

Step 1: Conversion of palmitic acid to palmitoyl CoA by fatty acyl CoA synthetase or fatty acyl thiokinase

Step 2: Dehydrogenation of palmitoyl CoA to the alpha-beta unsaturated palmitoyl CoA

Step 3: Hydroxylation of alpha-beta unsaturated palmitoyl CoA to form beta- hydroxy palmitoyl CoA

Step 4: Dehydrogenation of beta- hydroxy palmitoyl CoA to beta-keto palmitoyl CoA

Step 4: Thiolysis of beta-keto palmitoyl CoA to acetyl CoA and myristoyl CoA

3. Each acetyl COA which is oxidized in citric cycle gives 12 ATP (8 x 12 = 96 ATP)

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• 2 ATP are utilized in the activation of fatty acid (It occurs once).

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Energy gain = Energy produced - Energy utilized

= 35 ATP + 96 ATP - 2 ATP = 129 ATP