LIPOGENESIS

List the metabolically significant plasma lipids and their normal range?

• Free fatty acids (FFA) = 0.2-0.6 mmol/L (6-16 mg/dL)

• Triglycerides (TAG) = 0.9-2.0 mmol/L

• Phospholipids = 1.8-5.8 mmol/L

• Cholesterol = 3.8-6.7 mmol/L (150-250 mg/dL)

Define LIPOGENESIS? What is the major site of lipogenesis?

DEFINITION:

It is the synthesis of fatty acids from acetyl Co A during fed state.

SITE:

Cytosol of cells of liver, kidney, brain, lung, mammary gland and adipose tissues.

Most lipids absorbed in the blood are……………

Palmitic Acid

End product of LIPOGENESIS?

Free Palmitate

Steps involved in Lipogenesis?

1. Formation of Malonyl CoA

2. Formation of Fatty Acid from Malonyl CoA

Explain the 2 steps of LIPOGENESIS?

1. Formation of Malonyl CoA:

Acetyl CoA  carboxylase initiates the carboxylation of acetyl CoA to malonyl CoA in the presence of ATP, biotin (Vitamin), bicarbonate and Mn2+ (Cofactor).

2. Formation of Fatty Acid from Malonyl CoA:

Fatty acid is formed from Malonyl CoA under the enzyme Fatty Acid Synthase.

What activates and inhibits the enzyme Acetyl CoA carboxylase?

Activator: Citrate

Inhibitor: Long chain acyl CoA.

Name 2 Sources of NADPH?

1. HMP Pathway

2. Conversion of Malate → Pyruvate by the enzyme Malate dehydrogenase (Malic Enzyme).

Name the source of Acetyl CoA and how is it transported?

• Acetyl CoA is formed from the PDH reaction

• PDH Reaction takes place in the Mitochondria and Lipogenesis takes place in the cytosol

• Acetyl CoA cannot directly move out of the mitochondria

• So it first goes to the outer membrane of the mitochondria to condense with Oxaloacetate to form Citrate

• Citrate can be directly transported out to the cytosol by the citrate transporter.

• Citrate is broken down into Oxaloacetate and Acetyl CoA under the enzyme ATP citrate lyase in the presence of CoA and ATP.

• The acetyl-CoA is then available for malonyl CoA formation and synthesis to palmitate.

REGULATION OF LIPOGENESIS

1. NUTRITIONAL FACTORS:

Lipogenesis is ↑ in a high carbohydrate diet from sufficient supply of Acetyl CoA and it is ↓ in restricted caloric intake and a high fat diet.

REGULATION OF LIPOGENESIS (CONT.)

2. MOLECULAR FACTORS:

a) SHORT TERM CONTROL:

ALLOSTERIC CONTROL:

• Acetyl CoA carboxylase is the regulatory enzyme for lipogenesis.

• Activation of Acetyl CoA Carboxylase: Citrate

• Inhibition of Acetyl CoA Carboxylase: long chain acyl CoA.

• Long chain fatty acids also inhibit the citrate transporter.

COVALENT MODIFICATION:

• Acetyl CoA Carboxylase (activated) in dephosphorylated form by INSULIN.

• Acetyl CoA Carboxylase is (inactive) in phosphorylated form by GLUCAGON AND EPINEPHRINE.

b) LONG TERM CONTROL:

• High carbohydrates and a low fat diet increases Acetyl CoA Carboxylase and Fatty Acid Synthase.

• This is known as Adaptive Control.

REGULATION OF LIPOGENESIS (CONT.)

3. HORMONAL FACTORS:

• Insulin stimulates lipogenesis and glucagon & epinephrine inhibits Acetyl CoA Carboxylase.

• Catecholamines inhibit acetyl CoA carboxylase through adrenergic receptors and Ca2+ dependent protein kinase.