LIPOGENESIS

It is the metabolic pathway by which fatty acids are synthesized from Acetyl-CoA. It is not simply a reversal of the steps of degradation of fatty acids (the Beta- oxidation pathway).

OR

Lipogenesis is the metabolic process through which the body synthesizes fatty acids and converts them into fat (triglycerides) for long-term energy storage. It primarily occurs in the liver and adipose (fat) tissue.

1.0Types of Lipogenesis

1. De Novo Lipogenesis (DNL)
   This refers to the synthesis of fatty acids from non-lipid sources, mainly excess carbohydrates. These fatty acids are then stored as triglycerides in fat tissue.
2. Triglyceride Synthesis
   Fatty acids produced or obtained from the diet are esterified with glycerol to form triglycerides, which are stored in adipose cells.

2.0Steps of Lipogenesis

1. Conversion of Carbohydrates to Acetyl-CoA

• Glucose is broken down via glycolysis to form pyruvate
• Pyruvate enters the mitochondria and is converted to Acetyl-CoA

2. Formation of Malonyl-CoA

• Acetyl-CoA combines with CO₂ via the enzyme Acetyl-CoA Carboxylase to form Malonyl-CoA
  (This is the rate-limiting step in lipogenesis)

3. Fatty Acid Synthesis

• Malonyl-CoA and Acetyl-CoA are used by Fatty Acid Synthase (FAS) to form long-chain fatty acids (mainly palmitic acid)

4. Triglyceride Formation

• Fatty acids are esterified with glycerol-3-phosphate to form triglycerides, stored in fat cells.

3.0The Citrate- Malate Shuttle System

• The acetyl CoA is the starting material for lipogenesis.
• Because acetyl CoA generated in mitochondria and lipogenesis occurs in the cytosol, the acetyl CoA must be transported to the cytosol.
• It exits the mitochondria through a transport system that involves citrate ions.
• The outer mitochondrial matrix is freely permeable to acetyl CoA, as well as many other substances such as citrate, malate and pyruvate.
• The inner mitochondrial membrane, however, is not permeable to acetyl CoA.

• Mitochondrial acetyl CoA reacts with oxaloacetate to produce citrate, which is then transported through the inner mitochondrial membrane by a citrate transported.
• Once in the cytosol, the citrate undergoes the reverse reaction to its formation to regenerate the acetyl CoA and oxaloacetate with ATP involved in the Process.
• The acetyl CoA so generated becomes the “Fuel” for lipogenesis; the oxaloacetate so generated reacts further to produce malate, in an NADH dependent change.
• The malate reenters the mitochondrial matrix through a malate transporter and is then converted to oxaloacetate, which can then react with another acetyl CoA molecule to form citrate and the shuttle process repeats itself.

4.0ACP Complex Formation

• Two simple ACP complexes are needed to start the lipogenesis process.
• They are acetyl ACP, A C_{2 -} ACP and malonyl ACP a C₃ - ACP.
• Additional malonyl ACP molecules are needed as the lipogenesis process proceeds.
• Cytosolic acetyl CoA is the starting material for the production of both of these simple ACP complexes. Acetyl ACP is produced by direct reaction of acetyl CoA with an ACP molecule.

• The reaction to produce malonyl, ACP, requires two steps. The first step is a carboxylation reaction with ATP involvement.

The Chain Elongation

• This reaction occurs only when cellular ATP levels are high. It is catalyzed by acetyl CoA carboxylase complex, which requires both Mn²⁺ ion and the B vitamin biotin for its activity. The malonyl CoA produced then reacts with ACP to produce malonyl ACP.

• Four reactions that occur in a cyclic pattern within the multienzyme fatty acids synthase complex constitute the chain elongation process used for fatty acids.
• The reactions of the first turn of the cycle, in general terms.

 Step-1 Condensation

Acetyl ACP and malonyl ACP condense together to form acetoacetyl ACP.

 Step-2 First Hydrogenation

The Keto group of the acetoacetyl complex, which involves the β-carbon atom, is reduced to the corresponding alcohol by NADPH.

Step - 3 Dehydration

The alcohol produced in step- 2 is dehydrated to introduce a double bond into the molecule between ɑ and 𝛃 Carbon.

Step- 4 Second Hydrogenation

The double bond introduced in step-3 is converted to a single bond through hydrogenation. As in step-2, NADPH is the reducing agent.

 Differences Between Lipogenesis and β- oxidation pathway

5.0Hormonal Regulation of Lipogenesis

Insulin is the primary promoter of lipogenesis, especially after a high-carbohydrate meal.

6.0Why is Lipogenesis Important?

• Energy Storage: Converts excess calories into fat for future use
• Thermal Insulation: Fat helps maintain body temperature
• Organ Protection: Fat cushions and protects vital organs
• Metabolic Regulation: Key to managing energy balance

7.0Lipogenesis and Obesity

Excessive lipogenesis, especially in sedentary individuals consuming high-carb diets, can lead to:

• Increased body fat
• Insulin resistance
• Non-alcoholic fatty liver disease (NAFLD)
• Metabolic syndrome