Lipogenesis Fats not only obtained from the diet but also obtained from lipogenesis in the body. Lipogenesis means synthesis of fats from CHO and proteins present in excess of body need. Lipogenesis requires: 1- Synthesis of fatty acids (FA) and glycerol 2- Activation of fatty acids by CoA and glycerol by glycerokinase, 3- Combination of activated fatty acid and glycerol to give TAG (fats). De no vo synthesis of fatty acid (cytoplasmic synthesis): Occur mainly for the synthesis of palmitic acid Site: Cytoplasm of liver, mammary glands and adipose tissues.

Steps: 1- Transport of acetyl CoA to cytoplasm: Acetyl CoA is the precursor of fatty acid synthesis. It is produced from oxidation of glucose (by oxidative decarboxylation of pyruvate) and metabolism of ketogenic and mixed amino acids. Acetyl CoA is produced in mitochondria, and FA synthesis occurs in cytoplasm, so acetyl CoA must be transferred to cytoplasm across mitochondrial membrane which is impermeable to CoA. The transport occur through condensation of acetyl CoA inside mitochondria with oxaloacetate (OAA) to form citrate which can be transferred into cytoplasm. In cytoplasm, citrate is cleaved by ATP- citrate lyase or called citrate cleavage system in the presence of ATP and CoA to give acetyl CoA and OAA.

Transport of acetyl CoA from mitochondria to cytoplasm: Mitochondria: OAA + Acetyl CoA -CoA ↓ citrate synthase Citrate Inner mitochondrial membrane ↓ Citrate + CoA, ATP ↓ ATP citrate lyase OAA + Acetyl CoA Cystosol

2-Conversion of acetyl CoA into malonyl CoA by acetyl CoA carboxylase This step is the rate limiting step in FA synthesis and acetyl CoA carboxylase is the rate limiting enzyme. 3- Remaining series of the pathway is catalyzed by fatty acid synthase which is a multifunctional enzyme.

Reaction catalyzed by Acetyl CoA Carboxylase

For illustration only

Regulation of acetyl CoA carboxylase: A)Allosteric regulation: allosterically activated by citrate & ATP and inhibited by the end product of the pathway (palmitic acid). B)B) Hormonal regulation: activated by insulin, inhibited by adrenaline and glucagon (anti-insulin hormone). C) Dietary regulation: prolonged consumption of high claoric diet (e.g CHO diet) increases the synthesis of acetyl CoA carboxylase and so increase FA synthesis. Fat-free diet, fasting and low CHO reduce enzyme synthesis and so FA synthesis.

Elongation of fatty acids: Mitochondrial synthesis Palmitic acid - the end product of FA synthesis in cytoplasm can be elongated in mitochondria by the addition of two carbon atoms to give other long chain saturated FA e.g. stearic acid Unsaturation: occur also in mitochondria by desaturase enzyme to give unsaturated fatty acids e.g. oleic acid

Biosynthesis of TAG from synthesized fatty acid and glycerol: Site: cytoplasm of liver and adipose tissues Steps: see figure 1- Activation of fatty acids into acyl CoA 2- Activation of glycerol into 3-glycerophosphate 3-Combination of activated fatty acid and glycerol to form DAG then TAG as in figure.

Acyl CoA, acyl transferase TAG Synthesis of TAG (for illustration)

Comparison between de novo synthesis and degradation (β-oxidation) of long chain saturated fatty acids: Lioplysis (fatty acid β- oxidation Lipogenesis (fatty acid synthesis) Definition Degradation of depot fat (release of FFA from stored TAG, then oxidized to give energy fat) Synthesis of fat (triglycerides) from CHO and protein that exceed the body need Greatest flux of pathway (diet regulation) Hormonal state that favor pathway Major tissue site (organ) Tissue location for fatty acid synthesis or degradation Two-carbon donor/product Allosteric Activator Allosteric Inhibitor Carrier of acyl/acetyl groups between mitochondria and cytosol H-carrier NB: the synthesis of TAG occurs mainly in liver and mammary glands but it is stored mainly in adipose tissue and muscles

Types of body fat Depot fat (stored fat) It is a fat stored in the fat cells of adipose tissues. The amount and composition of depot fat varies according to the nutritional state of the individuals so it is called variable elements. Source: The origin of depot fat is dietary fat and lipogenesis. Composition: Triglycerides mainly Fate: Source of energy for body by first lipolysis (release of fatty acids from fats) by hormone sensitive lipase (HSL) which is inhibited by insulin and activated by adrenaline and glucagon. Tissue fat (constant element) Def. It is the fat present in each cell. It is the lipids that enter in the structure of body cells as cell membrane and mitochondria. It is not affected by hormones. It is never used as source of energy i.e. never oxidized to give energy.

Depot fatTissue fat It is the fat stored in fat cells of adipose tissue. This fat derived from dietary fat and lipogenesis It is the fat that enter in the structure of cell membranes Variable elementConstant element Present in certain tissues as liver and adipose tissues under the skin, around certain organs as kidney Present in every cells Formed mainly from triglyceridesFormed mainly of cholesterol, phospholipids and glycolipids Affected by hormones (How?)Not affected by hormones Used in starvationNot used Functions: source of energy, protection and insulator of heat, fixation of certain organs as kidney Enter in the structure of cell membrane Never used as source of energy.