Fatty Acid and Triglyceride Biosynthesis Notes

Outline the pathway for biosynthesis of palmitic acid and its elongation & desaturation.
Describe the biosynthesis of TAG.
Explain the allosteric and hormonal regulation of lipogenesis.
Explain how long-chain fatty acids are synthesized by the repeated condensation of two carbon units, with the formation of the 16-carbon palmitate being favored in most tissues, and identify the cofactors required.

Lipogenesis: Synthesis of FAs, their esterification, and storage as TAG.
Excess carbohydrates and proteins are converted to fatty acids and stored as fats.
glu --> glycerald-3-p --> glycerol --> Fats
pyruvate --> F.A
ketogenic a.a --> acetyl-coA --> TCA --> ketone bodies

Fatty acids are synthesized by de novo synthetic pathway in the cytoplasm.
Synthesis occurs primarily in the liver, kidney, brain, and lactating mammary glands, and to a lesser extent in adipose tissue.
Starting material for synthesis is Acetyl CoA.
The major fatty acid synthesized by this pathway is palmitate (C16 saturated FA).

SHUTTLE: Acetyl CoA is formed inside the mitochondria (from oxidation of pyruvate, FA, ketogenic a.a).
It is transported to the cytoplasm as citrate (Malate-citrate shuttle).
It occurs when the mitochondrial citrate & ATP concentrations are high.
Transport of acetyl is coupled with the production of $CO_2$ & NADPH which is highly advantageous to the cell for optimum production of F.A)

This is the committed & regulatory step in the pathway.
Key enzyme: Acetyl CoA Carboxylase (regulatory enzyme In F.A synthesis).
Coenzyme: Biotin
$HCO_3^-$ + ATP + acetyl-CoA --> ADP + Pi + malonyl-CoA
Citrate availability is important regulatory factor producing short term effect.

After a total of 7 cycles palmitoyl – S – ACP (16 C) is the end product.
Free palmitic acid is released from ACP (Thioesterase)
1 Acetyl – CoA + 7 Malonyl – CoA + 14 NADPH + 14 H+ --> Palmitate + 14 NADP+ + 8 CoA + 6H2O

Leads to synthesis of most of the fatty acids except the essential fatty acids.
VLCFA (C22 to 24) are produced in the brain by the elongation process.
Increases rapidly during myelination, producing fatty acids required for the synthesis of myelin sheath.

Liver and adipose tissue are the major site of TAG synthesis.
In the liver: TAG is synthesized by esterification of Fatty Acyl CoA with glycerol 3 – P. (glycerol kinase is active).
In adipose tissue: TAG is synthesized through Dihydroxyacetone phosphate (glycerol kinase is deficient).
In adipose tissue - TAG is the storage form of energy.
In the liver - TAG is mainly secreted as VLDL and is transported to other tissues.

Prolonged consumption of high calorie (carbohydrate diet) increases lipogenesis.
Low calorie diet or fasting --> Reduction in enzyme synthesis (down regulation) --> Decreases lipogenesis.

Acetyl-CoA --> Malonyl-CoA (rate-limiting step)
a. Allosteric Regulation
- Acetyl CoA carboxylase enzyme is activated by citrate. Citrate increases in the well-fed state.
- It is inactivated by Palmitoyl CoA [Feedback inhibition by product], therefore inhibiting fatty acid synthesis.

Insulin: Secreted in response to plasma glucose, promotes energy storage. Induces Glycogenesis, Lipogenesis, Protein synthesis. Leads to dephosphorylated (active) enzyme.
Glucagon / Epinephrine: Plasma glucose decreases, mobilize energy source/ catabolic. Induce Glycogenolysis, Lipolysis, Ketogenesis & Gluconeogenesis. Leads to Phosphorylated (inactive) enzyme.

*Insulin enhances the activity of Protein phosphatase.

*Glucagon and Epinephrine enhance the activity of CAMP-dependent protein kinase.

Mainly concerned with energy storage.
Made up of Spherical cells filled with TAG (80%) with oleic acid (50%) with very few mitochondria.

Involved in thermogenesis.
Are Polygonal cells with small lipid droplets, the brown color due to the presence of numerous mitochondria is important in newborn humans & adult hibernating animals.
Fatty acid oxidizes to produce energy.
Thermogenesis is a process found in brown adipose tissues that liberates heat by uncoupling oxidation from phosphorylation, so energy is released as heat instead of trapping it in high energy bonds of ATP by the action of thermogenins (uncoupling protein in brown adipose tissue ).
Note: Adipose tissue is an active endocrine gland- producing leptin.

Fatty acids are synthesized by de novo synthetic pathway in the cytoplasm.
Synthesis occurs primarily in liver and lactating mammary glands, and to a lesser extent in adipose tissue.
Starting material for synthesis is Acetyl CoA.
Reducing equivalents are provided by NADPH.
The major fatty acid synthesized by this pathway is palmitate (C16 saturated FA).
The nutritional state of the organism is the main factor regulating the rate of lipogenesis.
- Well fed [high carbohydrate diet] : High rate of lipogenesis.
Hormones also regulate lipogenesis.
- Glucagon and epinephrine: inhibit lipogenesis.
- Insulin: stimulate lipogenesis.
- Glucagon – Phosphorylated enzymes
- Insulin -- Dephosphorylated enzymes
Adipose tissue is an active endocrine gland- producing leptin.
Unsaturated long-chain fatty acids are achieved by desaturase and elongase enzymes, which introduce double bonds and lengthen existing acyl chains, respectively.