Fatty Acid Biosynthesis

Fatty Acid Biosynthesis

Fatty acids are synthesized from acetyl-CoA, which is produced from the breakdown of glucose and amino acids and oxidized in the citric acid cycle. Acetyl-CoA serves as a precursor for biosynthetic reactions.

In a well-fed state, acetyl-CoA is moved from the mitochondria to the cytosol for fatty acid biosynthesis. Acetyl-CoA is a key metabolic intermediate at the crossroads of many metabolic pathways.

Malonyl-CoA Formation

Fatty acid synthesis begins with the formation of malonyl-CoA. The conversion of acetyl-CoA to malonyl-CoA is an irreversible, committed step catalyzed by acetyl-CoA carboxylase (ACC), a key regulatory enzyme in fatty acid synthesis.

Acetyl-CoA + CO2 + ATP → Malonyl-CoA + ADP + Pi

Fatty Acid Synthesis

Fatty acid synthesis involves a repeating sequence of reactions where a malonyl group is transferred from CoA to fatty acid synthase (FAS). The sequence of reactions, catalyzed by multiple active sites, adds two carbons onto the growing fatty acid chain. Each cycle uses 1 ATP (to produce malonyl-CoA) and 2 NADPH. This process produces palmitate, a 16-carbon fatty acid.

Subcellular Localization of Lipid Metabolism

  • Mitochondria: Fatty acid oxidation and ketone body synthesis occur here. Acetyl-CoA is produced, but no fatty acid biosynthesis takes place.

  • Endoplasmic Reticulum: Phospholipid synthesis, late stages of sterol synthesis, fatty acid elongation, and fatty acid desaturation occur here.

  • Cytosol: NADPH production (via the pentose phosphate pathway and malic enzyme), early stages of isoprenoid and sterol synthesis, and fatty acid synthesis occur here. The ratio of [NADPH]/[NADP^+] is high in the cytosol.

  • Chloroplasts: In plant cells facilitate NADPH and ATP production and fatty acid synthesis

  • Peroxisomes: In plant cells facilitate fatty acid oxidation (producing H2O2)

Catalase, peroxidase, metabolize hydrogen peroxide into water: H2O2 → H2O

Acetyl-CoA Transport and NADPH Generation

Acetyl-CoA must be transferred from the mitochondria to the cytosol. This process generates NADPH, which is required for fatty acid synthesis. In a well-fed state, there is high acetyl-CoA in the cytosol. The pentose phosphate pathway produces the rest of the NADPH.

Regulation of Fatty Acid Synthesis

Fatty acid synthesis is maximal when metabolic fuel and ATP are abundant. Excess fuel is converted to fatty acids and stored as triacylglycerol (TAG).

Acetyl-CoA carboxylase (ACC) is the main regulatory point, controlled at multiple levels:

  • Activity (Fine Control): Covalent modification and allostery.

  • Quantity (Coarse Control): Transcription, translation, and degradation.

Multi-Level Control of ACC

  • Global/Hormonal Control: Hormones control the phosphorylation of ACC, regulating enzyme activity based on the organism's status.

  • Local/Cellular Control: Allosteric effectors (citrate, fatty acids, AMP) regulate enzyme activity based on conditions in individual cells.

  • Long-Term Control: Regulation of ACC synthesis and degradation by changes in diet/nutritional status.

Hormonal Signals

  • Insulin (High Glucose Signal): Stimulates synthesis of TAG, glycogen, and protein. Inhibits breakdown of TAG, glycogen, and protein. Stimulates glucose transport into cells.

  • Glucagon (Low Glucose Signal): Inhibits synthesis of TAG, glycogen, and protein. Stimulates breakdown of TAG, glycogen, and protein.

  • Adrenaline (Epinephrine - Energy Needed Immediately): Inhibits synthesis of TAG, glycogen, and protein. Stimulates breakdown of TAG, glycogen, and protein.

Global Control: ACC Phosphorylation

ACC activity is regulated by phosphorylation. Kinases and phosphatases control the phosphorylation state of ACC. Protein Kinase A (PKA) is activated by glucagon and adrenaline (via cAMP). ACC is inhibited when glucagon and adrenaline are released (e.g., during fasting or exercise), reducing fatty acid synthesis.

Insulin stimulates dephosphorylation of ACC by activating PP2A. ACC is activated when insulin is released, increasing fatty acid synthesis when glucose is abundant. Adrenaline and glucagon inhibit PP2A, reinforcing the phosphorylation of ACC by PKA.

Low ATP levels also trigger ACC phosphorylation. AMP-dependent protein kinase (AMPK) is activated by low energy status (low ATP, high AMP). ACC is inhibited when energy levels are low, reducing fatty acid synthesis. AMPK acts as an energy sensor.

Case Study: ACC Regulation in Hepatocytes

A research lab investigates how Acetyl-CoA Carboxylase (ACC) phosphorylation affects fatty acid synthesis using cultured liver cells (HepG2 cells). They generate two cell lines expressing mutant forms of ACC:

  • Cell Line A (Ser1200Asp): mimics phosphorylation

  • Cell Line B (Ser1200Ala): phosphorylation is not possible

The study explores how these mutations affect fatty acid synthesis rates compared to wild-type cells and how insulin affects the rate of fatty acid oxidation in each cell line.

Local Control: Allosteric Effectors

  • Citrate: Promotes polymerization of ACC into active filaments, overcoming inhibition by phosphorylation. Signals that acetyl-CoA and ATP are abundant.

  • Palmitoyl-CoA: Causes filaments to dissociate into inactive dimers. Signals that fatty acids are abundant.

Summary of ACC Regulation

Citrate promotes the polymerization and activation of acetyl-CoA carboxylase. Insulin triggers activation, while glucagon and epinephrine trigger phosphorylation/inactivation. Palmitoyl-CoA inhibits ACC, causing it to dissociate into inactive dimers.

Case Study: High-Carbohydrate Diet vs. Starvation

A researcher investigates how fatty acid biosynthesis is regulated under different metabolic conditions:

  • Group A: Mice fed a high-carbohydrate diet.

  • Group B: Mice subjected to prolonged fasting (48 hours).

The researcher measures ACC polymerization state, citrate levels, and fatty acid synthesis rates in liver tissue samples to understand regulatory mechanisms.

FAS and Therapeutic Targets

Fatty acid synthase (FAS) is highly expressed in breast and prostate cancers. FAS inhibitors can cause rapid weight loss and slow tumor growth. Inhibiting FAS represents a therapeutic target for cancer and obesity.

Synthesis of Long Chain and Unsaturated Fatty Acids

The product of FAS is palmitate, a 16-carbon saturated fatty acid. Fatty acid elongation systems in the endoplasmic reticulum and mitochondria add extra acetyl groups (from malonyl-CoA) to increase the chain length.

Desaturases in the endoplasmic reticulum introduce double bonds. Mammals cannot generate linoleate or α-linoleate, which are essential fatty acids required in the diet.

Key Points

  • Fatty acids are synthesized from acetyl-CoA biosynthesis.

  • Acetyl-CoA carboxylase is the major regulatory point.

  • ACC is regulated at multiple levels and by several mechanisms.

  • Acetyl-CoA is a key metabolic intermediate.