Biochemistry - Lesson 18: Fatty Acid Synthesis and Storage
Fatty acid synthesis is the anabolic pathway by which excess dietary carbohydrates and proteins are converted into long-chain fatty acids for energy storage. This process typically occurs in the cytosol (liver and adipose cells) and uses NADPH as the reducing power. Acetyl-CoA, generated in the mitochondria, must be exported to the cytosol (via citrate) when carbohydrate intake is high or energy needs are low. Understanding how cells coordinate fatty acid synthesis with catabolic processes like β-oxidation reveals the intricate balance of metabolic regulation.
Acetyl-CoA Carboxylation and Fatty Acid Synthase
The first committed step in fatty acid synthesis involves the carboxylation of acetyl-CoA to malonyl-CoA:
- Acetyl-CoA Carboxylase (ACC): Utilizes ATP, biotin, and CO₂ to form malonyl-CoA. This step is heavily regulated by phosphorylation (inhibited by glucagon/epinephrine, activated by insulin) and allosteric modulators (citrate stimulates, long-chain acyl-CoAs inhibit).
Subsequent steps are catalyzed by the Fatty Acid Synthase (FAS) complex, which extends the fatty acyl chain two carbons at a time using malonyl-CoA. This cyclical process uses a specialized acyl carrier protein (ACP) domain and consumes NADPH to reduce β-keto intermediates:
After ~7 cycles, palmitate (C16) is released. Elongation beyond 16 carbons or introduction of double bonds (desaturation) requires additional enzymes in the endoplasmic reticulum.
Fatty Acid Synthesis Flowchart
→ Malonyl-CoA"] ACC --> FAS["Fatty Acid Synthase (Cycles of 2C addition)"] FAS --> Pal["Palmitate (C16)"]
Esterification to Triacylglycerols
Newly synthesized fatty acids are often esterified with glycerol-3-phosphate to form triacylglycerols (TAGs) in the endoplasmic reticulum. TAGs are then packaged into VLDL particles (in liver) or stored directly (in adipose), serving as a primary energy reserve.
Regulation
- Hormonal Control: Insulin upregulates ACC (dephosphorylates, activating it) and enhances glycolysis (providing substrate). Glucagon/epinephrine promote ACC phosphorylation, inhibiting fatty acid synthesis.
- Allosteric Effectors: Citrate activates ACC polymerization; long-chain acyl-CoAs inhibit ACC. Malonyl-CoA itself inhibits carnitine acyltransferase I, preventing β-oxidation when synthesis is active.
These mechanisms align fatty acid anabolism with energy-rich states (high insulin, abundant glucose) and curtail it during fasting or high energy demand.
Integration with Carbohydrate Metabolism
Acetyl-CoA for fatty acid synthesis arises from citrate exported from mitochondria (formed in TCA cycle). ATP-citrate lyase splits citrate into acetyl-CoA and oxaloacetate in the cytosol. This ties fatty acid synthesis to carbohydrate availability. Conversely, malonyl-CoA blocks β-oxidation by inhibiting the carnitine shuttle, preventing simultaneous synthesis and breakdown of fatty acids.
Summary
Fatty acid synthesis is an energy-intensive pathway that builds long-chain acyl chains from acetyl-CoA units using malonyl-CoA and NADPH. Acetyl-CoA carboxylase initiates this pathway, while the multifunctional fatty acid synthase extends the chain in repetitive cycles. Under insulin-signaled conditions (fed state), cells divert surplus energy into lipid reserves (TAGs), ensuring long-term energy storage. Regulatory mechanisms at enzymatic and hormonal levels maintain a balance with fatty acid oxidation, so that lipids are synthesized and stored only when nutrient availability supports it.
Suggested Reading:
Lehninger Principles of Biochemistry (chapters on fatty acid synthesis and TAG formation)
Biochemistry by Berg, Tymoczko, and Stryer (sections on lipogenesis, ACC, and regulation)
MIT OpenCourseWare: General Biochemistry (problem sets and lectures on lipid anabolism)
