Chapter 23: Fatty Acid & Eicosanoid Biosynthesis

Lipogenesis occurs primarily in the cytosol of tissues like the liver, brain, and adipose tissue, where it converts acetyl-CoA into palmitate through a series of energy-intensive reactions. This process relies on two central enzyme systems: acetyl-CoA carboxylase, which facilitates the initial controlling step by forming malonyl-CoA, and the fatty acid synthase multienzyme complex, a functional homodimer that assembles the carbon chain. These pathways require critical cofactors, including biotin, ATP, and reducing equivalents from NADPH, which is mainly supplied by the pentose phosphate pathway. Because acetyl-CoA is generated within the mitochondria, the cell utilizes a citrate shuttle to transport these building blocks into the cytoplasm. Regulation of this process is highly sophisticated, involving short-term allosteric activation by citrate and inhibition by long-chain acyl-CoA, as well as hormonal control where insulin promotes synthesis and glucagon or epinephrine triggers inhibitory phosphorylation via AMP-activated protein kinase. Furthermore, the body modifies these fatty acids through elongation and desaturation in the endoplasmic reticulum. A key physiological limitation is the human inability to introduce double bonds beyond the delta-9 position of a fatty acid chain, which necessitates the dietary intake of essential fatty acids like linoleic and alpha-linolenic acids. These essential fats are the precursors for eicosanoids—including prostaglandins, thromboxanes, leukotrienes, and lipoxins—which function as potent local hormones that mediate inflammation, blood coagulation, and pain responses. The chapter also addresses clinical significance, detailing how imbalances in lipid metabolism contribute to conditions such as obesity, type 1 diabetes, and coronary heart disease, while explaining how nonsteroidal anti-inflammatory drugs like aspirin function by blocking specific eicosanoid pathways.