Biochemistry - Lesson 17: Fatty Acid Oxidation (Lipid Catabolism)
Triacylglycerols (TAGs), the main form of stored lipids in animals, constitute a highly efficient energy reserve. Upon demand, these TAGs undergo hydrolysis (lipolysis) in adipose tissue, releasing free fatty acids and glycerol. Fatty acids are transported to various tissues, where they are oxidized to generate ATP. In this lesson, we explore the mobilization of fats, the mitochondrial β-oxidation pathway that produces acetyl-CoA, NADH, and FADH₂, and the relationship between fatty acid oxidation and carbohydrate metabolism. We also introduce ketone bodies as an alternative product of acetyl-CoA under specific conditions like fasting.
Mobilization of Stored Fats
Adipocytes store triacylglycerols, releasing free fatty acids (FFAs) and glycerol via hormone-sensitive lipase (activated by low insulin and high glucagon/epinephrine). Glycerol travels to the liver for gluconeogenesis or glycolysis, while FFAs attach to albumin in the bloodstream, delivering energy to peripheral tissues.
Transport into Mitochondria
Long-chain fatty acids must enter mitochondria before β-oxidation. This involves two key steps:
- Activation: Fatty acids convert to fatty acyl-CoA by acyl-CoA synthetase at the outer mitochondrial membrane, consuming ATP (forming AMP and PPi).
- Carnitine Shuttle: Long-chain acyl-CoA esters are transferred to carnitine, cross the inner membrane via a translocase, then re-form acyl-CoA in the matrix. Malonyl-CoA inhibits carnitine acyltransferase I, preventing β-oxidation when fatty acid synthesis is active.
β-Oxidation Pathway
Within the mitochondrial matrix, β-oxidation cleaves two carbons from the fatty acyl-CoA at a time, producing acetyl-CoA, NADH, and FADH₂ each cycle. The four main reactions repeat until the chain is fully processed:
Each round shortens the fatty acyl-CoA by two carbons, generating acetyl-CoA (enters TCA cycle or ketogenesis), plus NADH and FADH₂ (fueling oxidative phosphorylation). Palmitate (16 carbons) yields 8 acetyl-CoA, 7 NADH, and 7 FADH₂, translating into a high ATP yield upon complete oxidation.
Ketone Bodies
During prolonged fasting or low carbohydrate states, oxaloacetate in the liver may be scarce (diverted to gluconeogenesis). Acetyl-CoA accumulates, favoring ketone body formation (acetoacetate, β-hydroxybutyrate) in hepatocytes. Ketone bodies travel to peripheral tissues, where they reconvert to acetyl-CoA for energy in muscle, heart, and brain. Chronic overproduction (e.g., untreated diabetes) can lead to ketoacidosis.
Integration with Carbohydrate Metabolism
Acetyl-CoA generated by β-oxidation enters the TCA cycle, but the cycle demands adequate oxaloacetate, derived partly from pyruvate in carbohydrate-fed states. "Fats burn in the flame of carbohydrates" reflects this requirement; insufficient carbohydrate can slow TCA flux, redirecting excess acetyl-CoA toward ketogenesis. Conversely, malonyl-CoA from fatty acid synthesis blocks carnitine acyltransferase I, avoiding simultaneous lipid synthesis and degradation.
Summary
Fatty acid oxidation liberates abundant ATP from stored or dietary lipids. Lipolysis mobilizes fatty acids to tissues for β-oxidation, generating acetyl-CoA, NADH, and FADH₂. Acetyl-CoA joins the TCA cycle or forms ketone bodies under specialized conditions. These processes intricately align with carbohydrate pathways, ensuring metabolic adaptability. Mastery of lipid catabolism elucidates key energy and regulatory mechanisms in animal physiology.
Suggested Reading:
Lehninger Principles of Biochemistry (chapters on lipid metabolism and β-oxidation)
Biochemistry by Berg, Tymoczko, and Stryer (topics on adipose tissue lipolysis, carnitine shuttle, β-oxidation,
and ketone bodies)
MIT OpenCourseWare: General Biochemistry (sections on fatty acid oxidation and metabolic integration)
