Beta-oxidation of fatty acids

Introduction

Beta-oxidation of fatty acids is the metabolic pathway by which fatty acids are broken down in the mitochondria (and peroxisomes) of cells to generate energy.
This process involves the sequential removal of two-carbon units from the fatty acid chain in the form of acetyl-CoA.
The term “beta-oxidation” comes from the fact that oxidation occurs at the beta carbon (the third carbon) of the fatty acid chain.
The acetyl-CoA produced enters the citric acid cycle (Krebs cycle), while NADH and FADH₂ generated during the process enter the electron transport chain to produce ATP, the energy currency of the cell.
Beta-oxidation plays a crucial role during fasting, prolonged exercise, and starvation, when the body relies on fat stores for energy instead of glucose.

Role of Fatty Acids in Metabolism

Fatty Acids as a Primary Energy Source

🔸 High Energy Yield

Fatty acids are highly reduced hydrocarbons; thus, their oxidation yields significantly more ATP compared to carbohydrates and amino acids.
For instance, the complete mitochondrial β-oxidation of palmitate (C16:0) yields:
- 8 Acetyl-CoA → TCA cycle → 80 ATP (via NADH, FADH₂)
- 7 NADH → 17.5 ATP
- 7 FADH₂ → 10.5 ATP
- Net yield: ~106 ATP

🔸 Tissue Specific Utilization

Liver, skeletal muscle, cardiac muscle, and kidneys rely heavily on FA oxidation during fasting states.
The brain cannot utilize fatty acids directly due to the blood-brain barrier, but can utilise ketone bodies derived from fatty acid metabolism.

Lipid Storage and Mobilization

🔸 Triglyceride Storage

Fatty acids are esterified with glycerol to form triacylglycerols (TAGs) and stored in adipose tissue.
TAGs represent the most concentrated form of energy storage in the human body.

🔸 Lipolysis and FA Transport

During fasting, hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) are activated by glucagon and epinephrine, catalyzing TAG hydrolysis.
Free fatty acids are released into circulation and transported bound to albumin.

Mitochondrial β-Oxidation

🔸 Activation and Transport

FA is activated to fatty acyl-CoA in the cytosol (via acyl-CoA synthetase).
Transported into mitochondria via the carnitine shuttle (CPT-I, translocase, CPT-II).

🔸 Sequential Oxidation

Each β-oxidation cycle includes:

Dehydrogenation (acyl-CoA dehydrogenase) → FADH₂
Hydration (enoyl-CoA hydratase)
Dehydrogenation (L-3-hydroxyacyl-CoA dehydrogenase) → NADH
Thiolysis (β-ketothiolase) → Acetyl-CoA

Ketogenesis: Adaptation to Glucose Sparing

In prolonged fasting, hepatic β-oxidation provides abundant acetyl-CoA, exceeding the TCA cycle capacity.
Acetyl-CoA is diverted to synthesize ketone bodies (acetoacetate, β-hydroxybutyrate, acetone).
Ketone bodies act as an alternative fuel for brain, heart, and skeletal muscles.

Fatty Acids as Signalling Molecules

Fatty acids modulate cell signalling by acting as:
- Ligands for PPARs (Peroxisome Proliferator-Activated Receptors): regulate lipid metabolism, insulin sensitivity, and inflammation.
- Precursors for eicosanoids (e.g., prostaglandins, leukotrienes, thromboxanes): derived from arachidonic acid, regulate immunity, vasodilation, and clotting.

Structural Role in Membranes

Fatty acids are integral to phospholipids and sphingolipids in cellular membranes.
Influence membrane fluidity, permeability, and lipid raft formation.
PUFAs (polyunsaturated fatty acids), especially omega-3 and omega-6, are vital for neural membranes and retinal function.

Biosynthesis and Anabolic Functions

De novo fatty acid synthesis occurs in the cytosol of liver and adipose tissue.
Enzyme: fatty acid synthase (FAS) complex elongates acetyl-CoA and malonyl-CoA to form palmitate.
NADPH from pentose phosphate pathway is required.

Fatty Acid Oxidation

The β-oxidation of fatty acids occurs in three stages.

Activation of fatty acids in the cytosol
Transport of fatty acids from the cytosol to the mitochondria
Reactions of β-oxidation in the mitochondrial matrix.

Activation of fatty acids in the cytosol

Transport of fatty acids from the cytosol to the mitochondria

Reactions of β-oxidation in the mitochondrial matrix.

Clinical Aspects

Inherited Disorders

These are a group of rare, genetic metabolic disorders caused by mutations in enzymes involved in beta-oxidation. Common examples include:

MCAD Deficiency (Medium-Chain Acyl-CoA Dehydrogenase Deficiency):
- Most common FAOD.
- Symptoms: Hypoglycemia, vomiting, lethargy, seizures, sudden death.
- Triggered by fasting or infections.
LCHAD Deficiency (Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency):
- Can lead to liver dysfunction, cardiomyopathy, and rhabdomyolysis.
- Seen in infancy or early childhood.
CPT-I and CPT-II Deficiency (Carnitine Palmitoyltransferase Deficiencies):
- Affects transport of long-chain fatty acids into mitochondria.
- CPT-I: Presents with hypoketotic hypoglycemia.
- CPT-II: Muscle weakness, myoglobinuria after prolonged exercise.

Clinical Features of FAODs

Fasting intolerance
Hypoketotic hypoglycemia (low blood sugar with low ketone bodies)
Liver dysfunction (hepatomegaly, elevated liver enzymes)
Cardiomyopathy (especially in long-chain FAODs)
Muscle weakness and rhabdomyolysis
Sudden infant death (SIDS) association in undiagnosed cases

Diagnosis

Blood and urine tests: Hypoglycemia without ketones, elevated liver enzymes, abnormal acylcarnitine profile.
Newborn screening: Tandem mass spectrometry.
Genetic testing: Identification of mutations.
Enzyme assay: To assess specific enzyme deficiencies.