Fatty Acid Metabolism

Biochemistry and Nutrition - Lecture 27: Fatty Acid Oxidation and Synthesis

• Specific Objectives: Students will be able to differentiate between fatty acid types, understand fatty acid metabolic pathways, and explain the carnitine shuttle's role in fatty acid oxidation.

Existence and Function of Fatty Acids

• Fatty acids exist freely (unesterified) in the body and as esters in complex molecules like triacylglycerols.
• Free fatty acids are present in low levels in tissues but can be substantial in plasma, particularly during fasting.

Plasma Free Fatty Acids

• Transported by serum albumin.
• Travel from origin (triacylglycerol in adipose tissue or lipoproteins) to consumption sites (mostly tissues).
• Oxidized by many tissues, primarily liver and muscle, for energy production.

Fatty Acid Functions

• Structural components of membrane lipids (e.g., phospholipids, glycolipids).
• Attached to intracellular proteins to enhance membrane association.
• Precursors for hormone-like prostaglandins.
• Stored as triacylglycerols in adipose tissue, serving as the body's primary energy reserve.

Structure of Fatty Acids

• Composed of a hydrophobic hydrocarbon chain with a terminal carboxyl group.
• The carboxyl group (COO-) has an affinity for water, giving the fatty acid an amphipathic nature (both hydrophilic and hydrophobic regions).
• Long-chain fatty acids (LCFAs) predominantly have a hydrophobic character.

Fatty Acid Saturation

• Can contain no double bonds (saturated) or one or more double bonds (unsaturated, including monounsaturated and polyunsaturated fatty acids, PUFAs).
• Presence of double bonds maintains the fluidity of lipids.

Important PUFAs

• Linoleic acid (omega-6): 2 double bonds.
• Linolenic acid (omega-3): 3 double bonds.
• Arachidonic acid (omega-6): 4 double bonds.
• Pentaenoic acid (omega-3): Important in fish oil.

Chain Lengths of Fatty Acids

• Carbon atoms are numbered from the carboxyl group (COOH) or the methyl end (omega Ω).
• Example numbering: arachidonic acid (20:4 ω-6), linoleic acid (18:2 ω-6), and linolenic acid (18:3 ω-3).

Essential Fatty Acids

• Two fatty acids are essential because humans cannot synthesize them.
• Linoleic acid, a precursor for omega-6 arachidonic acid (prostaglandin synthesis).
• Linolenic acid, a precursor for other omega-3 fatty acids (important for growth and development).
• Plants are sources for essential fatty acids.

Essential Fatty Acid Deficiency

• Can lead to scaly dermatitis (ichthyosis).
• Accompanied by visual and neurological abnormalities.
• Rare condition.

De Novo Synthesis of Fatty Acids

• A significant portion of fatty acids comes from the diet.
• Excess carbohydrates and proteins can be converted to fatty acids and stored as triacylglycerols.
• In adults, fatty acid synthesis happens mainly in the liver and lactating mammary glands, with less in adipose tissue.
• This cytosolic process uses carbons from acetyl-CoA, ATP, and NADPH to build the fatty acid chain.

Utilization of Fatty Acids

• After triacylglycerol (TAG) hydrolysis in adipose tissue, free fatty acids bind to plasma albumin.
• Fatty acids enter cells, converted into CoA derivatives, and transported to mitochondria for oxidation and energy production

Transport of Long-Chain Fatty Acids (LCFAs) into Mitochondria

• Carnitine is a key transporter facilitating the movement of long-chain acyl groups from the cytosol into the mitochondrial matrix.
• This is the carnitine shuttle; a rate-limiting step.

Carnitine

• Derived from the diet (primarily meat) and synthesized in the liver and kidneys, but not in skeletal or heart muscle.
• Deficiencies in carnitine can hinder fatty acid utilization and result in tissue dysfunction.

Carnitine Deficiency:

• Deficiencies lead to decreased LCFA usage as metabolic fuel.

Secondary Carnitine Deficiency

• Results from various conditions like liver disease, malnutrition, vegetarian diets, increased carnitine needs (pregnancy, infections, burns, or trauma), or hemodialysis.

Primary Carnitine Deficiency

• Caused by congenital defects in carnitine transport or metabolism.
• Genetic CPT-I deficiency: Inability to use LCFAs for fuel, potentially leading to hypoglycemia, coma, and death, primarily affecting the liver.
• CPT-II deficiency: Mostly affecting cardiac and skeletal muscle, symptoms range from cardiomyopathy to muscle weakness and myoglobinemia with prolonged exercise.

β-Oxidation of Fatty Acids

• Occurs in the mitochondrial matrix.
• Major pathway for fatty acid catabolism.
• Successive removal of two-carbon fragments from the fatty acyl CoA, producing acetyl CoA, NADH, and FADH₂ in each round, progressing according to the fatty acid chain's carbon count.

Energy Yield from Fatty Acid Oxidation

• Considerable energy is produced.
• Example: Palmitate (16 carbons) oxidation produces 129 ATP (including ATP from complete oxidation in TCA cycle).

Important Note:

• Plasma free fatty acids (FFAs) cannot be used as fuel by erythrocytes (lack mitochondria).
• The brain also does not primarily use fatty acids for energy; the reasons are less clear.

Reference:

• Biochemistry "Lippincott's Illustrated Reviews". By: Champe, P. C., Harvey, R. A., and Ferrier, D. R. (2007).