Lipids: Structure, Classification, and Functions

Definition and General Properties

Lipids are a diverse group of organic compounds characterized by their solubility in non-polar solvents and poor solubility in water. They can be classified as either polar or non-polar, with each class serving distinct biological functions.

• Polar lipids: Fatty acids, cholesterol, glycerophosphatides, glycosphingolipids

• Non-polar lipids: Triacylglycerols, cholesteryl esters

Functions of Lipids:

• Thermal insulation

• Energy storage (as triacylglycerols, TG)

• Metabolic fuels

• Membrane components (phospholipids & cholesterol)

• Hormones (steroids & vitamin D)

• Precursors of prostanoids & leukotrienes

• Vitamins A, D, E, & K

• Emulsifying agents in digestion & absorption (bile acids)

• Surfactants in alveolar membranes (phosphatidylcholine)

Fatty Acids: Types and Properties

Saturated Fatty Acids

Saturated fatty acids (SFAs) contain no double bonds between carbon atoms. They are commonly found in animal fats and have higher melting points compared to unsaturated fatty acids.

*Palmitic and stearic acids are the most abundant fatty acids in animal lipids.

Unsaturated Fatty Acids (USFAs)

Unsaturated fatty acids contain one or more double bonds, usually in the cis configuration. They are important for membrane fluidity and serve as precursors for bioactive molecules.

• Monounsaturated FAs: Palmitoleic acid (16:1Δ9), Oleic acid (18:1Δ9)

• Polyunsaturated FAs: Linoleic acid, α-Linolenic acid, Arachidonic acid

Double bonds are introduced by fatty acid oxygenases in the endoplasmic reticulum, requiring O2 and NADPH.

Functions of Unsaturated Fatty Acids

• Maintain fluidity of triglyceride reserves and phospholipid membranes

• Serve as precursors for eicosanoids (prostaglandins, prostacyclins, thromboxanes, leukotrienes)

Fatty Acid Oxidation

Overview and Cellular Compartmentalization

Fatty acid oxidation is an aerobic process that occurs primarily in the mitochondria. It is not a simple reversal of fatty acid biosynthesis and involves distinct enzymes and cellular compartments.

• Increased during starvation and diabetes mellitus, leading to ketone body production in the liver

• Requires molecular oxygen (O2)

Ketone Body Metabolism

Ketogenesis and Ketone Body Utilization

Ketone bodies are produced in the liver from acetyl-CoA during periods of increased fatty acid oxidation (e.g., fasting, diabetes). They serve as alternative energy sources for peripheral tissues, especially the brain during prolonged fasting.

• Major ketone bodies: Acetoacetate, β-hydroxybutyrate, acetone

• Formed via condensation of acetyl-CoA, catalyzed by HMG-CoA synthase and lyase

• Oxidized in extrahepatic tissues to generate acetyl-CoA for the TCA cycle

Key reactions:

• Acetyl-CoA → Acetoacetyl-CoA → HMG-CoA → Acetoacetate → β-hydroxybutyrate/acetone

Fatty Acid Synthesis

Pathway and Regulation

Fatty acid synthesis occurs mainly in the liver cytosol and involves the polymerization of two-carbon units from acetyl-CoA to form palmitic acid (16:0). The process requires NADPH and ATP and is catalyzed by a multi-enzyme complex called fatty acid synthase.

• Key regulatory enzymes: Acetyl-CoA carboxylase (rate-limiting), fatty acid synthase

• Acetyl-CoA is carboxylated to malonyl-CoA, which donates two-carbon units for chain elongation

• Elongation beyond 16 carbons occurs in the endoplasmic reticulum or mitochondria

Fatty Acid Elongation and Synthesis of Long-Chain FAs

Palmitate (16:0) is the primary product of cytoplasmic fatty acid synthesis. Longer-chain fatty acids (18, 20, 22, 24 carbons) are synthesized by elongation of palmitate in the endoplasmic reticulum or mitochondria, mainly in the liver.

Metabolism of Eicosanoids

Precursors and Biosynthesis

Eicosanoids are signaling molecules derived from 20-carbon polyunsaturated fatty acids, primarily arachidonic acid. They include prostaglandins, thromboxanes, prostacyclins, and leukotrienes.

• Arachidonic acid is released from membrane phospholipids by phospholipase A2

• Phospholipase A2 is activated by increased intracellular Ca2+ and calmodulin

• Glucocorticoids (e.g., cortisol) inhibit phospholipase A2 activity, reducing eicosanoid synthesis

Therapeutic Inhibition

Inhibitors of key enzymes in eicosanoid synthesis (e.g., NSAIDs inhibiting cyclooxygenase) are used as therapeutic agents to control inflammation and pain.

Summary Table: Common Unsaturated Fatty Acids