Unit 2: Lipids

I. Orientation — Hydrophobic molecules with diverse biological roles

Lipids are a chemically diverse group of mostly water-insoluble molecules that dissolve readily in nonpolar solvents. Their shared importance arises from hydrophobic carbon-rich structures, while oxygen-containing or charged groups determine their specific biological behavior.

• Defining properties: Many lipids contain long hydrocarbon chains or rings and have limited solubility in water.
• Amphipathic character: Phospholipids, glycolipids, and cholesterol possess both hydrophobic and hydrophilic regions, allowing them to organize at water–lipid interfaces.
• Energy density: Triacylglycerols store approximately 9 kcal of energy per gram, more than carbohydrates or proteins at about 4 kcal/g.
• Structural diversity: Lipids include fatty acids, esters, phospholipids, sphingolipids, sterols, and signaling molecules.
• Major biological principle: Nonpolar groups cluster away from water, whereas polar groups interact with water; this hydrophobic effect drives membrane formation.

II. Fatty acids — Hydrocarbon acids and their dietary importance

A. Fatty acids structure and function

Fatty acids are carboxylic acids containing a hydrocarbon chain, commonly represented as CH₃–(CH₂)n–COOH, whose length and unsaturation influence their physical and biological properties.

• Basic structure: The terminal carboxyl group is polar and acidic, while the hydrocarbon tail is nonpolar.
  • At physiological pH, the carboxyl group is usually ionized as –COO⁻.
• Notation: A fatty acid written as 18:1Δ9 has 18 carbons, one double bond, and the double bond beginning at carbon 9 from the carboxyl end.
• Saturated chains: Palmitic acid, 16:0, contains no carbon–carbon double bonds and packs relatively tightly.
• Unsaturated chains: Oleic acid, 18:1Δ9, contains one cis double bond that creates a bend and lowers the melting point.
• Cis and trans forms: Natural unsaturated fatty acids are usually cis; trans bonds maintain a straighter chain and can alter membrane and cardiovascular physiology.
• Biological functions: Fatty acids provide fuel through β-oxidation, form components of complex lipids, and act as precursors for signaling molecules.
• Activation: Before metabolism, a fatty acid is converted to fatty acyl-CoA, consuming the equivalent of two ATP molecules.

B. Essential fatty acids

Essential fatty acids are polyunsaturated fatty acids that humans cannot synthesize in sufficient amounts because human enzymes cannot introduce double bonds beyond carbon 9 from the carboxyl end.

• Linoleic acid: 18:2 n-6 is an omega-6 fatty acid required for membrane lipids and for synthesis of arachidonic acid.
• α-Linolenic acid: 18:3 n-3 is an omega-3 fatty acid that can contribute to synthesis of longer-chain omega-3 fatty acids.
• Omega notation: In 18:2 n-6, the first double bond is six carbons from the methyl, or omega, end.
• Physiological roles: Essential fatty acids support skin barrier function, neural development, vision, and production of eicosanoids.
• Deficiency effects: Severe deficiency may cause scaly dermatitis, impaired growth, poor wound healing, and increased susceptibility to infection.
• Dietary sources: Vegetable oils, nuts, and seeds commonly supply linoleic acid; flaxseed, walnuts, and oily fish supply omega-3 fatty acids.

III. Tri-acyl glycerol — Compact storage forms of metabolic energy

A. Tri-acyl glycerol

A triacylglycerol, also called a triglyceride, is an uncharged ester formed when glycerol is esterified with three fatty acids.

• Formation: Three ester bonds form between the three hydroxyl groups of glycerol and three fatty acid carboxyl groups.

Glycerol + 3 fatty acids → triacylglycerol + 3 H₂O

• Composition: The glycerol backbone is chemically identical in all triacylglycerols, but the three fatty acyl chains may differ in length and saturation.
• Energy storage: Oxidation of stored triacylglycerol releases fatty acids for β-oxidation, producing acetyl-CoA, NADH, and FADH₂.
• Storage location: Adipocytes store triacylglycerols in lipid droplets; the absence of associated water makes this storage highly concentrated.
• Mobilization: Adipose triglyceride lipase, hormone-sensitive lipase, and monoglyceride lipase sequentially release fatty acids and glycerol.
• Transport: Dietary triacylglycerols travel in chylomicrons, whereas liver-derived triacylglycerols are transported mainly in VLDL.
• Functional limitation: Triacylglycerols are excellent energy stores but do not form membrane bilayers because they lack a polar head group.

IV. Phospholipids — Amphipathic membrane-forming lipids

A. Phospholipids

Phospholipids contain a phosphate group and are major structural components of biological membranes because they are amphipathic.

• Glycerophospholipid structure: A glycerol backbone is linked to two fatty acids, phosphate, and a polar alcohol.

Glycerol + 2 fatty acids + phosphate + head group

• Common examples: Phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol differ mainly in their head groups.
• Bilayer formation: Hydrophobic tails face inward and hydrophilic head groups face the aqueous cytosol and extracellular fluid.
• Membrane properties: Chain length and unsaturation influence fluidity; more cis unsaturation generally increases fluidity at a given temperature.
• Surface charge: Phosphatidylserine contributes negative charge and is normally concentrated on the cytosolic leaflet.
• Cell signaling: Phosphatidylinositol 4,5-bisphosphate can be cleaved to produce diacylglycerol and inositol trisphosphate.
• Specialized roles: Dipalmitoylphosphatidylcholine is an important pulmonary surfactant that reduces alveolar surface tension.

V. Sphingolipids — Sphingosine-based structural and signaling lipids

A. Sphingolipids

Sphingolipids are built on a sphingosine backbone rather than glycerol and are abundant in plasma membranes, especially in nervous tissue.

• Core structure: Sphingosine combines with a fatty acid through an amide bond to form ceramide.

Sphingosine + fatty acyl-CoA → ceramide

• Ceramide: Ceramide is the central precursor for sphingomyelin and glycosphingolipids.
• Sphingomyelin: It contains ceramide, phosphate, and usually phosphocholine; it is abundant in myelin sheaths.
• Membrane organization: Sphingolipids associate with cholesterol in relatively ordered membrane microdomains called lipid rafts.
• Cell signaling: Ceramide can participate in pathways regulating apoptosis, differentiation, inflammation, and stress responses.
• Clinical relevance: Defects in lysosomal degradation cause sphingolipid storage diseases, such as Niemann–Pick disease involving sphingomyelin accumulation.

VI. Glycolipids — Carbohydrate-bearing membrane lipids

A. Glycolipids

Glycolipids are lipids containing one or more carbohydrate residues, with the sugar portion exposed on the extracellular surface of the plasma membrane.

• Main mammalian type: Glycosphingolipids contain ceramide linked to a carbohydrate rather than phosphate.
• Cerebrosides: These contain one sugar, commonly glucose or galactose, and are abundant in nervous tissue.
• Gangliosides: These contain oligosaccharides with at least one sialic acid residue, giving them a negative charge.
• Cell recognition: Exposed carbohydrate patterns contribute to cell–cell recognition, adhesion, immune interactions, and receptor activity.
• Blood groups: ABO blood-group antigens are carbohydrate structures displayed on glycolipids and glycoproteins.
• Nervous system function: Gangliosides are concentrated in neuronal membranes and participate in signaling and synaptic organization.
• Degradation: Lysosomal enzymes remove sugar residues stepwise; missing enzymes produce glycolipid accumulation disorders such as Tay–Sachs disease.

VII. Cholesterol — Sterol regulator and precursor molecule

A. Cholesterol

Cholesterol is a 27-carbon sterol with four fused hydrocarbon rings, a hydroxyl group, and a short hydrocarbon side chain.

• Amphipathic structure: Its single hydroxyl group interacts with water, while the fused rings and hydrocarbon tail are hydrophobic.
• Membrane role: Cholesterol inserts between phospholipid tails and regulates membrane fluidity and permeability.
  • At high temperatures, it restrains excessive phospholipid movement.
  • At low temperatures, it prevents tight packing and membrane solidification.
• Transport: Because cholesterol is poorly soluble in blood, it travels in lipoproteins such as LDL and HDL.
• Biosynthesis: Acetyl-CoA is converted through HMG-CoA to mevalonate and ultimately to cholesterol; HMG-CoA reductase is a major regulated enzyme.
• Precursor functions: Cholesterol provides the carbon skeleton for steroid hormones, bile acids, and vitamin D.
• Clinical significance: Elevated LDL-associated cholesterol promotes atherosclerotic plaque formation, whereas HDL participates in reverse cholesterol transport.
• Excretion: Conversion to bile acids and secretion into bile are major routes for eliminating excess cholesterol.

VIII. Eicosanoids — Local mediators from 20-carbon fatty acids

A. Eicosanoids

Eicosanoids are short-lived, locally acting signaling molecules derived primarily from 20-carbon polyunsaturated fatty acids, especially arachidonic acid.

• Precursor release: Phospholipase A₂ releases arachidonic acid from the sn-2 position of membrane phospholipids.
• Cyclooxygenase pathway: COX-1 and COX-2 convert arachidonic acid into prostaglandin and thromboxane precursors.
  • Prostaglandins influence pain, fever, inflammation, vascular tone, and uterine contraction.
  • Thromboxane A₂ promotes platelet aggregation and vasoconstriction.
• Lipoxygenase pathway: Lipoxygenases produce leukotrienes and lipoxins.
  • Leukotrienes contribute to bronchoconstriction and inflammatory responses.
  • Lipoxins can promote resolution of inflammation.
• Drug connection: Aspirin irreversibly inhibits cyclooxygenase by acetylating the enzyme; this decreases prostaglandin and thromboxane synthesis.
• Local action: Eicosanoids are generally synthesized on demand and act near their site of production rather than being stored in secretory vesicles.
• Balance of effects: Different eicosanoids may produce opposing actions, such as platelet aggregation by thromboxane A₂ versus anti-aggregatory effects associated with prostacyclin.

IX. Function of lipids — Integrated physiological significance

A. Function of lipids

Lipids support energy management, cellular architecture, signaling, protection, and regulation of body processes.

• Energy storage: Triacylglycerols store concentrated chemical energy in adipose tissue and release fatty acids during fasting or exercise.
• Membrane structure: Phospholipids, cholesterol, and sphingolipids form selectively permeable membranes and control membrane fluidity.
• Insulation and protection: Adipose tissue reduces heat loss, while fat around organs provides mechanical cushioning.
• Cell signaling: Eicosanoids, diacylglycerol, ceramide, and phosphoinositide derivatives transmit local or intracellular signals.
• Hormone production: Cholesterol is the precursor of glucocorticoids, mineralocorticoids, and sex steroids.
• Nutrient absorption: Dietary lipids assist absorption of vitamins A, D, E, and K in the intestine.
• Nervous system support: Sphingolipids and cholesterol contribute to myelin, axonal membranes, and synaptic function.
• Surface protection: Lipid-rich secretions contribute to skin waterproofing and the protective barrier of epithelial tissues.
• Metabolic transport: Lipoproteins package hydrophobic lipids with proteins so they can circulate through aqueous blood.
• Disease associations: Excess energy storage can contribute to obesity; abnormal lipoprotein balance can promote atherosclerosis; impaired lipid degradation can cause storage diseases.
• Functional principle: The same hydrophobicity that makes lipids valuable for energy storage and barriers also requires specialized transport, digestion, and membrane systems.