Lipids

Overview: What Makes a Lipid a Lipid?

Must know

A lipid is not defined by a single functional group. Lipids are unified by hydrophobicity — insoluble in water, soluble in nonpolar solvents — arising from long hydrocarbon chains or fused ring systems that cannot hydrogen-bond with water.

Priority labels: Must know = cold; Know the logic = mechanism not names; Passage-level = recognize, don't memorize; Optional = skippable.

Many lipids are amphipathic (hydrophobic tail + hydrophilic head). This single principle explains nearly all lipid self-assembly the MCAT tests (bilayers, micelles, soaps).

Functional categories: storage (triacylglycerols), structural (phospholipids, sphingolipids, cholesterol), signaling (prostaglandins, steroid hormones), and fat-soluble vitamins.

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Fatty Acid Structure and Nomenclature

Saturated and Unsaturated Fatty Acids

Must know

A fatty acid is a long-chain carboxylic acid (~12–20 carbons). At physiological pH the carboxyl is deprotonated ($\ce{-COO^{-}}$). "Free fatty acid" (FFA) means the carboxyl is not esterified.

• Saturated: no $\ce{C=C}$; chains pack tightly → high melting point, solid at room temp (butter, lard).
• Unsaturated: one or more $\ce{C=C}$. Natural double bonds are almost always cis (Z), introducing a kink that disrupts packing → lower melting point, liquid (oils). Mono = one double bond; PUFA = two or more.
• Trans fats behave like saturated fats (tighter packing, higher mp) and are linked to cardiovascular disease.

Passage-level

Palmitic (16C) and stearic (18C) are common saturated examples — don't memorize carbon counts.

Fatty Acid Naming: Delta (Δ) and Omega (ω)

Know the logic

• Delta (Δ): number from the carboxyl carbon (C-1). Δ9 = double bond at C-9.
• Omega (ω/n): number from the methyl end. ω-3/ω-6 = first double bond 3/6 carbons from the methyl terminus. Humans cannot make ω-3 or ω-6 (essential fatty acids) — we lack desaturases that act beyond Δ9.

Shorthand: 18:2 Δ9,12 = linoleic acid (essential ω-6); 18:3 Δ9,12,15 = α-linolenic (essential ω-3).

Quick check: Arachidonic acid is 20:4 Δ5,8,11,14. Omega classification?
Answer: From the methyl end, 20 − 14 = 6, so ω-6. Important because arachidonic acid is the prostaglandin precursor.

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Triacylglycerols (Triglycerides): Structure and Energy Storage

Structure

Must know

Glycerol is a 3-carbon backbone with an –OH on each carbon. A triacylglycerol (TAG) forms when all three –OH groups are esterified with fatty acids (ester bonds). Positions are sn-1, sn-2, sn-3; the sn-2 position preferentially holds unsaturated chains.

$\ce{Glycerol + 3 RCOOH -> Triacylglycerol + 3 H2O}$

Forming one TAG is a condensation releasing 3 water; hydrolysis (lipase, in digestion) consumes 3 water.

Why TAGs Are the Premier Energy Store

Must know

1. Highly reduced carbons: oxidizing $\ce{-CH2-}$ units yields more energy than the partially oxidized carbons of glucose.
2. Anhydrous: TAGs are nonpolar; glycogen binds ~3–4 g water per gram, so fat is far more compact per kcal.

A human stores ~6× more energy as TAG than as glycogen. In starvation, adipose FFAs are mobilized (hormone-sensitive lipase) and oxidized via β-oxidation.

Lipoprotein Transport (Conceptual)

Passage-level

Lipids travel in plasma inside lipoproteins — a hydrophobic core (TAGs, cholesteryl esters) wrapped in an amphipathic shell of phospholipids, cholesterol, and apolipoproteins — the same core/shell logic as micelles. Named classes (chylomicrons, VLDL, LDL, HDL) and cholesterol-transport detail belong to the metabolism guides.

Optional

The iodine number rises with unsaturation (iodine adds across $\ce{C=C}$); the saponification number is inversely related to chain length.

Quick check: Fat A has a higher iodine number than fat B — which has the lower melting point?
Answer: Higher iodine number = more $\ce{C=C}$ = more unsaturation. More cis double bonds disrupt packing, so Fat A has the lower melting point.

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Free Fatty Acids: Saponification

Saponification Reaction

Must know

Saponification is base-catalyzed hydrolysis of an ester. Treating a TAG with strong base ($\ce{NaOH}$/$\ce{KOH}$) cleaves the ester bonds, releasing fatty acids as carboxylate salts (soaps) plus glycerol.

$\ce{Triacylglycerol + 3 NaOH -> Glycerol + 3 RCOONa}$

It is irreversible because the carboxylate ($\ce{RCOO^-}$) is resonance-stabilized and not electrophilic enough to re-esterify.

How Soaps Work: Micelles

Must know

Soap ($\ce{RCOO^-Na^+}$) is amphipathic: nonpolar tail, charged carboxylate head. In water it self-assembles into micelles — spheres with tails inward, heads outward — trapping grease in the hydrophobic core.

Single-tailed amphiphiles (soaps, detergents, lysophospholipids) → micelles (spherical, single layer); double-tailed amphiphiles (phospholipids) → bilayers (planar, or vesicles/liposomes). Geometry drives the difference.

Optional

Acid-catalyzed ester hydrolysis is also possible but reversible — it is NOT saponification.

Worked example (saponification stoichiometry): React 884 g tristearin (MW ≈ 884; three 18:0 chains) with excess $\ce{NaOH}$.
884 g ÷ 884 = 1 mol TAG → needs 3 mol $\ce{NaOH}$ (one per ester). Products: 1 mol glycerol + 3 mol sodium stearate (the soap). The three soap molecules are the saponification products.

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Structural Lipids: Phospholipids and Phosphatides

Glycerophospholipids

Must know

Phospholipids are the main membrane structural lipid; the largest class, glycerophospholipids, are built on glycerol:

• sn-1, sn-2: fatty acids via ester bonds (sn-2 usually unsaturated).
• sn-3: phosphate via phosphoester bond, further esterified to a polar head group.

The phosphate + head group is the hydrophilic head; the two tails are hydrophobic. This amphipathic architecture drives bilayer formation — the basis of the fluid mosaic model: a 2-D fluid of lipids with proteins and cholesterol embedded and diffusing laterally.

Passage-level

The head group names the phospholipid. Charge matters for membrane asymmetry.

Head Group	Phospholipid	Note
Choline	Phosphatidylcholine (PC)	Zwitterionic; most abundant
Ethanolamine	Phosphatidylethanolamine (PE)	Zwitterionic; inner leaflet
Serine	Phosphatidylserine (PS)	Net negative; inner leaflet; apoptosis signal
Inositol	Phosphatidylinositol (PI)	Negative; IP₃/DAG signaling precursor

Membrane fluidity depends on chain chemistry: more cis unsaturation and shorter chains raise it. Cholesterol is a fluidity buffer — at low temperature it prevents crystallizing, at high temperature it restrains tails. The phase-transition temperature ($T_m$) separates the ordered gel phase from the fluid liquid-crystalline phase. (The membrane-fluidity biology — how cells tune composition and why it matters physiologically — is developed in the Biology lipids guide.)

Quick check: Two glycerophospholipids differ only in their sn-2 chain: one stearoyl (18:0), one oleoyl (18:1 cis). Which gives the more fluid membrane?
Answer: The oleoyl (cis 18:1): its kink disrupts packing, lowering $T_m$ and raising fluidity.

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Sphingolipids

Must know

Sphingolipids are built on sphingosine (an 18-carbon amino alcohol), not glycerol. A fatty acid attached to sphingosine by an amide bond (not ester) gives ceramide, the precursor to all sphingolipids.

$\text{Sphingosine} + \text{Fatty acid} \xrightarrow{\text{amide bond}} \text{Ceramide}$

• Sphingomyelin: ceramide + phosphocholine head; the only phospholipid not based on glycerol; major in the myelin sheath.
• Glycosphingolipids (ceramide + sugar via glycosidic bond): cerebrosides (one sugar; abundant in myelin) and gangliosides (oligosaccharide with sialic acid; abundant in neural tissue, cell recognition).

Passage-level

Sphingolipid storage diseases (e.g., Tay-Sachs = GM2 ganglioside accumulation) appear as biochem/genetics integration.

Quick check: What bond links the fatty acid to sphingosine in ceramide, vs. glycerophospholipids?
Answer: An amide bond in ceramide vs. ester bonds in glycerophospholipids — so ceramide resists alkaline (saponifying) hydrolysis better.

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Waxes

Must know

Waxes are esters of a long-chain fatty acid + long-chain primary alcohol (no glycerol).

$\ce{RCOOH + R'OH -> RCOOR' + H2O}$

The product is highly nonpolar, high-melting, and hydrolysis-resistant. Biologically waxes are protective/waterproofing coatings (leaf cutin, feathers, cerumen); not a human energy source. The MCAT tests only the structural definition and the protective function.

Quick check: Cetyl palmitate (cetyl alcohol, 16C; palmitic acid, 16C) — how many carbons total?
Answer: 16 + 16 = 32 carbons, joined by an ester linkage; nonpolar except the ester oxygen.

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Terpenes and Terpenoids

Know the logic

Terpenes are built from five-carbon isoprene units ($\ce{C5H8}$) joined head-to-tail (the isoprene rule); classified by unit count (mono-, sesqui-, di-, triterpene). Terpenoids are oxygen-modified terpenes.

Why it matters: squalene (a triterpene) is the precursor to cholesterol and all steroids, and isoprenoid units form the vitamin A tail and the coenzyme Q side chain. Branched lipid chains with methyl branches every fourth carbon = isoprenoid.

Steroid Structure and Properties

The Steroid Nucleus

Must know

All steroids share a tetracyclic ring system — three six-membered rings + one five-membered ring (sterane nucleus), rigid and planar.

Cholesterol is the most abundant animal steroid and the precursor to all other steroids. Key features: –OH at C-3 (slightly amphipathic), a $\ce{C=C}$ at C5–C6, the rigid core, and a branched C-17 tail.

Know the logic

Cholesterol is built from acetyl-CoA via isoprenoid intermediates; the rate-limiting step is HMG-CoA reductase, the target of statins — a high-yield drug-mechanism parallel to warfarin (vitamin K) and aspirin (COX).

Biological Steroids

Must know

Steroids derived from cholesterol include cortisol (glucocorticoid), aldosterone (mineralocorticoid), testosterone, estradiol, progesterone, vitamin D₃ (a secosteroid), and bile acids.

Because the steroid nucleus is lipophilic, steroid hormones cross the membrane and bind intracellular/nuclear receptors rather than cell-surface receptors. (The endocrine-signaling logic — steroid vs. peptide hormone time course and second messengers — is covered in the Biology lipids guide.)

Bile salts (cholate, deoxycholate) are amphipathic steroids that emulsify dietary fat in the small intestine, increasing surface area for pancreatic lipase. Made in liver, stored in gallbladder, secreted into duodenum.

Quick check: Why can a steroid hormone reach an intracellular receptor while a peptide hormone cannot?
Answer: The steroid is lipophilic and diffuses through the membrane; the peptide is too polar and must signal through a cell-surface receptor.

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Fat-Soluble Vitamins

Must know

The fat-soluble vitamins are A, D, E, K (ADEK). They are absorbed with dietary fat (need bile salts/chylomicrons), stored in liver and fat, and can reach toxic levels (hypervitaminosis), unlike water-soluble vitamins.

Vitamin A (Retinol)

Must know

Active forms: retinol (storage), retinal (visual chromophore; with opsin forms rhodopsin; light isomerizes 11-cis → all-trans-retinal to trigger transduction), and retinoic acid (gene regulation via nuclear receptors, like a steroid). Deficiency → night blindness; excess → teratogenic.

Vitamin D (Calciferol)

Know the logic

Skin (UV) → cholecalciferol (D₃) → liver (25-OH) → kidney (1,25-(OH)₂ = calcitriol, active). Calcitriol raises intestinal $\ce{Ca^{2+}}$ absorption and bone mineralization via nuclear receptors. Deficiency → rickets / osteomalacia. High-yield: CKD blocks the renal activation step.

Vitamin E (Tocopherol)

Must know

The major lipid-soluble antioxidant; scavenges radicals, interrupting lipid peroxidation. No enzymatic role.

Vitamin K

Must know

Cofactor for γ-carboxylation of glutamate in clotting factors II, VII, IX, X (and proteins C, S); the Gla residues bind $\ce{Ca^{2+}}$ for clot formation. Warfarin inhibits vitamin K epoxide reductase — classic drug mechanism. Deficiency → bleeding (newborns get a vitamin K injection).

Quick check: Obstructive jaundice (blocked bile duct) → prolonged bleeding. Which vitamin, and why?
Answer: Vitamin K. Without bile salts, fat-soluble vitamins aren't absorbed (no micelles); vitamin K deficiency impairs clotting-factor γ-carboxylation → bleeding.

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Prostaglandins and Eicosanoids

Must know

Prostaglandins are eicosanoids — 20-carbon signaling lipids from 20-carbon PUFAs. The main precursor is arachidonic acid (20:4, ω-6), released from membrane phospholipids at sn-2 by phospholipase A₂.

Cyclooxygenase (COX) converts arachidonic acid to prostaglandins — local (paracrine/autocrine) signals affecting inflammation, pain, fever, platelet aggregation, and smooth-muscle tone. Aspirin irreversibly inhibits COX (explaining its antipyretic, analgesic, anti-inflammatory, antiplatelet effects).

Optional

Other eicosanoids (thromboxanes, prostacyclin, lipoxygenase-derived leukotrienes) and the detailed COX mechanism are out of scope here. Prostaglandins have a cyclopentane ring, are not stored, and act locally.

Quick check: High-dose aspirin causes a GI bleed — mechanism?
Answer: Gastric prostaglandins normally protect the lining (mucus, less acid). Aspirin inhibits COX, lowering protective prostaglandins → ulceration and bleeding.

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Common Confusions & Tricks

1. Ester vs. amide bond. Glycerophospholipids use ester bonds; ceramide uses an amide bond. Sphingolipids resist saponification because amides are more stable than esters under base.

2. Saponification is always base-catalyzed. Acid hydrolysis is NOT saponification; saponification ($\ce{NaOH}$/$\ce{KOH}$) is irreversible.

3. Micelles vs. bilayers. Single-tailed amphiphiles → micelles; double-tailed → bilayers. Don't confuse emulsification (mechanical break-up) with micelle formation.

4. Cholesterol buffers fluidity both ways. Low temp → prevents crystallizing (more fluid); high temp → restrains tails (less fluid).

5. Fat-soluble vitamin toxicity. ADEK are stored → can accumulate. A (teratogenic) and D (hypercalcemia) are the classic toxic-in-excess vitamins.

6. Vitamin D activation order. Skin (UV) → D₃ → Liver (25-OH) → Kidney (1,25-OH active). CKD blocks the renal step.

7. Omega vs. delta numbering. Delta = from the carboxyl end; omega = from the methyl end.

8. Prostaglandins = arachidonic acid via COX. 20-carbon eicosanoids acting locally; aspirin irreversibly inhibits COX.

9. Phosphatidylserine flipping = apoptosis. PS is normally inner; flipping outward signals macrophages.

10. TAG hydrolysis gives glycerol + 3 FFAs (all three ester bonds), with mono-/diacylglycerol intermediates.

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Key Equations and Summary

Concept	Expression	Notes
Triacylglycerol formation	$\ce{Glycerol + 3 RCOOH -> TAG + 3 H2O}$	Condensation; 3 ester bonds
Saponification	$\ce{TAG + 3 NaOH -> Glycerol + 3 RCOONa}$	Base-catalyzed; irreversible; soap
Acid ester hydrolysis	$\ce{RCOOR' + H2O <=>[H+] RCOOH + R'OH}$	Reversible; NOT saponification
Degree of unsaturation	$\text{DoU} = \dfrac{2C + 2 + N - H - X}{2}$	1 DoU per double bond/ring
Vitamin D activation	$\ce{7-DHC ->[\text{UV}][\text{skin}] D3 ->[\text{liver}] 25-OH-D3 ->[\text{kidney}] 1,25-(OH)2-D3}$	CKD blocks renal step
COX pathway	$\ce{Arachidonic acid ->[\text{COX}] Prostaglandins}$	Local eicosanoids; aspirin inhibits COX
Ceramide bond	$\ce{Sphingosine + Fatty Acid ->[\text{amide bond}] Ceramide}$	Amide, not ester
Iodine number	Proportional to $\ce{C=C}$ per gram	Higher = more unsaturation = lower Tm