22.4 Lipid Structure, Membranes & Transport

Lipid Structure, Membranes & Transport

Lipids are water-insoluble (or sparingly soluble) biomolecules that serve as fuel stores, membrane building blocks, signaling molecules, and vitamins. The PA-CAT Bulletin of Information, rev. 20240815 places lipid biochemistry under Biochemistry; this section covers the chemistry that the previous chapter did not address.

Fatty Acid Structure and Nomenclature

A fatty acid is a long hydrocarbon chain with a terminal carboxyl group. Saturated fatty acids have no double bonds (palmitate 16:0, stearate 18:0); monounsaturated have one (oleate 18:1Δ9); polyunsaturated have two or more (linoleate 18:2Δ9,12; arachidonate 20:4Δ5,8,11,14). The shorthand is C:D (carbons:double bonds). Double bonds in mammalian fatty acids are cis, introducing a ~30° kink that disrupts packing and lowers melting temperature. ω (omega) numbering starts at the methyl end: linoleate is ω6, α-linolenate is ω3, and arachidonate is the elongation product of linoleate. Essential fatty acids — linoleate and α-linolenate — cannot be synthesized because humans lack Δ12 and Δ15 desaturases; deficiency causes dermatitis and poor wound healing.

Triglycerides, Phospholipids, Sphingolipids, and Sterols

Triglycerides (triacylglycerols) are glycerol esterified with three fatty acids; they are the densest energy store (~9 kcal/g) and the form used in adipose droplets. Phospholipids are glycerol + two fatty acids (sn-1 usually saturated, sn-2 usually unsaturated) + a phosphate head group esterified to an alcohol — phosphatidylcholine (lecithin), phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol (PIP2 source of IP3/DAG), and phosphatidylglycerol (precursor of cardiolipin in mitochondrial membranes). Phospholipids are amphipathic — hydrophilic head, hydrophobic tails — which drives bilayer self-assembly.

Sphingolipids are built on sphingosine, a long-chain amino alcohol, rather than glycerol. Ceramide (sphingosine + fatty acid) is the core; adding phosphocholine yields sphingomyelin (myelin sheath), and adding sugars yields glycolipids (cerebrosides have one sugar; gangliosides have sialic acid, e.g., GM1, GM2). Tay-Sachs disease is HEXA deficiency causing GM2 ganglioside accumulation; Gaucher disease is glucocerebrosidase deficiency causing glucocerebroside accumulation; Niemann-Pick is sphingomyelinase deficiency.

Cholesterol is a sterol — a four-ring steroid nucleus with a hydroxyl group at C-3 (the polar head) and an isooctyl side chain at C-17. Cholesterol is the precursor of bile acids, steroid hormones, and vitamin D, and is inserted between phospholipids in membranes where it modulates fluidity. Esters (cholesteryl esters, triglycerides) are the hydrophobic core cargo of lipoproteins.

Membrane Structure and Fluidity

The fluid mosaic model (Singer and Nicolson) describes the membrane as a phospholipid bilayer with embedded proteins that diffuse laterally. Integral (intrinsic) proteins span the bilayer (transmembrane helices, β-barrels); peripheral proteins attach to the surface (often via electrostatic interactions with head groups or anchored proteins); lipid-anchored proteins are covalently bound to lipid tails (GPI-anchored, prenylated, myristoylated, palmitoylated).

Membrane fluidity is tuned by three variables. (1) Fatty acid saturation: saturated chains pack tightly, lowering fluidity and raising melting temperature; unsaturated cis chains kink, increasing fluidity. (2) Cholesterol: at low temperature it prevents tight packing, increasing fluidity; at high temperature it restrains phospholipid motion, decreasing fluidity — cholesterol is a fluidity buffer. (3) Chain length: shorter chains melt at lower temperature. Cells remodel membranes by de novo desaturation (via acyl-CoA desaturases) and phospholipase A2 remodeling to maintain fluidity across temperatures (homeoviscous adaptation).

Membrane Transport

Small nonpolar molecules (O2, CO2, N2, steroid hormones) cross by simple diffusion down their concentration gradient. Facilitated diffusion moves polar molecules down their gradient through channel proteins (ion channels, aquaporins) or carrier proteins (GLUT glucose transporters; their Km values set tissue-specific uptake — GLUT4 in muscle/adipose is insulin-responsive). Primary active transport uses ATP directly: the Na+/K+ ATPase pumps 3 Na+ out and 2 K+ in per ATP, establishing the Na+ and K+ gradients that drive secondary transport and the resting membrane potential; Ca2+ ATPase (SERCA in ER, PMCA at the plasma membrane) pumps Ca2+ out of the cytosol; H+/K+ ATPase acidifies the stomach. Secondary active transport uses the energy of an ion gradient: Na+/glucose symport (SGLT1) in intestinal and renal epithelia drives glucose uptake against its gradient; Na+/Ca2+ exchange extrudes Ca2+ from cardiomyocytes; Na+/H+ exchange regulates intracellular pH.

Lipoprotein Metabolism

Lipoproteins are spherical particles with a phospholipid/cholesterol/apolipoprotein shell and a triglyceride/cholesteryl ester core. They are classified by density: chylomicrons (lowest density, highest triglyceride) → VLDL → IDL → LDL → HDL (highest density, highest protein).

Exogenous (dietary) pathway: dietary fat is packaged in enterocytes into chylomicrons (apoB-48), secreted into lymph, and enter blood. Lipoprotein lipase (LPL) on capillary endothelium (activated by apoC-II) hydrolyzes triglycerides, releasing free fatty acids to muscle and adipose. The chylomicron remnant is cleared by the liver via apoE receptors.

Endogenous pathway: the liver packages triglycerides and cholesterol into VLDL (apoB-100). LPL removes triglycerides, converting VLDL → IDL → LDL. LDL carries the majority of plasma cholesterol and delivers it to tissues via the LDL receptor (apoB-100/E receptor). LDL receptor deficiency causes familial hypercholesterolemia (tendon xanthomas, premature atherosclerosis).

Reverse cholesterol transport: HDL (apoA-I) is assembled in liver and intestine; it collects cholesterol from peripheral cells via ABCA1 and ABCG1 transporters, esterifies it via lecithin-cholesterol acyltransferase (LCAT), and delivers it to the liver via SR-B1 or by transferring cholesteryl esters to VLDL/LDL via CETP. This is the basis for HDL being termed 'good cholesterol'.

Clinical Relevance for the PA-CAT

Apolipoprotein identities (apoB-48 in chylomicrons; apoB-100 in VLDL/LDL; apoA-I in HDL; apoC-II as LPL cofactor; apoE as remnant ligand) appear on the exam, as do the LPL deficiency cause of type I hyperlipoproteinemia (familial chylomicronemia) and the LDL receptor defect of familial hypercholesterolemia. Statins inhibit HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis; ezetimibe blocks intestinal NPC1L1; PCSK9 inhibitors increase LDL receptor recycling.