Lipid Biochemistry & Membrane Structure

Lipids are a structurally diverse group of hydrophobic or amphipathic molecules with critical roles in energy storage, membrane architecture, signalling, and the synthesis of hormones and bile acids. Understanding lipid biochemistry is essential for interpreting metabolic disease, cardiovascular risk, and pharmacological targets such as statins.

Fatty Acid Structure: Saturated vs Unsaturated

Fatty acids consist of a hydrocarbon chain with a terminal carboxyl group. Saturated fatty acids have no double bonds and adopt an extended, linear conformation that allows tight packing (e.g., palmitate C16:0, stearate C18:0 -- solid at room temperature). Unsaturated fatty acids contain one (monounsaturated, e.g., oleate C18:1 delta9) or more (polyunsaturated, e.g., linoleate C18:2 delta9,12; arachidonate C20:4 delta5,8,11,14) double bonds, predominantly in the cis configuration. Cis double bonds introduce kinks in the chain, reducing packing efficiency and lowering melting points -- hence unsaturated fats are liquid at room temperature. Trans fatty acids (formed during partial hydrogenation of vegetable oils) behave more like saturated fats and are associated with increased cardiovascular risk. Essential fatty acids -- linoleic acid (omega-6) and alpha-linolenic acid (omega-3) -- cannot be synthesised by humans and must be obtained from diet.

Lipid Classes

Triglycerides (triacylglycerols, TAG) consist of a glycerol backbone esterified to three fatty acids; they are the primary form of energy storage in adipose tissue, providing more than twice the caloric density of carbohydrates per gram (9 kcal/g vs 4 kcal/g). Phospholipids have a glycerol backbone, two fatty acid chains, and a phosphate group esterified to a polar head group (choline -> phosphatidylcholine; ethanolamine -> phosphatidylethanolamine; serine -> phosphatidylserine; inositol -> phosphatidylinositol). Sphingolipids are based on the sphingosine backbone rather than glycerol; ceramide (sphingosine + fatty acid) is the precursor to sphingomyelin and glycosphingolipids (gangliosides, cerebrosides). Sterols include cholesterol, bile acids, steroid hormones, and vitamin D; cholesterol has a rigid four-ring steroid nucleus with a hydroxyl group and a branched hydrocarbon tail.

Membrane Structure: The Fluid Mosaic Model

The fluid mosaic model (Singer and Nicolson, 1972) describes biological membranes as a two-dimensional fluid phospholipid bilayer in which proteins are embedded or associated. The hydrophobic fatty acid tails face inward; the polar head groups face the aqueous environments on either side. Membrane fluidity is influenced by fatty acid composition (more unsaturation = more fluid) and cholesterol content (at physiological temperatures, cholesterol reduces fluidity by intercalating between phospholipids and restricting their motion; at low temperatures it prevents gel formation). Lipid rafts are dynamic, cholesterol- and sphingolipid-enriched microdomains that serve as platforms for receptor signalling and membrane trafficking. Membrane proteins are classified as integral (transmembrane or monotopic, requiring detergent for extraction) or peripheral (associated with the membrane surface by electrostatic or lipid-anchor interactions). The membrane is asymmetric: phosphatidylcholine and sphingomyelin are enriched in the outer leaflet; phosphatidylserine and phosphatidylethanolamine predominate in the inner leaflet. Phosphatidylserine externalisation is an early signal in apoptosis, recognised by phagocytes.

Beta-Oxidation of Fatty Acids

Fatty acid oxidation (beta-oxidation) occurs in the mitochondrial matrix. Activation: cytoplasmic fatty acids are activated to acyl-CoA by acyl-CoA synthetase (consuming 2 ATP equivalents: ATP -> AMP + PPi). Transport: long-chain acyl-CoA cannot cross the inner mitochondrial membrane directly; carnitine palmitoyl transferase I (CPT-I) on the outer mitochondrial membrane transfers the acyl group to carnitine; acylcarnitine crosses via the carnitine-acylcarnitine translocase; CPT-II on the inner membrane regenerates acyl-CoA. CPT-I is inhibited by malonyl-CoA (the first committed intermediate in fatty acid synthesis), preventing futile simultaneous synthesis and oxidation. The beta-oxidation spiral for a saturated even-chain fatty acid involves four repeating reactions per cycle: oxidation by FAD-linked acyl-CoA dehydrogenase (yields FADH2), hydration by enoyl-CoA hydratase, oxidation by NAD+-linked hydroxyacyl-CoA dehydrogenase (yields NADH), and thiolytic cleavage by thiolase, releasing acetyl-CoA and a shortened acyl-CoA. For palmitate (C16), seven cycles yield 8 acetyl-CoA, 7 FADH2, and 7 NADH. Including TCA cycle and oxidative phosphorylation, complete oxidation of palmitate yields approximately 106 ATP (net, subtracting activation cost).

Ketone Body Synthesis and Utilisation

During prolonged fasting or uncontrolled type 1 diabetes, hepatic acetyl-CoA from beta-oxidation exceeds the capacity of the TCA cycle (which is also slowed by low oxaloacetate, diverted to gluconeogenesis). Excess acetyl-CoA is converted to ketone bodies in the liver mitochondria: two acetyl-CoA condense to acetoacetyl-CoA, which reacts with another acetyl-CoA to form HMG-CoA (by HMG-CoA synthase); HMG-CoA lyase releases acetyl-CoA and acetoacetate; acetoacetate is reduced to beta-hydroxybutyrate (by beta-hydroxybutyrate dehydrogenase) or spontaneously decarboxylates to acetone. Ketone bodies are exported to peripheral tissues (brain, muscle, heart), where they are reconverted to acetyl-CoA and oxidised. The brain adapts to use beta-hydroxybutyrate as its primary fuel during starvation. In diabetic ketoacidosis (DKA), unregulated ketogenesis causes life-threatening acidosis.

Lipoprotein Classes and Metabolism

Lipids are transported in blood as lipoproteins -- complexes of lipids and apolipoproteins. Chylomicrons (formed in intestinal enterocytes): transport dietary triglycerides and cholesterol from gut to peripheral tissues; lipoprotein lipase (LPL) on capillary endothelium hydrolyses their TAG; chylomicron remnants are taken up by the liver. VLDL (very-low-density lipoprotein): secreted by the liver to export endogenous TAG; LPL progressively removes TAG, converting VLDL -> IDL -> LDL. LDL (low-density lipoprotein): cholesterol-rich; taken up by cells via the LDL receptor (LDLR); high LDL is the primary modifiable cardiovascular risk factor. HDL (high-density lipoprotein): participates in reverse cholesterol transport -- accepts cholesterol from peripheral tissues via ABCA1 and ABCG1 transporters; LCAT esterifies cholesterol on HDL; cholesterol is delivered to the liver via SR-BI or transferred to other lipoproteins by CETP. ApoB-100 is the main apolipoprotein of VLDL and LDL; ApoE mediates receptor-mediated clearance of remnants; ApoC-II activates LPL; ApoA-I is the major HDL apolipoprotein and activates LCAT.

Cholesterol Synthesis and Statin Pharmacology

Cholesterol is synthesised in the cytoplasm and smooth ER via the mevalonate pathway. Acetyl-CoA -> HMG-CoA (by HMG-CoA synthase) -> mevalonate (by HMG-CoA reductase, the rate-limiting step) -> isopentenyl pyrophosphate -> squalene -> lanosterol -> cholesterol. HMG-CoA reductase is regulated by: sterol-mediated SREBP-2 transcriptional repression (when intracellular cholesterol is high, SCAP-SREBP complex is retained in ER and LDLR and reductase genes are not transcribed); phosphorylation by AMPK (inactivating); and proteasomal degradation. Statins (e.g., atorvastatin, rosuvastatin) are competitive inhibitors of HMG-CoA reductase; they lower intracellular cholesterol, upregulate LDLR expression, and reduce plasma LDL cholesterol by 30-55%. They also inhibit synthesis of other mevalonate-pathway products (isoprenoids), contributing to pleiotropic anti-inflammatory effects.

Eicosanoids from Arachidonic Acid

Arachidonic acid (C20:4 omega-6) is released from membrane phospholipids by phospholipase A2 and is the precursor of eicosanoids -- local lipid mediators with diverse physiological roles. Cyclooxygenases (COX-1 and COX-2) convert arachidonate to prostaglandin H2 (PGH2), the precursor to prostaglandins (PGE2 -- fever, pain, vasodilation; PGI2/prostacyclin -- vasodilation, platelet inhibition), thromboxane A2 (vasoconstriction, platelet aggregation), and leukotrienes (via 5-lipoxygenase -- bronchoconstriction in asthma, LTC4/LTD4 are the slow-reacting substances of anaphylaxis). Aspirin irreversibly acetylates COX-1 and COX-2, inhibiting thromboxane A2 synthesis in platelets (which cannot regenerate COX because they lack nuclei), providing antiplatelet effects. Selective COX-2 inhibitors (celecoxib) reduce PGI2 production in endothelium while sparing platelet TXA2, increasing thrombotic risk.

Lipid-Related Diseases

Atherosclerosis is initiated when modified (oxidised) LDL accumulates in the arterial intima, is taken up by macrophages via scavenger receptors (forming foam cells), and triggers chronic inflammation, plaque formation, and eventual thrombosis. Familial hypercholesterolaemia (FH) results from loss-of-function mutations in the LDLR gene (most commonly), ApoB, or PCSK9; heterozygous FH affects 1 in 250 people and dramatically elevates LDL and cardiovascular risk. PCSK9 normally promotes LDLR degradation; PCSK9 inhibitors (alirocumab, evolocumab) are monoclonal antibodies that allow LDLR recycling and markedly lower LDL. Metabolic syndrome involves central obesity, insulin resistance, hypertriglyceridaemia, low HDL, and hypertension, with associated non-alcoholic fatty liver disease (NAFLD). Gaucher disease (glucocerebrosidase deficiency) and Niemann-Pick disease (sphingomyelinase deficiency) are lysosomal storage disorders caused by impaired sphingolipid catabolism.