10.2 Lipids

Lipid chemistry: what the molecules actually are

Lipids are 12% of Chemistry. The test plan wants catabolic and anabolic pathways, structure/properties/function/transport, and food sources plus digestion. Transport means the lipoprotein cascade, not a vague “fat travels in blood.”

Quick Answer: Fatty acids are stored as triglycerides, carried on apoB lipoproteins, oxidized in mitochondria after the carnitine shuttle, and synthesized in cytosol from acetyl-CoA via malonyl-CoA. ACC is the committed synthetic enzyme; CPT-I is the committed oxidative gate. HDL reverse-transports cholesterol; LDL delivers it via apoB-100.

Fatty acids are carboxylic acids with long hydrocarbon tails. Saturated tails pack (higher melting point); each cis double bond kinks the chain (lower melting point, membrane fluidity). Humans can desaturate at Δ9 (stearoyl-CoA desaturase) but cannot place double bonds beyond Δ9, so linoleic (18:2 ω-6) and α-linolenic (18:3 ω-3) are essential. Arachidonic acid (20:4 ω-6) from linoleate is the precursor of prostaglandins, thromboxanes, and leukotrienes.

Triacylglycerol (triglyceride) is glycerol plus three fatty acyl chains — the storage form in adipocytes and in circulating chylomicrons/VLDL. Phosphoglycerides (phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol) replace one acyl with a polar head and make bilayer membranes. Sphingomyelin and glycosphingolipids use a sphingosine backbone; the IVD and myelin are sphingolipid-rich. Cholesterol is a 27-carbon sterol that stiffens membranes, is the precursor of steroid hormones, bile acids, and vitamin D, and is esterified for transport.

Micelles versus liposomes versus lipoproteins. Bile-salt mixed micelles solubilize digested lipids in the intestinal lumen. Lipoproteins are protein-coated emulsion particles in plasma, not the same as a micelle.

Digestion and food sources

Dietary lipid is mostly triglyceride from animal fat, oils, dairy, and fried food, plus phospholipid and cholesterol from animal products. Lingual and gastric lipases nibble medium-chain triglycerides (important in neonates). The main enzyme is pancreatic lipase plus colipase at the emulsion-water interface in the duodenum. Bile salts (from hepatic cholesterol via 7α-hydroxylase) emulsify; colipase anchors lipase despite bile salts. Products are 2-monoacylglycerol and free fatty acids.

Phospholipase A2 releases a fatty acid from phospholipid (including arachidonate at sn-2). Cholesterol esterase hydrolyzes cholesteryl esters. Mixed micelles deliver the products to the enterocyte. Medium-chain fatty acids (C8–C12) can enter portal blood bound to albumin. Long-chain fatty acids are re-esterified in the enterocyte, packaged with apoB-48 on chylomicrons, and exit via lymph (thoracic duct).

Exam trap: bile salts are reabsorbed in the terminal ileum (Na+-dependent ASBT) and returned in the portal vein (enterohepatic circulation). Ileal resection or a bile-acid resin changes both fat absorption and hepatic cholesterol demand. Steatorrhea plus fat-soluble vitamin loss is a digestion item, not automatically a pancreatic-enzyme item — ask whether bile, lipase, or mucosa is missing.

Orlistat inhibits pancreatic lipase; the undigested triglyceride is the point of the drug and of the oily-stool side effect.

Lipoprotein transport: particles, apoproteins, enzymes

A lipoprotein has a hydrophobic core (triglyceride, cholesteryl ester) and a phospholipid/free-cholesterol/apoprotein shell. Density rises as triglyceride is stripped and protein/cholesterol remain.

ApoB-48 versus apoB-100 is the same gene. Intestinal cytidine deaminase (APOBEC-1) edits the mRNA CAA codon to UAA, so translation stops at ~48% of the liver protein. Chylomicrons therefore cannot bind the LDL receptor via apoB (they use apoE after remnant conversion). Liver makes full-length apoB-100, the LDL-receptor ligand.

ApoC-II is transferred from HDL onto chylomicrons and VLDL and is the obligate activator of lipoprotein lipase (LPL) on capillary endothelium of muscle and adipose. LPL deficiency or apoC-II deficiency: fasting chylomicronemia, eruptive xanthomas, pancreatitis. ApoC-III opposes LPL. ApoA-I activates LCAT (lecithin-cholesterol acyltransferase), which esterifies HDL surface cholesterol so the particle can keep accepting more. ACAT is the intracellular esterifying enzyme — do not swap the two.

CETP (cholesteryl ester transfer protein) moves CE from HDL onto apoB particles in exchange for triglyceride. SR-B1 is the hepatic HDL receptor for selective CE uptake. ABCA1 on peripheral cells loads free cholesterol onto apoA-I (Tangier disease when missing).

LDL receptor binds apoB-100 (and apoE). Internalization, lysosomal hydrolysis, free cholesterol in the cell: (1) suppresses HMG-CoA reductase, (2) suppresses new LDL-receptor synthesis via SREBP-2 retention in the ER, (3) activates ACAT. Familial hypercholesterolemia (LDL-receptor defects) raises plasma LDL because clearance fails and hepatic synthesis is not repressed.

Worked particle math. After a steak-and-butter meal, plasma is lactescent from chylomicrons (apoB-48). Overnight, those are gone; fasting triglyceride is mostly VLDL (apoB-100). A Type I pattern (very high TG, normal-ish cholesterol, apoB-48 particles) is LPL/apoC-II. A Type IIa pattern (high LDL cholesterol, apoB-100) is LDL-receptor / apoB ligand disease.

Fatty-acid oxidation versus fatty-acid synthesis

These two pathways are a paired exam machine. Learn them as opposites that share acetyl-CoA but cannot run in the same cell at the same time because of malonyl-CoA.

Activation and the carnitine shuttle. Cytosolic fatty acyl-CoA synthetase (outer mitochondrial membrane / ER) uses ATP to AMP to make acyl-CoA. Long-chain acyl-CoA cannot cross the inner membrane. CPT-I (outer membrane) transfers the acyl to carnitine. CACT (translocase) shuttles acylcarnitine in and carnitine out. CPT-II (inner face) regenerates acyl-CoA in the matrix. Medium-chain fatty acids skip CPT-I — the reason MCAD deficiency is a different disease from CPT-I deficiency, and the reason MCT oil can feed a CPT-I-blocked patient.

β-oxidation (matrix): acyl-CoA dehydrogenase (FAD → ETF → ETF dehydrogenase → ubiquinone) → hydratase → NAD+-dependent hydroxyacyl-CoA dehydrogenase → thiolase (acetyl-CoA out). Each cycle shortens the chain by two carbons. Palmitoyl-CoA (C16) yields 8 acetyl-CoA, 7 NADH, and 7 FADH2. Odd-chain chains leave propionyl-CoA, which is carboxylated by propionyl-CoA carboxylase (biotin) to methylmalonyl-CoA, then methylmalonyl-CoA mutase (adenosylcobalamin, B12) to succinyl-CoA. That is the only net glucogenic contribution of fatty acids.

Unsaturated fatty acids need enoyl-CoA isomerase (and a reductase for polyunsaturates). Peroxisomes shorten very-long-chain fatty acids first (Zellweger, X-linked ALD). ω-oxidation in ER makes dicarboxylic acids when β-oxidation is overloaded — the laboratory fingerprint of MCAD deficiency includes medium-chain dicarboxylic aciduria.

Regulation of oxidation. Malonyl-CoA inhibits CPT-I. Fed state: insulin dephosphorylates acetyl-CoA carboxylase (ACC) → malonyl-CoA high → CPT-I off. Fasted state: glucagon/epinephrine/AMPK phosphorylate ACC (inhibitory) → malonyl-CoA falls → CPT-I on. Muscle CPT-I also sees falling malonyl-CoA when AMPK is active during exercise.

De novo fatty-acid synthesis (cytosol, mainly liver, also adipose, lactating breast). Acetyl-CoA from mitochondria is exported as citrate (citrate synthase when matrix acetyl-CoA and NADH are high). ATP-citrate lyase splits citrate to acetyl-CoA + OAA in cytosol. ACC (biotin) carboxylates acetyl-CoA to malonyl-CoA — the committed step. Fatty-acid synthase is a multifunctional dimer that loads acetyl and malonyl onto ACP as thioesters and, each round, condenses, reduces (NADPH), dehydrates, and reduces (NADPH) until palmitate (C16) is released by thioesterase. NADPH comes from the pentose phosphate pathway and from malic enzyme (malate → pyruvate + NADPH).

ACC regulation in one recitation: allosteric citrate polymerizes/activates ACC; palmitoyl-CoA depolymerizes/inhibits. Covalent: AMPK and PKA phosphorylation inhibit. Insulin (via phosphatase) activates. Induction: high-carb diets increase ACC and FAS transcription; fasting and glucagon decrease them.

Worked futile-cycle block. If ACC ran while CPT-I ran, newly made palmitate would immediately re-enter mitochondria, wasting ATP and NADPH. Malonyl-CoA binding to CPT-I is the hardware interlock. An exam stem that mentions “malonyl-CoA rises after a carbohydrate meal” is asking you to turn oxidation off, not to name a ketone.

Ketone bodies and cholesterol

When β-oxidation floods hepatic mitochondria with acetyl-CoA and NADH, oxaloacetate is diverted to malate (gluconeogenesis), citrate synthase slows, and acetyl-CoA is shunted to ketones.

Ketogenesis (liver mitochondria only): two acetyl-CoA → acetoacetyl-CoA (thiolase) → HMG-CoA (mitochondrial HMG-CoA synthase, rate-limiting, induced in fasting) → acetoacetate (HMG-CoA lyase) → acetone (spontaneous decarboxylation, exhaled) or 3-hydroxybutyrate (NADH-dependent dehydrogenase). The 3-hydroxybutyrate/acetoacetate ratio tracks the mitochondrial NADH/NAD+ ratio.

Extrahepatic tissues (muscle, brain in starvation, kidney) activate acetoacetate with succinyl-CoA:acetoacetate CoA-transferase (thiophorase) and feed acetyl-CoA into the TCA cycle. Hepatocytes lack thiophorase, so the liver is an exporter, not a consumer. RBCs cannot use ketones (no mitochondria). The brain still needs some glucose; ketones spare but do not fully replace it.

Ketoacidosis versus physiologic ketosis: high glucagon/low insulin (DKA, alcoholic ketoacidosis, starvation) plus available fatty acids. Urine nitroprusside detects acetoacetate, not 3-hydroxybutyrate — a trap when NADH is very high (alcohol) and the stick looks weakly positive despite a large ketone load.

Cholesterol synthesis (cytosol/ER): acetyl-CoA → acetoacetyl-CoA → cytosolic HMG-CoA → mevalonate via HMG-CoA reductase (ER, NADPH) — the committed step. Then isopentenyl pyrophosphate, squalene, lanosterol, cholesterol. Do not confuse cytosolic HMG-CoA (sterols) with mitochondrial HMG-CoA (ketones).

HMG-CoA reductase control: SREBP-2/SCAP in the ER senses low cholesterol, travels to the Golgi, releases the SREBP transcription factor, and induces reductase and LDL receptors. High cholesterol and lanosterol promote reductase ubiquitination. AMPK phosphorylation inactivates reductase in the energy-poor cell. Statins are competitive inhibitors of HMG-CoA reductase (they look like the tetrahedral intermediate of HMG-CoA). Insulin induces; glucagon represses.

Bile-acid synthesis committed enzyme is cholesterol 7α-hydroxylase (CYP7A1). That is the main quantitative drain on cholesterol besides shedding in skin and bile as free sterol.

Adipose hormone-sensitive lipase (HSL) and adipose triglyceride lipase mobilize stored TG when PKA is active (glucagon, epinephrine). Insulin opposes via phosphatase and via PDE3B-mediated cAMP destruction. Free fatty acids travel on albumin; glycerol goes to liver gluconeogenesis.

/practice/nbce-part1Practice questions with detailed explanations