Lipid metabolism

Digestion and transport of dietary fat

• Bile salts emulsify fat; pancreatic lipase forms fatty acids and monoglycerides, which enter enterocytes in micelles. Without pancreatic secretion, fat is not digested, no chylomicrons form and steatorrhoea results.
• Enterocytes re-form triglyceride in the smooth endoplasmic reticulum, add apo B-48 and package chylomicrons in the Golgi. Chylomicrons are too large for capillaries, so they enter lacteals and travel through the lymphatics and thoracic duct to the blood.
• The liver similarly makes triglyceride in the SER and exports it as VLDL with apo B-100.

Fatty acid synthesis and the malonyl-CoA switch

• Occurs in the cytoplasm of liver, adipose tissue and lactating breast in the fed state. Acetyl-CoA leaves mitochondria as citrate.
• Acetyl-CoA carboxylase (rate-limiting, biotin-dependent) forms malonyl-CoA; it is activated by insulin and citrate and inhibited by glucagon and AMP kinase. Fatty acid synthase uses NADPH (from the pentose phosphate pathway) to build palmitate (C16).
• Malonyl-CoA inhibits carnitine palmitoyltransferase I (CPT-I), so newly made fatty acids cannot enter mitochondria to be oxidised: synthesis and breakdown cannot run together.
• Essential fatty acids: linoleic (omega-6) and alpha-linolenic (omega-3). Arachidonic acid is made from linoleic acid.

Beta-oxidation

• Fatty acids are activated to acyl-CoA and carried into mitochondria by carnitine via CPT-I (rate-limiting). Each cycle removes two carbons as acetyl-CoA plus one NADH and one FADH2; palmitate yields about 106 ATP.
• Odd-chain fatty acids give propionyl-CoA, converted to succinyl-CoA using biotin and vitamin B12.
• Very long-chain fatty acids (C22 and longer) are first shortened in peroxisomes. X-linked adrenoleukodystrophy (ABCD1 transporter defect) lets VLCFAs accumulate in white matter and adrenal cortex: a boy with declining behaviour and school work, then visual and gait loss, with Addison disease (pigmentation, low cortisol). Check VLCFAs in any boy with unexplained adrenal failure. Zellweger syndrome is a global peroxisome defect.
• MCAD deficiency and carnitine deficiency cause fasting hypoketotic hypoglycaemia.

Ketone bodies

• In fasting or insulin deficiency (low insulin, high glucagon), lipolysis floods the liver with fatty acids. Beta-oxidation produces more acetyl-CoA than the citric acid cycle can use (oxaloacetate is diverted to gluconeogenesis), so liver mitochondria convert it to ketones via HMG-CoA synthase.
• Ketones are acetoacetate, beta-hydroxybutyrate (the main ketone in DKA; not detected by nitroprusside strips) and acetone (fruity breath). In DKA the H⁺ they release is buffered first by bicarbonate, causing a high anion gap acidosis with Kussmaul breathing.
• Brain (after a few days of fasting), heart, muscle and kidney use ketones. The liver cannot use them (no thiophorase, succinyl-CoA:acetoacetate CoA transferase), and red cells cannot (no mitochondria).

Cholesterol and statins

• Made from acetyl-CoA, mainly in the liver; rate-limiting enzyme HMG-CoA reductase, activated by insulin and inhibited by cholesterol and glucagon. Products: bile acids (7-alpha-hydroxylase), steroid hormones, vitamin D, membranes.
• How statins lower LDL: inhibiting hepatic HMG-CoA reductase lowers liver cell cholesterol, which activates SREBP; hepatocytes then make more LDL receptors and clear more LDL from plasma. Homozygous familial hypercholesterolaemia with no working receptors therefore responds poorly.
• Saturated and trans fats raise LDL most (they suppress LDL receptor activity); mono- and polyunsaturated fats lower it.

Lipoproteins

• Lipoprotein lipase on capillary endothelium (activated by apo C-II and insulin) hydrolyses TG in chylomicrons and VLDL. Hormone-sensitive lipase in fat cells is activated by adrenaline and glucagon (cAMP) and inhibited by insulin.
• Lipoprotein(a): apo(a) closely resembles plasminogen, so it competes with plasminogen, impairs fibrinolysis and adds a thrombotic risk, while its LDL part enters the arterial wall. High Lp(a) can cause premature MI with normal LDL.

Inherited lipid disorders

Sphingolipidoses

Metabolic syndrome

• Central obesity (high waist), triglycerides 150 mg/dL (1.7 mmol/L) or above, low HDL (below 40 mg/dL, 1.0 mmol/L, in men), BP 130/85 or above and fasting glucose 100 mg/dL (5.6 mmol/L) or above. The common underlying defect is insulin resistance.

Eicosanoids and phospholipids

• Phospholipase A2 frees arachidonic acid from membrane phospholipids (blocked by corticosteroids). Cyclo-oxygenase makes prostaglandins and thromboxane; lipoxygenase makes leukotrienes.
• Aspirin irreversibly acetylates cyclo-oxygenase-1 in platelets, which cannot make new enzyme, so thromboxane A2 falls for the platelet's life. Prostaglandins protect the gastric mucosa, hence NSAID ulcers.
• Phospholipids are amphipathic (hydrophilic head, hydrophobic tails), forming the bilayer of membranes. Dipalmitoyl phosphatidylcholine is the main surfactant lipid; a lecithin:sphingomyelin ratio above 2 shows lung maturity.

Lipid-lowering drugs

Remember Malonyl-CoA blocks CPT-I, so fat is never made and burned at once; the liver makes ketones but cannot use them.

Exam trap Statins work mainly by increasing hepatic LDL receptors, not by blocking cholesterol absorption.

Exam trap Niemann–Pick and Tay–Sachs both give cherry-red spots; hepatosplenomegaly means Niemann–Pick.

How FCPS asks about this

• Dietary fat carried from the gut: chylomicrons through the lymphatics.
• Acanthocytes, retinitis pigmentosa, no apo B lipoproteins: abetalipoproteinaemia.
• Molecule preventing oxidation of new fatty acids: malonyl-CoA blocking CPT-I.
• Why Lp(a) is atherogenic and prothrombotic: apo(a) mimics plasminogen.
• Burning pain, angiokeratomas, renal failure: Fabry disease, alpha-galactosidase A.
• Boy with behavioural decline, Addison disease and high VLCFAs: X-linked adrenoleukodystrophy.
• Obesity, high TG, low HDL, high BP and glucose: insulin resistance (metabolic syndrome).