Library Core Topics
Foundational Science Series

Core Topics: Lipid Metabolism

High-yield reference for fatty acid oxidation/synthesis, ketogenesis, cholesterol metabolism, lipoproteins, and eicosanoids — mapped to USMLE Step 1/2 CK foundational science objectives.

How to Use This Resource

Each pathway section includes: Core Concepts (location, net reaction), Key Enzymes (regulatory steps), and High-Yield Facts (clinical correlations, deficiencies). Use for active recall, spaced repetition, and integration with clinical cases.

Fatty Acid Oxidation (β-Oxidation)

Mitochondrial breakdown of fatty acids to acetyl-CoA for energy production

Location & Transport
  • Location: Mitochondrial matrix (long-chain FA); peroxisomes (VLCFA)
  • Carnitine Shuttle: Transports long-chain fatty acids across inner mitochondrial membrane
  • CPT-I: Outer membrane; converts acyl-CoA → acyl-carnitine; inhibited by malonyl-CoA
  • CPT-II: Inner membrane; converts acyl-carnitine → acyl-CoA
  • Regulation: Malonyl-CoA (from fatty acid synthesis) prevents simultaneous synthesis/oxidation
β-Oxidation Cycle (4 Repeating Steps)
1
Acyl-CoA Dehydrogenase
Oxidation → FADH₂ (MCAD, LCAD, VLCAD isoforms)
2
Enoyl-CoA Hydratase
Hydration → 3-hydroxyacyl-CoA
3
3-Hydroxyacyl-CoA Dehydrogenase
Oxidation → NADH + 3-ketoacyl-CoA
4
Thiolase
Thiolysis → acetyl-CoA + shortened acyl-CoA
Energy Yield & Special Cases
  • Palmitoyl-CoA (C16): 7 cycles → 8 acetyl-CoA + 7 FADH₂ + 7 NADH → ~108 ATP (after subtracting 2 ATP for activation)
  • Odd-chain FA: Final product = propionyl-CoA → methylmalonyl-CoA (B12-dependent) → succinyl-CoA → TCA cycle
  • Very Long Chain FA: Initial shortening in peroxisomes → medium-chain FA → mitochondria
  • Disorders: Carnitine deficiency (hypoketotic hypoglycemia); MCAD deficiency (most common; fasting intolerance); Zellweger (peroxisomal biogenesis)
High-Yield: β-Oxidation
Key Regulation
Malonyl-CoA inhibits CPT-I → prevents futile cycle of simultaneous FA synthesis/oxidation
MCAD Deficiency
Most common FA oxidation disorder; presents with hypoketotic hypoglycemia after fasting; dicarboxylic aciduria
Odd-Chain FA
Propionyl-CoA → methylmalonyl-CoA (requires vitamin B12) → succinyl-CoA; deficiency → methylmalonic acidemia
Clinical Pearl
Jamaican vomiting sickness: hypoglycin A (unripe ackee fruit) inhibits acyl-CoA dehydrogenase → hypoglycemia

Fatty Acid Synthesis

Cytoplasmic de novo synthesis of palmitate from acetyl-CoA

Location & Requirements
  • Location: Cytoplasm (primarily liver, adipose, lactating breast)
  • Substrates: Acetyl-CoA (from mitochondria), ATP, NADPH
  • Citrate Shuttle: Exports mitochondrial acetyl-CoA to cytoplasm as citrate → cleaved by ATP-citrate lyase
  • NADPH Sources: Pentose phosphate pathway (major), malic enzyme
  • End Product: Palmitate (C16:0); further elongation/desaturation in ER
Key Enzymes
Acetyl-CoA Carboxylase (ACC)
Rate-limiting; Acetyl-CoA + CO₂ + ATP → malonyl-CoA; requires biotin
Fatty Acid Synthase
Multi-enzyme complex; uses malonyl-CoA + NADPH → palmitate
Elongases/Desaturases
ER enzymes; add carbons or introduce double bonds (cannot make ω-3/ω-6)
Regulation
Activators
Insulin (fed state); Citrate (signals abundant acetyl-CoA); dephosphorylation activates ACC
Inhibitors
Glucagon/Epinephrine (fasting); Palmitoyl-CoA (end-product feedback); phosphorylation inactivates ACC
High-Yield: Fatty Acid Synthesis
Rate-Limiting Step
Acetyl-CoA carboxylase is the committed, regulated step; biotin-dependent carboxylation
Essential Fatty Acids
Humans cannot synthesize ω-3 (α-linolenic) or ω-6 (linoleic) acids → must obtain from diet
NADPH Source
Pentose phosphate pathway provides most NADPH for fatty acid synthesis; G6PD deficiency impairs lipogenesis
Clinical Correlation
Biotin deficiency (raw egg whites: avidin binds biotin) → impaired fatty acid synthesis → dermatitis, alopecia

Ketogenesis

Hepatic production of ketone bodies during fasting or uncontrolled diabetes

Location & Triggers
  • Location: Liver mitochondria (only organ that produces ketones)
  • Triggers: Fasting, starvation, prolonged exercise, uncontrolled diabetes (type 1)
  • Substrate: Acetyl-CoA from β-oxidation (exceeds TCA cycle capacity)
  • Ketone Bodies: Acetoacetate, β-hydroxybutyrate (major), acetone (minor, exhaled)
  • Liver Cannot Use Ketones: Lacks thiophorase (succinyl-CoA:acetoacetate CoA transferase)
Pathway Steps
1
Thiolase
2 acetyl-CoA → acetoacetyl-CoA
2
HMG-CoA Synthase
Acetoacetyl-CoA + acetyl-CoA → HMG-CoA (rate-limiting)
3
HMG-CoA Lyase
HMG-CoA → acetoacetate + acetyl-CoA
4
β-Hydroxybutyrate Dehydrogenase
Acetoacetate ↔ β-hydroxybutyrate (NAD⁺/NADH dependent)
Utilization & Clinical
  • Extrahepatic Use: Brain, heart, skeletal muscle convert ketones → acetyl-CoA → TCA cycle
  • Brain Adaptation: After 3-5 days fasting, ketones supply ~70% of brain energy needs
  • Diabetic Ketoacidosis: Uncontrolled type 1 DM → excessive ketogenesis → metabolic acidosis, fruity breath (acetone)
  • Diagnostic: Urine ketones (nitroprusside test detects acetoacetate, not β-hydroxybutyrate)
High-Yield: Ketogenesis
Rate-Limiting Enzyme
HMG-CoA synthase (mitochondrial) is rate-limiting for ketogenesis; distinct from cholesterol synthesis enzyme
Liver Paradox
Liver produces but cannot use ketones (lacks thiophorase) → exports to peripheral tissues
DKA Labs
High glucose, high anion gap metabolic acidosis, ↑ β-hydroxybutyrate, ↑ acetone (fruity breath), K⁺ shifts
Alcoholic Ketoacidosis
Chronic alcohol + starvation → ↑ NADH/NAD⁺ ratio → favors β-hydroxybutyrate → high anion gap acidosis with normal/low glucose

Cholesterol Metabolism

Synthesis, regulation, and elimination of cholesterol

Synthesis & Regulation
  • Location: Cytoplasm and ER (primarily liver, also intestine, adrenal, reproductive tissues)
  • Rate-Limiting Enzyme: HMG-CoA Reductase (converts HMG-CoA → mevalonate)
  • Regulation: Inhibited by statins, cholesterol (feedback), glucagon; activated by insulin, thyroxine
  • Uses of Cholesterol: Cell membrane fluidity, bile acid synthesis, steroid hormones, vitamin D
Bile Acid Synthesis
  • Rate-Limiting Enzyme: 7α-Hydroxylase (CYP7A1)
  • Primary Bile Acids: Cholic acid, chenodeoxycholic acid (synthesized in liver)
  • Secondary Bile Acids: Deoxycholic acid, lithocholic acid (formed by gut bacteria)
  • Enterohepatic Circulation: 95% of bile acids reabsorbed in ileum → returned to liver via portal vein
  • Elimination: Fecal excretion of bile acids is major route of cholesterol elimination
Clinical Correlations
  • Statins: Competitive inhibitors of HMG-CoA reductase → ↓ cholesterol synthesis → ↑ LDL receptor expression
  • Bile Acid Sequestrants: Cholestyramine, colestipol bind bile acids in gut → ↑ fecal excretion → ↑ hepatic cholesterol use for bile acid synthesis
  • Cerebrotendinous Xanthomatosis: Deficiency of 27-hydroxylase → impaired bile acid synthesis → cholesterol deposition in tendons, CNS
  • Smith-Lemli-Opitz Syndrome: Defect in cholesterol synthesis (7-dehydrocholesterol reductase) → multiple congenital anomalies
High-Yield: Cholesterol Metabolism
Rate-Limiting Enzymes
Cholesterol synthesis: HMG-CoA reductase; Bile acid synthesis: 7α-hydroxylase
Statin Mechanism
Inhibit HMG-CoA reductase → ↓ hepatic cholesterol → ↑ LDL receptor expression → ↓ serum LDL
Bile Acid Recycling
Enterohepatic circulation: Ileal reabsorption via ASBT transporter; disrupted in Crohn disease → bile acid diarrhea
Vitamin D Synthesis
7-dehydrocholesterol (skin) → UV light → cholecalciferol (D₃) → liver/kidney hydroxylation → active 1,25-(OH)₂D

Lipoproteins

Transport vehicles for hydrophobic lipids in aqueous plasma

Structure & Classes
  • Structure: Hydrophobic core (cholesterol esters, triglycerides); hydrophilic surface (phospholipids, free cholesterol, apolipoproteins)
  • Classification by Density: Chylomicrons (least dense) → VLDL → IDL → LDL → HDL (most dense)
  • Size vs. Density: Larger particles = more triglyceride = less dense
ClassOriginMajor LipidApoFunction
ChylomicronsIntestineDietary TGB-48, C-II, EDeliver dietary TG to tissues
VLDLLiverEndogenous TGB-100, C-II, EDeliver hepatic TG to tissues
IDLVLDL catabolismTG/CE mixB-100, EIntermediate; liver uptake or LDL conversion
LDLIDL conversionCholesterolB-100Deliver cholesterol to peripheral tissues
HDLLiver/intestineProtein/PLA-I, A-IIReverse cholesterol transport to liver
Key Apolipoproteins & Enzymes
ApoB-48
Chylomicrons only (intestine); truncated form of B-100
ApoB-100
VLDL, IDL, LDL (liver); ligand for LDL receptor
ApoC-II
Activates lipoprotein lipase (LPL) on capillary endothelium
ApoE
Mediates remnant (chylomicron/IDL) uptake by liver via LDL receptor-related protein
ApoA-I
Major HDL protein; activates LCAT for cholesterol esterification
Key Enzymes & Disorders
  • Lipoprotein Lipase (LPL): Hydrolyzes TG in chylomicrons/VLDL → releases FA to tissues; activated by ApoC-II, insulin
  • Hepatic Lipase: Converts IDL → LDL; remodels HDL
  • LCAT: Esterifies cholesterol on HDL (ApoA-I activated) → mature HDL
  • CETP: Transfers cholesterol esters from HDL → VLDL/LDL in exchange for TG
  • Disorders: Familial hypercholesterolemia (LDL receptor defect); Familial hypertriglyceridemia (↑ VLDL); Abetalipoproteinemia (no ApoB); Tangier disease (ABCA1 defect → no HDL)
High-Yield: Lipoproteins
ApoB Mnemonic
"B-48 from Intestine (48 states); B-100 from Liver (100%)"
LPL Deficiency
Type I hyperlipoproteinemia: ↑ chylomicrons, ↑ TG, pancreatitis, eruptive xanthomas; ApoC-II deficiency has same phenotype
LDL Receptor
Binds ApoB-100/ApoE; defective in familial hypercholesterolemia (autosomal dominant) → ↑ LDL, tendon xanthomas, premature CAD
HDL Function
Reverse cholesterol transport: HDL collects cholesterol from peripheral tissues → liver for excretion; "good cholesterol"

Eicosanoids

Local hormones derived from arachidonic acid with diverse physiological roles

Cyclooxygenase (COX) Pathway

  • Arachidonic acid → PGG₂ → PGH₂ (via COX-1/COX-2)
  • COX-1: Constitutive; gastric protection, platelet function, renal blood flow
  • COX-2: Inducible; inflammation, pain, fever
  • Products: Prostaglandins (PGE₂, PGD₂), prostacyclin (PGI₂), thromboxane A₂ (TXA₂)
  • Drugs: Aspirin (irreversible COX inhibition), NSAIDs (reversible)

Lipoxygenase Pathway

  • Arachidonic acid → 5-HPETE → LTA₄ (via 5-lipoxygenase)
  • LTB₄: Potent neutrophil chemotactic factor
  • LTC₄, LTD₄, LTE₄: "Cysteinyl leukotrienes" → bronchoconstriction, ↑ vascular permeability
  • Drugs: Zileuton (5-LOX inhibitor); Montelukast/Zafirlukast (CysLT₁ receptor antagonists)

Cytochrome P450 Pathway

  • Arachidonic acid → EETs (epoxyeicosatrienoic acids), HETEs (hydroxyeicosatetraenoic acids)
  • EETs: Vasodilation, anti-inflammatory, cardioprotective
  • 20-HETE: Vasoconstriction, renal sodium handling
  • Less clinically targeted than COX/LOX pathways
Key Functions & Balance
EicosanoidPrimary EffectsClinical Relevance
PGE₂Vasodilation, pain, fever, gastric protectionNSAIDs block → ↓ pain/fever but ↑ ulcer risk
PGI₂ (prostacyclin)Vasodilation, inhibits platelet aggregationEndothelial-derived; counteracts TXA₂
TXA₂Vasoconstriction, promotes platelet aggregationPlatelet-derived; aspirin blocks → antithrombotic
LTB₄Neutrophil chemotaxis, activationInflammatory response; target in asthma/COPD
LTC₄/D₄/E₄Bronchoconstriction, ↑ vascular permeabilityAsthma pathogenesis; leukotriene antagonists treat
Drug Targets
  • Aspirin: Irreversibly acetylates COX-1 (platelets) and COX-2; low dose preferentially inhibits platelet TXA₂ → antithrombotic
  • NSAIDs (ibuprofen, naproxen): Reversible COX inhibition; anti-inflammatory, analgesic, antipyretic
  • Celecoxib: Selective COX-2 inhibitor; ↓ GI toxicity but ↑ cardiovascular risk (imbalance PGI₂/TXA₂)
  • Leukotriene Modifiers: Zileuton (5-LOX inhibitor); Montelukast/Zafirlukast (CysLT₁ antagonists) for asthma prophylaxis
  • Zafirlukast Warning: Rare Churg-Strauss syndrome (eosinophilic vasculitis) when steroids are tapered
High-Yield: Eicosanoids
COX Inhibition
Aspirin: Irreversible (acetylation); NSAIDs: Reversible; Acetaminophen: Weak peripheral COX inhibition, central antipyretic
PGI₂ vs TXA₂
PGI₂ (endothelium): Vasodilation, antiplatelet; TXA₂ (platelets): Vasoconstriction, proplatelet; aspirin shifts balance toward PGI₂
Leukotrienes in Asthma
Cysteinyl leukotrienes (LTC₄/D₄/E₄) cause bronchoconstriction; montelukast blocks receptor → asthma prophylaxis
Arachidonic Acid Release
Phospholipase A₂ releases arachidonic acid from membrane phospholipids; inhibited by corticosteroids (via annexin-1/lipocortin)
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Evidence & Further Reading