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Lipid Metabolism – Vocabulary Flashcards

Lipoprotein Metabolism

• Two parallel systems move dietary vs. endogenously-made lipids.

Exogenous (Dietary) Pathway

• Source = intestinal chylomicrons (CM).
• Apolipoproteins: Apo B-48 (structural), Apo C-II (activates lipoprotein lipase, LPL), Apo E (remnant receptor ligand).
• Sequence
– CM enter blood via lymph, acquire Apo C-II & Apo E from high-density lipoproteins (HDL).
– Endothelial LPL (requires Ca^{2+}, activated by Apo C-II) hydrolyses core triacylglycerol (TAG):
( ext{TAG} + 3 H_2O \xrightarrow{\text{LPL}} 3 \text{FA} + \text{Glycerol})
– Fatty acids enter muscle (ATP production) or adipose (re-esterified & stored).
– Glycerol returns to liver (glycerol kinase → glycerol-3-P).
– CM remnants, now cholesterol-rich, bind hepatic Apo E–receptors and are endocytosed.

Endogenous (Hepatic) Pathway

• Very-low-density lipoprotein (VLDL) assembled in liver.
• Apolipoproteins: Apo B-100 (structural), Apo C-II, Apo E.
• Plasma LPL removes TAG → intermediate-density lipoprotein (IDL).
• Fates of IDL
– ~50 % taken up by liver (Apo E receptor).
– Remainder loses Apo E & more TAG via hepatic lipase → low-density lipoprotein (LDL).
• LDL is cholesterol-rich (≈ 45 % cholesteryl ester) and delivers cholesterol to extra-hepatic tissues via LDL-receptor–mediated endocytosis that recognises Apo B-100.
– ~50 % of circulating LDL returns to liver for degradation.

Reverse Cholesterol Transport (HDL)

• HDL nascent particles secreted by intestine & liver (Apo A-I, phospholipid, little cholesterol).
• Plasma enzyme LCAT (lecithin–cholesterol acyl-transferase) esterifies peripheral cholesterol:
\text{Lecithin} + \text{Cholesterol} \xrightarrow{\text{LCAT}} \text{Lysolecithin} + \text{Cholesteryl Ester}
• Mature HDL delivers esterified cholesterol to liver directly or by swapping with VLDL/LDL via CETP.

• Clinical links: Familial hypercholesterolaemia (defective LDLR); Apo E 2 homozygosity (type III hyperlipoproteinaemia); statins up-regulate LDLR expression.

Triglyceride (TAG) Biosynthesis

• Occurs mainly in liver, adipose, lactating mammary, intestinal mucosa.
• Precursors: glycerol-3-phosphate (G-3-P) + 3 acyl-CoA.
– In liver: glycerol → G-3-P via glycerol kinase.
– In adipose: dihydroxyacetone phosphate (DHAP) + NADH → G-3-P via G-3-P dehydrogenase (requires glycolysis, explains insulin dependence).
• Reaction sequence (Kennedy pathway)

  1. \text{G-3-P} + \text{Acyl-CoA}_1 \rightarrow \text{Lysophosphatidic Acid} + \text{CoA-SH} (acyl-transferase 1)
  2. + Acyl-CoA$_2$ → phosphatidic acid (diacyl-glycerol-P).
  3. Phosphatidic acid phosphatase removes P_i → diacylglycerol (DAG).
  4. + Acyl-CoA$3$ → TAG. \text{DAG} + \text{Acyl-CoA}3 \rightarrow \text{TAG} + \text{CoA-SH}

• Net stoichiometry :
\text{G-3-P} + 3 \text{Acyl-CoA} \rightarrow \text{TAG} + 3 \text{CoA-SH}

Triglyceride Degradation (Lipolysis)

• Adipose TAG → free fatty acids (FFA) + glycerol; hormonally controlled.
• Key enzymes
– Adipose triglyceride lipase (ATGL) – TAG → DAG.
– Hormone-sensitive lipase (HSL) – DAG → MAG.
– Monoacylglycerol lipase – MAG → glycerol + FA.
• Regulation
– Catecholamines, glucagon → \uparrow cAMP → protein kinase A (PKA) → phosphorylation → ATGL & HSL active → lipolysis; perilipin also phosphorylated to expose lipid droplet.
– Insulin → activates phosphodiesterase (cAMP → AMP) + protein phosphatase → dephosphorylation → lipases inactive, storage favoured.
• Released FFA circulate bound to serum albumin; glycerol to liver for gluconeogenesis.

Fatty-Acid (FA) β-Oxidation

Activation & Mitochondrial Entry

• Cytosolic acyl-CoA synthetase (thiokinase):
\text{FA} + \text{ATP} + \text{CoA-SH} \rightarrow \text{Acyl-CoA} + AMP + PPi (PP$i$ hydrolysis makes step irreversible.)
• Long-chain acyl-CoA must use carnitine shuttle:

  1. CPT-I (outer membrane) forms acyl-carnitine, releasing CoA.
  2. Acyl-carnitine translocase exchanges carnitine ↔ acyl-carnitine across inner membrane.
  3. CPT-II (matrix) regenerates acyl-CoA + free carnitine (returns to cytosol).
    • Malonyl-CoA (FA synthesis intermediate) inhibits CPT-I → prevents futile cycle.

Spiral of β-Oxidation (each turn shortens chain by 2 C)

  1. Dehydrogenation: acyl-CoA dehydrogenase + FAD → trans-Δ$^2$-enoyl-CoA + \text{FADH}_2.
  2. Hydration: enoyl-CoA hydratase → L-β-hydroxy-acyl-CoA.
  3. Dehydrogenation: β-hydroxy-acyl-CoA dehydrogenase + NAD$^+$ → β-keto-acyl-CoA + \text{NADH}.
  4. Thiolysis: β-ketothiolase + CoA-SH → acyl-CoA (−2 C) + acetyl-CoA.

Energy Yield Example – Palmitate (C_{16})

• 7 cycles → 8 acetyl-CoA, 7 NADH, 7 FADH$2$. • ATP equivalents (P/O ratios \approx 2.5 per NADH, 1.5 per FADH$2$, 10 per acetyl-CoA via CAC):
8 \times 10 + 7 \times 2.5 + 7 \times 1.5 = 80 + 17.5 + 10.5 = 108 \text{~ATP}
• −2 ATP for activation → net 106\,\text{ATP}.
• Unsaturated & odd-chain FAs give slightly less because they bypass first dehydrogenation or require extra reactions (propionyl-CoA → succinyl-CoA requires \text{B}_{12}, biotin, ATP, yields +5\,\text{ATP} per propionyl unit).

Transport of Mitochondrial Acetyl-CoA to Cytosol

• Acetyl-CoA cannot cross inner membrane; exported as citrate.
• Steps

  1. \text{Acetyl-CoA} + \text{Oxaloacetate} \xrightarrow{\text{Citrate Synthase}} \text{Citrate} (matrix).
  2. Citrate antiporter moves citrate → cytosol.
  3. ATP-citrate lyase (cytosol):
    \text{Citrate} + \text{ATP} + \text{CoA-SH} \rightarrow \text{Acetyl-CoA} + \text{Oxaloacetate} + \text{ADP} + P_i.
  4. Oxaloacetate → malate (cytosolic malate DH) ± malic enzyme (malate → pyruvate + \text{NADPH}). Generated NADPH supports FA synthesis.

Fatty-Acid Biosynthesis (De Novo)

Committed Step

• Acetyl-CoA carboxylase (ACC):
\text{Acetyl-CoA} + CO2 + ATP \xrightarrow{\text{Biotin}} \text{Malonyl-CoA} + ADP + Pi.
• Regulation
– Allosteric activation : citrate (signals abundant acetyl-CoA/ATP).
– Allosteric inhibition : long-chain acyl-CoA (feedback).
– Covalent: insulin favours dephosphorylated (active) ACC; glucagon/epinephrine activate AMPK/PKA → phosphorylated (inactive) ACC.

Fatty-Acid Synthase (FAS) Complex

• Dimeric, multifunctional; each monomer has acyl-carrier protein (ACP, phosphopantetheine -SH) + cysteine -SH.
• Cycle

  1. Loading: acetyl group on cysteine, malonyl on ACP.
  2. Condensation → β-ketoacyl-ACP + CO_2 (drives reaction).
  3. Reduction (NADPH), dehydration, second reduction (NADPH) → saturated acyl-ACP (length +2 C).
  4. Transfer acyl to cysteine; repeat with new malonyl-ACP until 16 C (palmitoyl-ACP); then thioesterase releases palmitate.
    • Overall:
    \text{Palmitate} + 14 \text{NADPH} + 14 H^+ + 7 ATP \leftarrow 8 \text{Acetyl-CoA} + 14 \text{NADP}^+ + 7 ADP + 7 Pi + 6 H2O
    • Further elongation/desaturation occurs in ER (humans cannot insert double bonds beyond \Delta^9 → linoleate & linolenate are essential).

Ketone-Body Metabolism

Hepatic Synthesis (Ketogenesis)

• Occurs in liver mitochondrial matrix when \uparrow\,\text{β-oxidation} and \downarrow\,\text{CAC intermediates} (fasting, uncontrolled diabetes, high-fat diet).
• Steps

  1. 2 Acetyl-CoA → acetoacetyl-CoA (thiolase).
  2. + Acetyl-CoA → \beta-hydroxy-\beta-methylglutaryl-CoA (HMG-CoA synthase). Rate-limiting.
  3. HMG-CoA lyase → acetoacetate + acetyl-CoA.
  4. Acetoacetate ↔ \beta-hydroxybutyrate (BHB) (BHB DH, NADH-dependent); spontaneous decarboxylation → acetone (exhaled).

Extra-Hepatic Utilisation (Ketolysis)

• BHB → acetoacetate (NAD$^+$).
• Acetoacetate + succinyl-CoA → acetoacetyl-CoA + succinate (β-ketoacyl-CoA transferase; absent in liver, prevents futile cycle).
• Thiolase: acetoacetyl-CoA → 2 acetyl-CoA → CAC → energy.
• ATP yield per BHB ≈ \text{(1 NADH)}\times2.5 + 2 \times10 - 1\,\text{GTP} \approx 21.5 (text often simplified to 24–26 ATP).
• Clinical: excessive production → ketoacidosis (blood pH ↓↓) → dehydration, coma.

Cholesterol Biosynthesis

Stage 1 – Mevalonate Formation (Rate-Limiting)

• 3 Acetyl-CoA → HMG-CoA (thiolase + HMG-CoA synthase).
• HMG-CoA reductase (ER membrane, needs 2 NADPH) → mevalonate.
\text{HMG-CoA} + 2 \text{NADPH} + 2 H^+ \rightarrow \text{Mevalonate} + 2 \text{NADP}^+ + \text{CoA-SH}
• Regulation
– Sterol-sensing (SREBP-2) ↓ transcription when cholesterol high.
– AMPK phosphorylation inactivates; insulin dephosphorylates/activates; glucagon opposite.
– Statin drugs are competitive inhibitors.

Stage 2 – Activated Isoprenes

• Mevalonate + 3 ATP → isopentenyl-pyrophosphate (IPP, 5 C).
• Isomerisation: IPP ↔ dimethylallyl-PP (DMAPP).

Stage 3 – Squalene (30 C)

• IPP + DMAPP → geranyl-PP (10 C) → farnesyl-PP (15 C).
• 2 Farnesyl-PP + NADPH → squalene (30 C) + 2 PP$_i$.

Stage 4 – Cyclisation

• Squalene mono-oxygenase (NADPH, O$_2$) → squalene-2,3-epoxide.
• Oxidosqualene cyclase → lanosterol → 19 further reactions (ER) → cholesterol (27 C, 4 rings).

Fates & Transport

• Exported as VLDL, converted to bile acids, steroid hormones, vitamin D, or esterified by ACAT for storage.
• Excretion pathway is bile acid synthesis; no route for degradation of ring system.

Integrated Regulation & Clinical Connections

• Insulin (fed state):
– Activates ACC & FAS (↑ malonyl-CoA, FA synthesis).
– Stimulates LPL on adipose capillaries → TAG storage.
– Inhibits HSL → ↓ lipolysis.
• Glucagon/Epinephrine (fast/starved):
– Activate PKA/AMPK → ACC off (↓ FA synthesis), HSL on (↑ lipolysis), HMG-CoA R off.
– Malonyl-CoA ↓ → CPT-I active → β-oxidation.
• CPT-I deficiency or carnitine deficiency → hypoketotic hypoglycaemia, muscle weakness.
• MCAD deficiency → impaired β-oxidation of 6–12 C FA; episodes of hypoglycaemia & sudden infant death.
• Statins, ezetimibe, PCSK9 antibodies target different points of cholesterol homeostasis.

Key Numbers, Equations & Facts (Quick Reference)

• Lipolysis yields: 1 TAG → 3 FA + glycerol.
• Palmitate β-oxidation net: 106\,\text{ATP}.
• Acetyl-CoA → malonyl-CoA (ACC) consumes 1\,\text{ATP}.
• FA synthesis: 14 NADPH + 7 ATP per palmitate.
• Ketone bodies supply up to 60 % of brain energy after ≥ 2 weeks fasting.
• LDL delivers ≈ 70 % of total plasma cholesterol; half cleared by liver LDLR.