Cholesterol Biosynthesis, Regulation, and Pathogenesis of Atherosclerosis

Cholesterol Structure and Biosynthesis Overview

Cholesterol is an essential $C_{27}$ sterol ($C_{27}H_{46}O$) containing a cyclopentanoperhydrophenanthrene (steroid) nucleus ($17\,\text{carbon}$ backbone), two methyl groups ($C_{18}$ and $C_{19}$), a hydroxyl ($-\text{OH}$) group at $C_3$, and an $8\text{-carbon}$ hydrocarbon side chain at $C_{17}$ ($C_{20}\text{--}C_{27}$).

• Daily Synthesis Rate: Adults synthesize approximately $1\,\text{g/day}$.

• Major Tissues: Liver ($50\%$), intestine ($15\%$), skin, adrenal cortex, and reproductive tissues.

• Cellular Location: Cytosol and smooth endoplasmic reticulum.

• Stoichiometry per $1\,\text{mole}$ Cholesterol: Requires $18\,\text{moles}$ acetyl CoA, $36\,\text{moles}$ ATP, and $16\,\text{moles}$ NADPH.

Stages of Cholesterol Biosynthesis

1. Condensation to Mevalonate (Cytosol):

   • $\text{2 Acetyl CoA} \rightarrow \text{Acetoacetyl-CoA } (4C)$

   • $\text{Acetoacetyl-CoA} + \text{Acetyl CoA} \xrightarrow{\text{HMG-CoA Synthase}} \text{HMG-CoA } (6C)$

   • $\text{HMG-CoA} + 2\text{NADPH} + 2\text{H}^+ \xrightarrow{\text{HMG-CoA Reductase}} \text{Mevalonate } (6C) + \text{CoA-SH} + 2\text{NADP}^+$

   • HMG-CoA Reductase is the primary rate-limiting enzyme.

2. Formation of Activated Isoprenoid Units (Cytosol):

   • Mevalonate undergoes phosphorylation and decarboxylation requiring $3\,\text{ATP}$ to form $5C$ isoprenoid units.

3. Polymerization to Squalene (Endoplasmic Reticulum):

   • $5C \text{ Isoprenoid} \rightarrow 10C \text{ Geranyl pyrophosphate} \rightarrow 15C \text{ Farnesyl pyrophosphate}$

   • $2 \times 15C \text{ Farnesyl pyrophosphate} \xrightarrow{\text{Squalene synthase, NADPH}} 30C \text{ Squalene}$

4. Cyclization to Lanosterol (Endoplasmic Reticulum):

   • $30C \text{ Squalene} \xrightarrow{\text{Cyclase}} 30C \text{ Lanosterol}$

5. Conversion of Lanosterol to Cholesterol (Endoplasmic Reticulum):

   • $30C \text{ Lanosterol} \rightarrow 27C \text{ Cholesterol}$ (involves removing $3\,\text{methyl groups}$, reducing the double bond at $C_{24}\text{--}C_{25}$, and shifting the double bond from $C_8$ to $C_5$).

Regulation of De Novo Cholesterol Synthesis

• Transcriptional Regulation (SREBP-2 / SCAP):

  • Low Cholesterol: SCAP transports SREBP-2 from ER to Golgi $\rightarrow$ cleaved by S1P and S2P enzymes $ ightarrow$ active transcription factor translocates to nucleus $ ightarrow$ binds Sterol Regulatory Element (SRE) $ ightarrow$ activates HMG-CoA reductase gene.

  • High Cholesterol: SREBP-2 is retained in ER bound to SCAP and Insig, turning off transcription.

• Proteasomal Degradation: High sterols promote ubiquitination and proteasomal breakdown of HMG-CoA reductase.

• Covalent Modification & Hormonal Control:

  • Active Form: Dephosphorylated (promoted by Insulin and Thyroxine).

  • Inactive Form: Phosphorylated (promoted by Glucagon and Glucocorticoids via cAMP).

• Pharmacological Inhibition: Statins (Atorvastatin, Fluvastatin, Lovastatin, Pravastatin, Rosuvastatin, Simvastatin) are structural analogues of HMG-CoA that act as reversible competitive inhibitors.

Pathogenesis of Atherosclerosis

Atherosclerosis is a chronic inflammatory disorder of arteries featuring intimal fibrofatty plaques (atheromas).

1. Endothelial Dysfunction & Injury: Triggered by hypertension, smoking, hyperlipidemia, or homocysteine, causing increased vascular permeability.

2. Lipid Accumulation & Foam Cells: LDL enters the intima and undergoes oxidation. Recruited monocytes differentiate into macrophages, engulf oxidized LDL, and become lipid-laden foam cells (forming fatty streaks).

3. Smooth Muscle Proliferation & Fibrous Cap: Smooth muscle cells migrate to the intima and produce extracellular matrix (collagen), creating a fibrous cap over the necrotic lipid core.

4. Plaque Rupture & Thrombosis: Erosion or rupture of the fibrous cap exposes thrombogenic contents, triggering platelet aggregation, thrombus formation, and vessel occlusion.

Lipoproteins & Cardiovascular Disease

• Low-Density Lipoprotein (LDL): "Bad cholesterol"; delivers cholesterol to peripheral tissues. Oxidized LDL promotes foam cell creation and plaque progression.

• High-Density Lipoprotein (HDL): "Good cholesterol"; conducts reverse cholesterol transport to the liver.

  • Anti-atherogenic Actions:

  • Inhibits LDL oxidation.

  • Prevents monocyte adhesion to endothelium.

  • Prolongs half-life of endothelial prostacyclin ($\text{PGI}_2$), encouraging vasodilation.

Inflammatory Biomarkers & Risk Factors

• High Sensitivity C-Reactive Protein (hsCRP):

  • $< 1\,\text{mg/L}$: Low risk

  • $1\text{--}3\,\text{mg/L}$: Borderline risk

  • $> 3\,\text{mg/L}$: High risk for future myocardial infarction (MI)

  • $> 10\,\text{mg/L}$: Acute phase reaction (non-cardiac origin)

• Homocysteine: Inhibits collagen cross-linking, forms reactive homocysteine thiolactone, and thiolates LDL to drive macrophage endocytosis.

• Lipoprotein(a) [Lp(a)]: Contains Apo(a) linked to ApoB-100; structurally resembles plasminogen and enhances thrombosis risk.

• Cigarette Smoking: Nicotine increases lipolysis $\rightarrow$ elevates Acetyl CoA $ ightarrow$ increases cholesterol synthesis; enhances LDL oxidation; lowers HDL; raises CRP; induces transient arterial constriction.

Ischemia vs Infarction Comparison