Cholesterol metabolism and excretion, bile acid biosynthesis and its regulation .

Introduction

Cholesterol is a vital lipid molecule essential for membrane structure, precursor biosynthesis (e.g., steroid hormones, vitamin D), and bile acid formation. It is synthesized by most cells, especially in the liver, and its homeostasis is tightly regulated. Cholesterol is either synthesized de novo, obtained from the diet, or recycled. One major catabolic pathway of cholesterol is its conversion to bile acids, which are essential for lipid digestion and cholesterol elimination.

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Structure and properties of cholesterol

• Steroid nucleus (four fused hydrocarbon rings: A–D)
• Hydroxyl group at C3 (amphipathic character)
• 27 carbon atoms
• Hydrophobic, poorly soluble in water
• Transported in plasma as lipoprotein complexes

Source: Nelson DL, Cox MM. Lehninger Principles of Biochemistry. 8th ed. 2021.

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De novo cholesterol synthesis

Occurs mainly in the cytosol and smooth ER of hepatocytes, adrenal cortex, and intestinal mucosa. All carbons come from acetyl-CoA. The process consumes NADPH and ATP.

Further images can be found in the Harper’s Illustrated Biochemistry (Chapter 26 - Figures 26-2, 26-3)

Steps of cholesterol biosynthesis:

1. Synthesis of mevalonate

HMG-CoA reductase is the rate-limiting enzyme:

HMG-CoA + 2NADPH → Mevalonate + 2NADP+ + CoA

This step is irreversible and highly regulated.

2. Formation of isoprenoid units

Mevalonate is phosphorylated and decarboxylated to form isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) (C₅ units).

3. Synthesis of squalene (C₃₀)

Six isoprene units condense to form squalene via intermediate steps (e.g., geranyl and farnesyl pyrophosphate).

4. Cyclization and conversion to cholesterol

Squalene undergoes epoxidation and cyclization (via squalene monooxygenase and lanosterol synthase) to form lanosterol, which is then converted to cholesterol by several demethylation and reduction reactions.

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Regulation of cholesterol synthesis

1. HMG-CoA reductase

• Inhibited by cholesterol (feedback inhibition)
• Inhibited by phosphorylation (via AMPK in low-energy states)
• Activated by insulin
• Statins (e.g., simvastatin) are competitive inhibitors

2. SREBP pathway

Sterol regulatory element-binding proteins (SREBPs) control transcription of the HMG-CoA reductase gene.

• High cholesterol retains SREBP in the ER
• Low cholesterol allows SREBP activation → increased transcription

Source: Murray RK et al. Harper’s Illustrated Biochemistry. 31st ed. 2018.

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Cholesterol transport

• Liver is the central organ for distributing cholesterol
• Transported via lipoproteins:
  • Chylomicrons: dietary cholesterol from intestine to liver
  • VLDL/LDL: endogenous cholesterol from liver to tissues
  • HDL: reverse transport from tissues to liver

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Bile acid synthesis

Bile acids are amphipathic derivatives of cholesterol synthesized in the liver and secreted into the bile. Their primary function is to emulsify dietary fats and promote micelle formation for lipid absorption in the intestine.

Primary bile acids (in liver):

• Cholic acid
• Chenodeoxycholic acid

Hydroxylation occurs at C7 (first and rate-limiting step) via cholesterol 7α-hydroxylase (CYP7A1), a cytochrome P450 enzyme.

Secondary bile acids (by gut microbiota):

• Deoxycholic acid (from cholic acid)
• Lithocholic acid (from chenodeoxycholic acid)

Bile acids are conjugated with glycine or taurine to form bile salts → increased solubility.

Source: Murray RK et al. Harper’s Illustrated Biochemistry. 31st ed. 2018 (Figure 26-7)

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Enterohepatic circulation

• 95% of bile acids are reabsorbed in the terminal ileum
• Returned to the liver via the portal vein
• 5% lost in feces → major route of cholesterol excretion
• Liver synthesizes bile acids to replace this loss

Source: Devlin TM. Textbook of Biochemistry with Clinical Correlations. 7th ed. 2010.

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Clinical relevance

Hypercholesterolemia

• Primary (genetic): Familial hypercholesterolemia (LDL receptor mutations)
• Secondary: Due to diet, diabetes, hypothyroidism
• Associated with atherosclerosis, coronary artery disease

Treatment:

• Statins: HMG-CoA reductase inhibitors
• Ezetimibe: inhibits intestinal cholesterol absorption
• PCSK9 inhibitors: prevent LDL receptor degradation
• Bile acid sequestrants (e.g., cholestyramine): bind bile acids in intestine → increase bile acid synthesis → lower plasma cholesterol

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Gallstones (cholelithiasis)

Formed when cholesterol precipitates from bile due to:

• Excess cholesterol
• Decreased bile salts or phospholipids
• Gallbladder stasis

Risk factors: Female, Fat, Fertile, Forty, Family history

Treatment: Ursodeoxycholic acid (UDCA), surgery if symptomatic

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Bile acid malabsorption

Occurs in:

• Ileal resection (Crohn disease)
• Small intestinal bacterial overgrowth

→ Leads to steatorrhea, fat-soluble vitamin deficiency, and diarrhea

→ Treated with bile acid binders or fat-restricted diet

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Summary

Cholesterol is essential for cell structure and function, but its overaccumulation is harmful. Its synthesis is a multistep, energy-intensive process tightly regulated by feedback and hormonal signals. Bile acids, the major route of cholesterol catabolism, play key roles in digestion and are efficiently recycled via enterohepatic circulation. Dysregulation of cholesterol and bile acid metabolism is implicated in common conditions such as atherosclerosis, gallstones, and hypercholesterolemia.