Cholesterol Biosynthesis

Sections

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CHOLESTEROL

• Maintains membrane fluidity
• Precursor for bile acids and salts
• Sterol with a double bond between C5 and C6
• Obtained from diet or de novo synthesis

Sterol

Any steroid that has a side chain at C17 with 8-10 carbons and a hydroxyl group at C3.

DE NOVO CHOLESTEROL SYNTHESIS

• All tissues can synthesize cholesterol --- mostly from liver, intestines, adrenal cortex and reproductive tissues
• Cellular level: occurs in the cytosol

Reactions

1. HMG-CoA formation:
   Acetyl CoA + Acetoacetyl CoA + H2O --> HMG CoA + CoA

2. Committed step: HMG CoA reductase (rate-limiting enzyme)
   HMG CoA + 2NADPH --> Mevalonate + 2NADP+

3. Phosphorylation
   Mevalonate + 3ATP --> Isopentenyl pyrophosphate (IPP) + Pi + 3ADP + CO2

4. Condensation reactions
   IPP + 2IPP --> Farnesyl pyrophosphate (FPP) + 2PPi
   FPP + FPP + NADPH --> Squalene + 2PPi + NADP+

5. Cholesterol formation
   Squalene + O2 + NADPH --> Cholesterol + H2O + NADP+

CHOLESTEROL FUNCTION

1. Bile acids and salts: emulsify fats and facilitate digestion in small intestine

• Only mechanism for cholesterol excretion

2. Steroid hormones: homeostatic regulators in the body
3. Vitamin D: synthesized in skin upon light exposure

CHOLESTEROL CIRCULATION

Lipoproteins

Transport lipids in circulation; contain lipids, proteins, triacylglycerol, free and esterified cholesterol

• Chylomicron: only transport dietary lipids
• LDL (low density lipoprotein): carries most esterified cholesterol
• HDL (high density lipoprotein): carries 2nd most esterified cholesterol
• VLDL (very low density lipoprotein)
  Total fasting cholesterol = LDL +HDL + VLDL

CLINICAL CORRELATIONS

Statins (HMG CoA reductase inhibitors)

Cholesterol-lowering medications

FPP

Chemotherapeutic target that links Ras (small GTP-binding protein) to the membrane.

• Ras mutations ~ 1/3 human cancers

Atherosclerosis

Narrowing of blood vessels due to plaque formation

• Vessel walls become leaky and vulnerable: LDL's accumulate
• Vessels become more vulnerable with age, smoking, poor diet and lack of exercise

Full-Length Text

• Here we will learn how cholesterol is synthesized in the body.

• To begin, start a table and denote some key functions of cholesterol.
  • It plays a structural role in cell membranes and maintains their fluidity.
  • It is a precursor for bile acids and salts, steroid hormones, and vitamin D.

To start off, let's illustrate the Lewis structure of cholesterol.

• Draw a 6-carbon ring and number carbons 1 through 5.

• Fuse this ring to another 6-carbon ring, number it: 6 through 10.

• Then, a final 6-carbon ring, number it: 11 through 14.

• Finally, fuse it with a 5-carbon ring, number it: 14 through 17.

• Next, add methyl groups at C13 and C10.

• An hydroxyl group to C3.

• A 6-carbon-long hydrocarbon tail at C17.

• Add a methyl group (21) to the first carbon in this tail and one to the second to last carbon (26).

• Number the remaining carbons: 20 through 27.

• Indicate that this structure is a sterol, because a sterol is any steroid that has:
  • A side chain at C17 that has 8-10 carbons
  • A hydroxyl group at C3.

• Finally, add a double bond between C5 and C6.
  • Thus, cholesterol is a sterol with a double bond between C5 and C6.

Next, let's show the source of cholesterol, its de novo synthesis, and its function in the body.

• Indicate cholesterol comes from our diet, and is also produced de novo.

• All tissues can synthesize cholesterol, but most synthesis occurs in the liver, intestines, adrenal cortex and reproductive tissues.

Let's illustrate the de novo synthesis of cholesterol; we will focus on this process as it occurs in the liver and intestines.

• Show that we can divide these reactions into five parts.
  • HMG-CoA formation
  • The committed step
  • Phosphorylation
  • Condensation reactions
  • Cholesterol formation.

• All of these parts take place in the cytosol.

Let's start with part I.

• Show that acetyl CoA and acetoacetyl CoA combine to form HMG-CoA (a 6-carbon molecule) in a condensation reaction. Acetyl CoA derives from fatty acids and carbohydrates.

Now, for part two, the committed and regulated step.

• Show that it is catalyzed by HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis.

• Indicate that it decarboxylates 6-carbon HMG-CoA to form 6-carbon mevalonate.

• Show that this reaction consumes 2 NADPH. NADPH is the reducing power in this pathway, not NADH.
  • Both are derived from the vitamin niacin, but NADPH functions in synthetic pathways, and NADH in oxidative pathways.

• As a clinical correlation, write that HMG CoA reductase inhibitors (statins) are important cholesterol-lowering medications.

Now, for part 3: phosphorylation.

• Indicate that mevalonate is phosphorylated and decarboxylated to form 5-carbon isopentenyl pyrophosphate (IPP).

• Show that the multistep phosphorylation reaction requires 3 ATP.
  • Phosphorylation keeps the following intermediates in solution, otherwise they would be insoluble and require a carrier.

• Next, indicate that 5-carbon IPP polymerizes to form 15-carbon farnesyl pyrophosphate (FPP).
  • This conversion requires three separate reactions. We will not draw them here.

• Show that two pyrophosphates are released.

• As a clinical correlation, write that FPP is a chemotherapeutic target. It is not only an intermediate in cholesterol synthesis, but links a protein called Ras to the membrane.
  • Ras is a small GTP-binding protein involved in signaling pathways that regulate the cell cycle.
  • Ras mutations are involved in about a third of human cancers!

Now, let's return to the final step in part 3: two 15-carbon FPP's condense to form 30-carbon squalene.

• Show that this reaction requires one NADPH.

• Illustrate that 2 more pyrophosphates are released.
  • Thus, squalene and the intermediates that follow are not phosphorylated: they are hydrophobic and need an intracellular carrier.

Finally, part 4.

• Show that squalene converts to cholesterol.

• Indicate that this requires 1 NADPH, and that it reduces O2 to H2O.

• From here, show that cholesterol can be diverted into 3 routes:
  • Bile acids and salts, which emulsify fats and facilitate their digestion in the small intestine. This is also the only mechanism by which cholesterol can be excreted.
  • Steroid hormones, which are homeostatic regulators in the body.
  • Vitamin D, which is synthesized in the skin upon exposure to light.

• However, free cholesterol is hydrophobic and cannot travel in the blood plasma. It is packaged and circulates as a component of lipoproteins.

How is it packaged?

• Circle the hydroxyl group in our cholesterol molecule.

• Now, attach a fatty acid group to it.

• Label this process cholesterol esterification: it makes cholesterol more hydrophobic, and allows for more efficient packaging into lipoproteins.

What are lipoproteins?

• Draw a spherical structure and label it lipoprotein.

• Indicate that it contains lipids, proteins, triacylglycerols, and cholesterol in both free and esterified forms.

• Write that this lipoprotein transports cholesterol (along with other lipids) in the body.
  • There are four different classes of lipoproteins and we discuss them in detail elsewhere.

• Let's just list them for now:
  • Chylomicron
  • LDL (low density lipoprotein)
  • HDL (high density lipoprotein)
  • VLDL (very low density lipoprotein).

• Write that the total fasting plasma cholesterol in the body is equal to the total cholesterol in LDL's, HDL's and VLDL's.
  • Chylomicrons are not included because they only transport lipids in the fed state.

• Star LDL and HDL to indicate that they transport the most esterified cholesterol, with LDL's carrying the most.

• As a clinical correlation, denote that atherosclerosis is the narrowing of blood vessels due to plaque formation.
  • This process begins when vessel walls become leaky and vulnerable, allowing LDL's to accumulate there.
  • Vessels become more vulnerable to atherosclerosis with age, smoking, poor diet or lack of exercise.