Untitled Notes

Define the structure and function of cholesterol.
Identify the key regulatory enzyme in cholesterol synthesis and explain how this enzyme is regulated by insulin and glucagon.
List the fates of cholesterol and the roles cholesterol plays in cells.
Describe the role of bile acids.
Describe the role of steroid hormones and how they bind nuclear receptors to modulate gene expression.
Explain how dietary lipids are transported via chylomicrons.
Describe the role of lipoproteins and define the classes of lipoproteins: chylomicron, LDL, HDL, and VLDL.
Explain the cause of cardiovascular disease in terms of cholesterol and plaque formation.
Describe how arterial plaques form from cholesterol.

Cholesterol is a molecule with a polar hydroxyl (HO) head group and a hydrophobic alkyl side chain, featuring a steroid nucleus.

Cholesterol is derived from Acetyl-CoA.
Synthesis is completed in four stages:
1. Formation of Mevalonate: Three acetyl-CoAs condense to form HMG-CoA, which is then reduced to form mevalonate.
2. Activation of Isoprene Units: Mevalonate is converted into activated isoprene units.
3. Formation of Squalene: Six isoprenes polymerize to form linear squalene.
4. Cyclization to Cholesterol: Squalene cyclizes to form cholesterol, characterized by four fused carbon rings.

The formation of mevalonate is the rate-limiting step in cholesterol synthesis.
- HMG-CoA reductase is the key regulatory enzyme and is regulated as follows:
  1. Covalent Modification: Dephosphorylation of HMG-CoA reductase activates it.
  2. Protein Degradation: An increase in cholesterol levels leads to proteolytic degradation of HMG-CoA reductase.
  3. Transcriptional Regulation: The regulation of the gene for HMG-CoA reductase and the LDL receptor gene involves transcriptional changes.
Hormonal Regulation:
- Glucagon triggers phosphorylation, which inhibits HMG-CoA reductase.
- Insulin promotes dephosphorylation, thus activating HMG-CoA reductase.
Statins are pharmaceutical drugs that inhibit HMG-CoA reductase to decrease cholesterol levels.

Small fraction is incorporated into the membranes of liver cells.
Most cholesterol is exported in one of three forms:
1. Bile Acids: Serve as emulsifiers and are principal components of bile.
2. Steroid Hormones: Cholesterol serves as the precursor for steroid hormone synthesis.
3. Cholesteryl Esters: Formed by attaching a fatty acid to the hydroxyl group of cholesterol.
A small fraction of cholesterol is converted into oxysterols, which are regulators of cholesterol synthesis.
In other tissues, cholesterol can be converted to Vitamin D.

Bile acids are hydrophilic derivatives of cholesterol stored in the gallbladder and excreted into the small intestine to aid in digestion.

Five major classes of steroid hormones include:
1. Progesterone (Progestagen): Prepares the uterus for implantation and supports pregnancy.
Steroid hormones bind to specific intracellular receptor proteins that modulate gene expression through nuclear receptors.

Lipids are not water-soluble and must be packaged into water-soluble complexes called lipoproteins for transport through the body.
Apolipoproteins: Specific carrier proteins that facilitate lipid transport.
Plasma Lipoproteins: Composed of apolipoproteins, phospholipids, cholesterol, cholesteryl esters, and triacylglycerols.

Four major classes of human plasma lipoproteins differ in density and composition:

Lipoprotein	Density (g/mL)	Protein (%)	Free Cholesterol (%)	Cholesteryl Esters (%)	Triacylglycerols (%)
Chylomicrons	<1.006	2	1	3	85
VLDL	0.95–1.006	10	7	12	50
LDL	1.006–1.063	23	8	37	10
HDL	1.063–1.210	55	2	15	4

Transport Mechanisms

Chylomicrons carry dietary fats (triacylglycerols) to peripheral tissues from the intestine.
VLDL transports triacylglycerols to adipose and muscle tissues. Upon removal of triacylglycerols, LDL is formed, delivering cholesterol to tissues.
HDL is the most protein-dense lipoprotein and assists in reverse cholesterol transport by picking up excess cholesterol and returning it to the liver.

Excess LDL can be phagocytosed by macrophages in blood vessels, turning into foam cells and leading to plaque formation, a significant risk factor for cardiovascular disease (CVD).
The formation of cholesterol-rich arterial plaques occurs through:
1. Attraction of monocytes to oxidized lipoproteins, which aggregate in the extracellular matrix (ECM).
2. Monocytes differentiate into macrophages, forming foam cells.
3. Foam cells release cholesterol and lead to apoptosis, necrosis, tissue damage, and atherosclerosis, increasing the risk of myocardial infarction and stroke.

A genetic disorder resulting from a defective LDL receptor, causing impaired receptor-mediated uptake of LDL and the accumulation of cholesterol in foam cells, contributing to atherosclerotic plaques. Homozygous individuals can experience severe cardiovascular disease from a young age.

High levels of LDL-cholesterol correlate with atherosclerosis, while low levels of HDL-cholesterol are associated with heart disease.
Saturated fats can negatively impact cholesterol levels, increasing heart disease risk. Replacing saturated fats with unsaturated ones like canola, soybean, and olive oil can lower this risk.

Non-Drug Treatments: Lifestyle changes such as diet and exercise.
Drug Treatments:
- Statins: Lower cholesterol levels by inhibiting HMG-CoA reductase.
- PCSK9 Inhibitors: Increase LDL receptor levels, promoting LDL recycling, which decreases plasma LDL levels.

Statins act as competitive inhibitors of HMG-CoA reductase to reduce cholesterol synthesis.

PCSK9 promotes degradation of LDL receptors; inhibition of PCSK9 (e.g., Repatha) facilitates LDL receptor recycling and decreases plasma LDL cholesterol levels.
Clinical studies show that adding a PCSK9 inhibitor to statin therapy significantly reduces the occurrence of cardiovascular events compared to statin monotherapy.