Cholesterol

Definition: Cholesterol is a sterol molecule that is hydrophobic in nature.
Location:
- Found in cell membranes and lipid droplets.
- It is a ubiquitous component of animal tissues.
Dietary Sources: Obtained mainly from animal products or synthesized de novo (newly).
Storage: Stored as cholesterol esters in the body.

Total Body Content: In an average adult, the total body cholesterol content is approximately 30-40 grams.
Cholesterol Distribution:
- The majority is free cholesterol, predominantly found in cell membranes.
- About 25% of the body's free cholesterol is located in the brain.
Cholesterol Input:
- New cholesterol input into the body is about 0.7 – 1.5 grams per day.
- 10 – 20% (0.1-0.3 grams/day) is sourced from the diet.
- 80 – 90% is derived from endogenous synthesis (internally generated).
Sites of Synthesis:
- De novo synthesis occurs in all nucleated cells.
- There is a notably high rate of synthesis in:
- Liver
- Small intestine
- Testes
- Ovaries
- Adrenal cortex
- Skin
- Fetal brain

Initial substrates include components such as 6 H₂O, 12 COA, 12 NADPH, and 6 HMG-CoA.
Key Steps:
- Conversion of acetyl-CoA through various intermediates ultimately leads to the formation of cholesterol.
- Notably requires 18 molecules of acetyl-CoA and 18 ATP,
- The synthesis is regulated at several points, particularly the conversion of HMG-CoA to mevalonate by the enzyme HMGCR (Hydroxymethylglutaryl-CoA reductase).
- Key regulatory step of cholesterol synthesis is 6HMG-CoA → 6 Mevalonate through HMGCR

Sterol Regulation:
- High cellular levels of sterols result in the binding of INSIG protein to the sterol-sensing domain, which leads to ubiquitination and degradation of HMGCR enzyme.
  - Will bind when there is high levels of cholesterol in the cell
- Conversely, low sterol levels decrease INSIG association, leading to decreased degradation of HMGCR.
SREBP2 (Sterol Regulatory Element Binding Protein 2):
- Acts as a transcriptional activator for the HMGCR gene.
- When INSIG binds to SREBP2, it leads to decreased synthesis of HMGCR.
- Low levels of INSIG release SREBP2, resulting in increased synthesis of HMGCR.

HMGCR activity is subject to covalent modification:
- Active when it’s not phosphorylated
  - Regulated by hormones such as glucagon and epinephrine via the cAMP pathway.
  - Increased AMP/ATP ratios trigger the activity of AMP-activated protein kinase (AMPK), which can decrease the levels of active HMGCR (HMG-CoA reductase).
Hormonal Control:
- Insulin stimulates phosphatase (PPI-1), promoting the active form of HMGCR over its inactive phosphorylated form, thus enhancing cholesterol synthesis.

HMGCR is targeted by statins

CM: Synthesized by SI, carry dietary lipids, TAG, dietary lipids (DL), and cholesterol ester (CE), apo B-48
VLDL: Synthesized by liver, contain endogenous lipids (lipids synthesized by liver), CE (dietary and synthesized by liver)
- Converted to IDL, and then LDL, which mostly contains CE and is responsible for transporting cholesterol to peripheral tissues. High levels of LDL are associated with an increased risk of cardiovascular diseases.
- HDL: Synthesized by SI and liver. Synthesized as empty carrier and picks up cholesterol while in circulation. Returns excess C and CE back to liver.
Apolipoprotein A-I (ApoA-I):

Secreted by hepatocytes (liver cells) and intestinal cells.
Interacts with ABCA1 to form lipid-poor pre-β-HDL particles.
Gradual transformation to α-HDL particles occurs through further lipidation and action of enzyme LCAT (lecithin-cholesterol acyltransferase).

Role of CETP (Cholesteryl Ester Transfer Protein):
- Mediates the exchange of triacylglycerol (TAG) from LDL (low-density lipoprotein) for cholesterol esters from HDL (high-density lipoprotein).
Lipid Uptake by the Liver:
- Liver uptake of cholesterol is facilitated by scavenger receptors, leading to formation of smaller, denser HDL.

Most mammalian cells express LDL receptors (LDLR), with an increased presence in adrenal glands.
Cholesterol Regulation:
- Cellular cholesterol levels regulate the expression of LDL receptors; high cholesterol levels decrease LDLR synthesis to reduce further cholesterol uptake into the cells.
- The liver can remove 50-70% of LDL from the circulation, thereby contributing to overall cholesterol homeostasis.

Each pass through the intestine results in a 2% to 5% loss of the total bile acid pool, equating to a cholesterol equivalent loss of approximately 0.2 to 0.6 grams per day; this is an important route for cholesterol excretion.

Early stages of atheroma formation include:
- Vascular insult leading to an inflammatory response and immune cell infiltration.
- Macrophages ingest modified LDL particles, transforming into foam cells, which contribute to fatty streaks.
Fatty streaks can progress to atherosclerotic plaques, causing narrowing of blood vessels that can compromise blood flow. These plaques pose a risk of rupture, leading to blood clot formation that can further block blood flow.