Cholesterol Metabolism and Structure

Study Notes

Cholesterol is a vital animal steroid, maintaining membrane fluidity and insulating nerve fibers.
It's the precursor for bile acids/salts, steroid hormones, and vitamin D₃.
The liver plays a central role in cholesterol homeostasis.
Dietary cholesterol, chylomicron remnants, and de novo synthesis in the liver contribute to the liver cholesterol pool.
Cholesterol is secreted in bile and converted to bile acids/salts, before it leaves the liver.

Cholesterol has a four-ring structure (steroid nucleus) with a hydrocarbon tail.
It's often esterified with a fatty acid to form cholesteryl esters (CEs).
CEs are not found in cell membranes, but are present in small amounts within cells.
CEs are more hydrophobic than cholesterol.

Cholesterol is synthesized in all tissues, the major sites being liver, adrenal cortex, testes, ovaries, and the intestines.
All carbon atoms originate from acetyl CoA.
Enzymes involved in biosynthesis are both in the endoplasmic reticulum (ER) and the cytoplasm.

HMG CoA is found in both the cytosol and mitochondria of the liver.
It has a role in both mitochondrial ketogenesis and cytosolic cholesterol synthesis.

Subsequent phosphorylation crucial for keeping metabolites dissolved.
The steps create isopentenyl pyrophosphate (IPP), farnesyl pyrophosphate (FPP), geranyl pyrophosphate (GPP), and 3,3-dimethylallyl pyrophosphate (DPP) intermediate compounds.
These compounds play a crucial role in the final creation of squalene and lanosterol, intermediates prior to cholesterol formation.
After squalene, multiple steps lead to the formation of lanosterol, and finally to cholesterol.

HMG CoA reductase is the rate-limiting enzyme in cholesterol synthesis.
Its regulation involves sterol-dependent gene expression control.
- When cholesterol levels are high, transcription is reduced.
- The opposite occurs when cholesterol levels are low - stimulating enzyme production.
- Sterol Regulatory Element-binding protein (SREBP) binds to the Sterol Response Element (SRE) in the DNA to facilitate transcription of genes involving this process. SREBP cleavage-activating protein (SCAP) is an intracellular cholesterol sensor.
Sterol-independent regulation via phosphorylation/dephosphorylation.
- AMP-activated protein kinase (AMPK) is the key enzyme involved in phosphorylation events. High AMP levels signify low energy levels in the cell, and trigger decreased cholesterol synthesis.
Hormonal regulation also plays a role: insulin and thyroxine upregulate enzyme expression, while glucagon and cortisol affect it in the other way.
Statins actively inhibit HMG CoA reductase, thus decreasing cholesterol levels.

Cholesterol is excreted from the body via conversion into bile acids/salts and elimination in feces.
It's secreted in bile and transported to the intestine.
Some cholesterol is converted to coprostanol and cholestanol by intestinal bacteria before excretion.

Elevated cholesterol in the blood causes atherosclerosis.
Statins are structural analogs of HMG CoA reductase.
Statins reduce cholesterol levels by competitively inhibiting HMG CoA reductase.

Cholesterol is oxidized to form various bile acids, conjugated by glycine, taurine, and glucuronic acid in the liver.
A mix of conjugated and non-conjugated bile acids, plus cholesterol, is released into bile.
Almost 95% of bile acids are reabsorbed in the intestine and the remainder is lost in the feces.
Bile salt deficiency causes cholelithiasis, the precipitation of cholesterol in the gallbladder leading to gallstones.