Cholesterol DO Flashcards
Describe the structure of cholesterol
Most common steroid in animal cells.
- Very Hydrophobic
- Contains 4 ring sterol nucleus.
- In blood, found as cholesterol esters in lipoproteins.
- Plants synthesize a range of sterols – not cholesterol.
- Plant sterols are not generally absorbed by mammalian G-I tract
- Block cholesterol absorption (pharmaceutical application).
Describe the influx and efflux of cholesterol in the liver
Yes, we need a certain amount of cholesterol for normal cellular Function
Cholesterol metabolism is an intricate balance –
biosynthesis/transport/utilisation.
The liver plays a central role in cholesterol homeostasis
What are the functions of cholesterol?
• Precursor for vitamin D
• Component of cell membrane – fluidity
• Cholesterol is used for bile acid synthesis only in the liver
• Cholesterol synthesis is needed in the brain due to the blood-brain barrier.
• Precursor for steroid hormones
• in the adrenal cortex (cortisol, aldosterone,
androgens)
• in ovaries (estrogen and progesterone) • in testes (testosterone)
What are the sites of De novo synthesis of cholesterol?
- Occurs primarily in the liver. • Brain
- Intestine
- Reproductive tissues, including • ovaries,
- testes,
- placenta
- Adrenal cortex
Give an overview of synthesis of cholesterol
- Just like fatty acid synthesis, synthesis of cholesterol requires cytosolic acetyl CoA, NADPH and ATP
- Rate Limiting Enzyme(RLE) is HMG CoA reductase
• Occurs in the cytoplasm with enzymes in cytosol and Endoplasmic reticulum (ER).
• Cholesterol levels are carefully regulated:
– too much plasma cholesterol can lead to atherosclerosis
– too much cholesterol secretion causes formation of gall stones
What are sources of NADPH for cholesterol synthesis?
The NADPH required to provide reducing equivalents for cholesterol biosynthesis is produce by:
1. Pentosephosphatepathway
• Major pathway.
- Malic enzyme
What are the steps of de novo for cholesterol?
Begins in the cytosol with acetyl-CoA acting as a source of
carbon units.
• Can be split into the following basic steps:
- SynthesisofHMG–CoA
- Synthesis of six-carbon mevalonate
- Formation of a five-carbon isopentenyl pyrophosphate
- Condensation of isoprenes to form squalene (C30).
- Cyclization of squalene to lanosterol followed by cholesterol (C27) formation.
Describe synthesis of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)
- Involves 3 molecules of acetyl-CoA.
- Thiolase catalyses the linkage of 2 acetyl-CoA molecules to produce acetoacetyl-CoA.
- HMG-CoA synthase catalyses the linkage of 3rd Acetyl-CoA.
- Resulting in production of HMG- CoA (a six-carbon compound.)
Describe the synthesis of mevalonate
- HMG CoA is reduced to mevalonate.
- Reaction is catalysed by HMG-CoA reductase, the RLE of cholesterol synthesis
- Requires 2 NADPH (reducing equivalent).
- Is the primary regulatory step of cholesterol biosynthesis
How is mevalonoate derived from cholesterol?
- Mevalonic acid is converted to 5- pyrophosphomevalonate, requiring two ATP molecules.
- Followed by decarboxylation to form a 5 carbon isopentenyl pyrophosphate (IPP), using one ATP.
- IPP is isomerized to 3,3-dimethylallyl pyrophosphate (DPP).
- IPP and DPP are linked to form geranyl pyrophosphate (GPP)
- a second IPP is added to form farnesyl pyrophosphate (FPP)
- two FPPs are linked to form squalene (30 carbons). In the process, pyrophosphate is released. NADPH serves as reducing equivalent.
7.Squalene is cyclized with NADPH and O2 to form lanosterol
• Close rings – initial cyclical molecule
• without pyrophosphate, this compound and the downstream
intermediates to cholesterol are so hydrophobic, they require carrier proteins to keep them solubl
- Lanosterol (30C) is converted to cholesterol (27C) by a series of reactions performed in the ER by many enzymes
– Lanosterol converted to cholesterol via several steps
– Requires NADPH and the removal of 3 carbon atoms
– Finally, a 27 carbon compound (cholesterol) formed.
Describe degradation of cholesterol
The ring structure of cholesterol cannot be metabolized to CO2 and H2O in humans.
• Cholesterol metabolized by:
- Conversion to bile acids – secreted in bile and released in feces
• Total fecal excretion of bile salts balances hepatic synthesis. This is a major catabolic path in cholesterol metabolism. - Reduction by intestinal microorganisms to coprostanol & cholestanol which are found in feces.
What are the action of intestinal flora of bile salts?
• Intestinal bacteria can remove taurine or glycine from bile salts
• Other intestinal bacteria convert primary bile acids into
secondary bile acids by removing hydroxyl groups
• deoxycholic acid and lithocholic acid from cholic acid and chenodeoxycholic acid, respectively
Describe the enterohepatic circulation of bile salts
- Continous secretion of bile salts into bile (stored in gall bladder)
- Passage into duodenum, uptake in the illeum and return to the liver.
• 95% of bile acids reabsorbed via
enterohepatic circulation • 5% excreted
- Primary bile acids (cholic & chenocholic) metabolized by intestinal bacteria producing secondary bile acids.
- Involves deconjugation and dehydroxylation.
- Secondary bile acids - reabsorbed by the liver, reconjugated but not rehydroxylated – also become component of bile.
