Lecture Cholesterol Flashcards
What are the sources of cholesterol?
Diet: animal sources
✓De novo synthesis
✓Sites of De novo synthesis of cholesterol
- Primarily in the liver.
- Brain
- Intestine
- Reproductive tissues, including • Ovaries,
- Testes,
- Placenta
- Adrenal cortex
Give a comprehensive overview of cholesterol synthesis
✓Cytosolic acetyl CoA (which is formed by citrate lyase from citrate) is used.
✓HMG CoA is synthesized using 3 acetyl CoAs in cytosol.
✓Mevalonate is formed in the regulated step catalyzed by HMG CoA
reductase.
✓Mevalonate-PP is decarboxylated to isopentenyl-PP (IPP): the 5 “C” building block.
✓The 5-carbon building block is used to form geranyl-PP (10 C) and then farnesyl-PP (15 C).
✓Two farnesyl-PP are linked to each other to form squalene (30 C). ✓The first sterol formed is lanosterol (30 C).
✓After many steps cholesterol (27 C) is formed.
Note: The synthesis of cholesterol uses many molecules of NADPH especially after formation of lanosterol.
What are the intermediates of cholesterol synthesis pathway?
Intermediates of Cholesterol Synthesis Pathway:
Important Biological Functions
- Geranyl-groups are used to anchor proteins in the cell membrane.
- Farnesyl-groups are needed in specific proteins.
- Farnesyl-PP (FPP) branches out for the synthesis of: a. CoQ of the ETC (FPP and many IPPs are used).
b. Dolichol-PP needed for N-glycosylation of proteins
What is Smith-Lemeli-Optiz Syndrome (SLOS)?
SLOS caused by a deficiency of 7-Dehydrocholesterol reductase
• 7-Dehydrocholesterol reductase is responsible for the final step in the production of cholesterol
• For the correct double bond formation in ring B.
• Loss-of-function mutations in DHCR7 gene results in decreased
7-dehydrocholesterol reductase.
What is SLOS/7-dehydrocholesterol reductase deficiency?
Autosomal recessive disorder (incidence 1 in
20/40,000). High infant mortality rate.
- Heart defects, malformation of limbs, growth retardation, microcephaly (small head) with associated mental disability & ambiguous genitalia in males.
- Cholesterol administration helps with growth but not CNS defects due to embryonic microcephaly.
Summarize the 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.
Describe the synthesie of the bile acids, cholic acids and chenodeoxycholic acid, from cholesterol
- 1st step catalysed by cholesterol 7α- hydroxylase (P450 )
- Requires NADPH & O2
- Rate limiting step
- Activated by high cytosolic cholesterol
- Inhibited by high cholic acid
- Products are cholic acid or chenodeoxycholic acid – primary bile acids
Describe the conjugated bile salts
Conjugated with – glycine or taurine.
• Glyco or Tauro bile acid.
- glycocholic acid and glycochenodeoxycholic acid
- taurocholic acid and taurochenodeoxycholic acid
- Changes pKa of bile acid.
- Only in hepatocytes.
- Usually present as Na+ or K+ salts – bile salts
- Bile salts like glycocholic acid or taurochenodeoxycholic acid are much more effective at solubilizing lipids than bile acids.
What is the clinical sognoficabce of bile acid synthesis?
• Bile, synthesized in the liver, enters the duodenum through the common bile duct or is stored in the gall bladder
• Bile acids/salts perform four physiologically significant functions:
1. Their synthesis and subsequent excretion in the feces represent the only significant mechanism for the elimination of excess cholesterol.
- Bile acids and phospholipids solubilize cholesterol in the bile, thereby preventing the precipitation of cholesterol in the gallbladder.
- They facilitate the digestion of dietary triacylglycerols by acting as emulsifying agents that render fats accessible to pancreatic lipases.
- They facilitate the intestinal absorption of fat-soluble vitamins.
What is cholelithiais?
- Precipitation of cholesterol (in bile) in the gall bladder due to deficiency of lecithin and/or bile salts.
- Cholelithiasis & Biliary Disease
- Diagnosis is by CT scanning or ultra-sound radiography
- Cholestatic disease i.e. biliary obstruction of either the small bile ducts or the larger extrabiliary ducts.
- Bile flow blockage leads to lipid malabsorption with steatorrhea (foul-smelling diarrhoea).
- Jaundice caused by hyperbilirubinaemia. Bile acids also escape into systemic circulation.
What are the potential causes of cholelithiasis?
Potential causes:
• Decreased bile production (hepatic dysfunction)
• Increased secretion of cholesterol into bile
• Malabsorption of bile acids from the intestine • Obstruction of the biliary tract
• Interruption of the enterohepatic circulation
• Accelerated rate of bile recycling (excessive suppression of bile synthesis)
What is the treatment of cholelithiasis?
Treatment:
• Surgical removal of gall bladder (Laparoscopic cholecystectomy)
• Administration of chenodeoxycholic acid (chenodiol)
• Disintegration of stones by shock waves
• Contact dissolution with methyl-tert-butyl ether
Summarize the regulation of cholesterol synthesis
The Rate of de novo biosynthesis of cholesterol is related to the amount of dietary cholesterol:
– high intake, low
de novo synthesis:
– low intake, high
de novo synthesis
