Q2-CB16/Cholesterol Flashcards
What are the 3 important lipid components of the biological membrane?
phospholipids, spingolipids, and cholesterol
which of the lipid components of the biological membrane is the least solube?
cholesterol
cholesterol is more ______ than other membrane lipids
rigid
cholesterol inserts itself between __________
fatty acid chains
cholesterol inserts itself between fatty acid chains to prevent their ___________
crystallization
cholesterol is synthesised from acetyl CoA in ______ stages
three
What is the structure of cholesterol?
condensed 4 ring structure
How many atoms does cholesterol have?
27 carbon atoms
What are the 3 stages of cholesterol synthesis?
- synthesis of isopentenyl pyrophosphate
- condensation of 6 mols of isopentenyl pyrophosphate to form squalene
- squalene cyclizes and the tetracyclic product is turned into cholesterol
What reaction does HMG CoA reductase help in?
it turns acetoacetyl CoA + acetyl CoA into mevalonate
How is mevalonate converted to isopentenyl pyrophosphate?
it is converted in 3 consecutive reactions that require ATP
squalene is made from ______ mols of isopentenyl pyrophosphate
6
What is the reaction sequence from isopentenyl pyrophosphate to squalene?
Explain how squalene cyclizes for form cholesterol.
squalene is first oxidized to squalene 2,3-epoxide.
squalene 2,3-epoxide cyclizes to form lanosterol.
a few 1,2-methyl groups and hydrides (H-) on the lanosterol shift along the molecule to turn into 4 rings which finally turns the lanosterol into cholesterol
What are normal cholesterol levels in adult humans?
140g cholesterol, 3.7 - 5.2 mmol/L
where are the major sites of cholesterol synthesis?
liver, intestine, reproductive tissues, adrenal gland
What regulates cholesterol biosynthesis?
negative feedback mechanism controlled mostly by changes in the amt and activity of HMG CoA reductase (3-hydroxy-3-methylglutaryl CoA reductase)
What is HMG CoA reductase inhibited by?
statins
What are the 4 ways to control HMG CoA reductase?
rate of synthesis of reductase mRNA, rate of translation of reductase mRNA, degradation of the reductase, and phosphorylation
explain how the rate of synthesis of reductase mRNA controls HMG CoA reductase
the process of making reductase mRNA is controlled by the sterol regulatory element binding proteins (SREBP). When cholesterol levels are low this transcription factor starts transcription of HMG CoA reductase.
What is the rate of translation of reductase mRNA inhibited by?
it is inhibited by nonsterol metabolites derived from mevalonate and dietary cholesterol
Why would reductase mRNA become degraded?
in response to increasing levels of cholesterol, the enzyme can undergo proteolysis
What does phosphorylation do to the activity of reductase?
it decreases the activity of reductase in response to low levels of ATP
cholesterol and triacylglycerols are transported in the form of ___________
lipoprotein particles
What are VLDLs?
cholesterol in excess of the liver’s own needs are exported to the blood in the form of Very Low Density Lipoproteins (VLDLs)
What are the precursors of LDLs?
VLDLs
What is the role of LDLs?
- they carry cholesterol esters, primarily linoleate
- they carry this cholesterol to peripheral tissues
- they regulate de novo cholestrol synthesis at these sites
Explain the role of HDLs? (high density lipoproteins)
HDL picks up extra cholesterol that has been released into the plasma after a cell has died
the acyltransferase in HDL esterifies the cholesterol
once the cholesterol has been esterified, it is shuttled back to LDLs or returned to the liver
What do statins do?
inhibition of de novo synthesis of cholesterol in the liver, HMG CoA inhibitors
What do cholestyramine/colestipol do?
they sequester bile acids in the intestine, reduces the absorption of exogenous cholesterol and inc. the metabolism of endogenous cholesterol into bile acids
What do fibrates do?
the change the relative levels of diff. lipoproteins
What do PCSK9 inhibitors do?
PCSK9 is ubiquitously expressed across tissues.
Blocking PCSK9 enhances the number of LDL receptors on target tissue and also lowers circulating LDLs.
What are some derivates of cholesterol?
humans can/cannot metabolism cholesterol to CO2 + H2O
cannot
Since we cant metabolise cholesterol, how do we eliminate it from the body?
by secreting cholesterol into the bile and converting it into bile acids and bile salts. this is then excreted in the feces
What is bile?
watery mixture of organic and inorganic compounds including bile salts and lecithin
After bile is made by the liver where does it go?
it is either excreted via the common bile duct or stored in the gall bladder
What is the chemical structure of bile acids?
24 Carbons, 2-3OH, and a COOH group
What is the PKa of the COOH group on a bile acid?
around 6, therefore it is not fully ionized at physiologic pH
Bile acids are _____ molecules
amphipathic
Why is the fact that bile acids are amphipathic molecules a good thing?
since they have a hydrophilic or hydrophobic face, they can act as emulsifying agents in the intestine (bile acids help to break down dietary triglycerides)
cholesterol is turned into 7-alpha-hydroxycholesterol via ___________
7-alpha-hydroxylase
how are bile salts produced?
they are produced in the liver by conjugating bile acids with either glycine or taurine
bile salts are _____ at physiologic pH
fully ionised, negative charge
bile salts are more effective ________
detergents
bile salts are exposed to ____________ of the intestine
bacterial flora
what can happen after bile salts are exposed to bacterial flora of the intestine?
the regeneration of bile acids by removal of glysine or taurine
OR
production of secondary bile salts by removed of an OH group
What is cholesterol gall-stone disease caused by?
not enough bile salts being secreted to handle the amt of cholesterol being secreted.
What are some causes of cholesterol gall-stone disease?
What is the result of cholesterol gall-stone disease?
cholesterol precipitatees in the gall bladder
What is the operation that removes gall bladder stones called?
cholecystectomy
Cholesterol is the precursor of the 5 major classes of steroid hormones. what are they?
progestagens, glucocorticoids, mineralocorticoids, androgens, estrogens
What is progesterone?
- a progestagen
- prepares uterine lining for ovum implantation
- essential for the maintenance of pregnancy
What are androgens?
- ex. testosterone
- responsible for development of male secondary sex characteristics
What are estrogens?
- responsible for development of female secondary sex characteristics
- participates in ovarian cycle (like progesterone)
What are Glucocorticoids?
- promotes gluconeogenesis and breakdown of glycogen
- enhance breakdown of fats and proteins
- inhibits inflammatory response
What are mineralocorticoids?
- ex. aldosterone
- acts on distal tubules of kidney to inc. reabsorption of sodium and excretion of potassium and hydrogen
What is the precursor of vitamin D?
cholesterol
Explain the role of 7-dehydrocholesterol in vitamin d3 production.
7-dehydrocholesterol is photolysed by UV light from the sun to pre-vitamin D3, which spontaneously isomerizes to Vitamin D3
What is another name for vitamin d3?
cholecalciferol
Hydroxylation rxns in the liver and kidneys turns vitamin D3 to ________
calcitriol
What does vitamin d bind onto on proteins?
intracellular receptors (similar to steroid receptors)
Vitamin D selectively stimulates ___________
gene transcription
Vitamin D regulates plasma levels of _____ and _______
calcium and phosphorus
What is rickets?
Vitamin D deficiency in kids, characterized by inadequate calcification of cartilage and bone
When does a vitamin D deficiency occur?
deficiency occurs when 7-hydrocholesterol in the skin is not photolysed to pre-vitamin D3 and dietary intake of vitamin D is low
What is osteomalacia?
a vitamin D deficiency in adults that leads to the softening and weakening of bones
recommended daily intake of vitamin D?
400 international units
