Cholesterol biosynthesis, transport, and genetics 1 Flashcards by Andrea Luzaic

Cholesterol is required as a precursor for the biosynthesis what?

Vit D
Steroids
Bile salts(acids)

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What is cholesterol necessary for?

membrane stability

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What is a major structural component of myelin sheaths?

cholesterol

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What synthesizes the myelin sheath in the CNS?

oligodendrocytes

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What synthesizes the myelin sheath in the PNS?

Schwann cells

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What types of cells are the oligodendrocytes and Schwann cells?

glial cells

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Where is the myelin sheath located?

surrounds axons in vertebrates

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What is the function of the myelin sheath?

myelination increases the speed of action potentials down an axon (broken into segments)

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Are action potentials multi-directional or unidirectional?

unidirectional (cannot go back)

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What are the non-myelinated parts of the axon between the myelin sheath segments?

Nodes of Ranvier

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What acts as an insulator on axons?

myelin sheath

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Is the myelin sheath continuous or broken up?

broken into segments

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Why is an action potential unidirectional?

When Na+ channels close, they cannot depolarize until they are reactivated.

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What is the major component of myelin sheath?

CHOLESTEROL

30%

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What is the basic structure of steroids?

four hydrocarbon rings

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Is the major portion of cholesterol hydro(philic/phobic)

hydrophobic

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What is the function of cholesterol’s hydrophobic portion?

imbed in lipid bilayer

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What are the major synthesizing organs of cholesterol?

liver (70-80%)
small intestine (10%)
(also adrenal glands and gonads)

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Cholesterol is either synthesizes from _____ sources or _______.

dietary

de novo

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Function of cholesterol in cell membranes?

membrane fluidity
intracellular transport
cell signaling
nerve conduction

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What is a desirable total cholesterol?

under 200

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What is the most desirable LDL?

under 100

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Which cholesterol is considered “bad cholesterol”?

LDL

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Why is LDL considered “bad cholesterol”?

can lead to formation of plaques in vascular system

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What is a desirable and undesirable HDL?

over 60 = good | under 40 = bad

What is the first stage of Do Novo biosynthesis of cholesterol?

synthesis of ISOPENTENYL PYROPHOSPHATE

What is the second stage of Do Novo biosynthesis of cholesterol?

condensation of 6 molecules of isopentenyl pyrophosphate to form SQUALENE

What is the third stage of Do Novo biosynthesis of cholesterol?

cyclization of squalene to form Lanosterol which is converted to CHOLESTEROL

What does stage 1 of De Novo begin with?

condensation of acetyl-CoA to acetoacetyl-CoA

Where does the condensation of acetyl-CoA and acetoacetyl-CoA take place?

cytoplasm

What does the condensation of acetyl-CoA to acetoacetyl-CoA form?

3-hydroxy-3-methylglutaryl CoA (HMG-CoA)

3-hydroxy-3-methylglutaryl CoA (HMG-CoA) is reduced to form what?

mevalonate

What reduces 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) to mevalonate?

enzyme HMG-CoA reductase

What is the first committed step of cholesterol biosynthesis?

reduction of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) to mevalonate

What is the key regulatory step in biosynthesis of cholesterol?

HMG-CoA reductase

What is mevalonate converted into?

isopentyl pyrophosphate

Where does the reduction of HMG-CoA to mevalonate take place?

cytosol

Where is HMG-CoA is converted into acetyl CoA and acetoacetate to form ketone bodies?

mitochondria

What produces all of the acetyl-CoA?

fatty acid beta oxidation

What synthesizes cytoplasmic acetyl-CoA?

citrate in the mitochondrial matrix get transported across the inner and outer mitochondrial membrane and into the cytosol ATP-citrate lyase acts on citrate to form ACETYL-CoA and oxaloacetate

What is the rate limiting step of cholesterol biosynthesis?

production of mevalonate from HMG-CoA by the enzyme HMG-CoA reductase

The rate of synthesis of reductase mRNA is controlled by?

Sterol Regulatory Element Binding Protein (SREBP)

What is the gene that encodes HMG-CoA?

reductase mRNA

What is the Sterol Regulatory Element Binding Protein (SREBP)?

transcription factor

What is the rate of synthesis of reductase mRNA regulated by?

the levels of cholesterol available by the INSIG and SCAP proteins that bind cholesterol

What is the rate of translation of reductase mRNA inhibited by?

metabolites derived from mevalonate and dietary cholesterol

Degradation of the reductase is tightly controlled by what?

Lanosterol

What decreases the activity of the mRNA reductase?

phosphorylation of lanosterol enzyme

lanosterol and acetyl-CoA carboxylase is switched off by what?

AMP-activated protein kinase

What happens to fatty acid and cholesterol biosynthesis when ATP is low in the cell?

cease

synthesis of cholesterol and fatty acids is regulated by which 2 transcription factors?

SREBP1 and SREBP2

SREBP1 and SREBP2 are located where?

ER membrane associated proteins

What happens to the insig protein when cholesterol levels are LOW?

dissociates from SREBP-SCAP complex and allows it to move from the ER membrane into the Golgi

What happens to the SRENP-SCAP complex in the golgi?

proteolytic enzymes cleave the loop domain on the lumen side of the Golgi first, and then on the transmembrane side to release the SREBP protein which contains the targeting sequence that moves it into the nucleus

What is a very important molecule in overall regulation of cholesterol and fatty-acid metabolism?

SREBP

What are 2 types of drugs that regulate cholesterol synthesis?

statins | bisphosphonates

Drugs that act by COMPETITIVELY INHIBITING HMG-CoA reductase

statins

What happens when statins competitively inhibit HMG-CoA reductase?

reduce amount of mevalonate produced

What ULTIMATELY happens when statins competitively inhibit HMG-CoA reductase causing reduction in mevalonate?

cholesterol synthesis reduced

What happens when the liver can no longer produce cholesterol?

levels in blood will fall

Where does most circulating cholesterol come from?

internal synthesis (rather than diet)

What time of day does cholesterol synthesis mostly occur?

at night

Statins with a short life-span are usually taken when?

at NIGHT to maximize benefit since cholesterol synthesis occur mostly at night

What is the extra potential benefit of statins?

inhibiting bone resorption by osteoclasts

drug used for treating bone diseases such as osteoporosis and osteogenesis imperfecta to inhibit osteoclast resorption of bone

bisphosphonates

Which drug has an affect on protein prenylation?

bisphosphonates

post-translational modification of proteins that adds a FARNESYL or GERANYLGERANYL moiety to C-terminal cysteines of target proteins

protein prenylation

What does prenylation add to the target protein?

hydrophobic molecules

What is the function of adding hydrophobic molecules to target protein in prenylation?

anchor protein to membrane surface

What is the role of prenylation in osteoclast function?

prevent osteoclasts from resorbing bone by inhibiting processes needed to resorb bone

Small GTPase localize to specific membrane compartments and assist in cytoskeleton rearrangement needed to form what?

sealing zone

Localization of GTPase is dependent upon what?

post-translational prenylation of these GTPases

What inhibits prenylation of GTPases needed to create sealing zone?

bisphosphonates

Where are bile and bile salts created and stored?

created in LIVER | stored in GALLBLADDER between meals

Our hormones send signals to which organ to release bile?

gallbladder

What are the 3 main functions of bile salts?

- aid digestion by breaking down fats - help absorb fat soluble vitamins - eliminate waste products

Dietary lipids (fats) have (high/low) solubility.

low

Bile salts act as the. ____ to emulsify dietary lipids.

detergent

What is bile a mix of?

water phosphatidylcholine (lecithin) bile salts cholesterol

What is the precursor of bile salts?

cholesterol

process of bile salts being reabsorbed in the GI tract for re-circulation back to the liver

enterohepatic circulation

What is the major way that cholesterol is eliminated from the body?

bile salt excretion (in feces)

T/F: bile acids are amphipathic.

true

What is the purpose of the amphipathic nature of bile acids?

- emulsification of lipid aggregates | - solubilization and transport of lipids in an aqueous environment

What is a common oral bisphosphonate?

Alendronate (Fosamax)

aggregates of lipids such as fatty acids, cholesterol and monoglycerides - that remain suspended in water.

micelles

Which drug is involved in Isopentenyl pyrophosphate ---> Geranyl PP

bisphosphonates

Which drug is involved in Geranyl PP ----> Farnesyl PP

bisphosphonates

Which drug is involved in HMG-CoA --> mevalonate

statins

SREBP target genes are involved in:

Cholesterol metabolism Fatty acid metabolism Triglyceride synthesis Plasma lipoprotein metabolism