40 Cholesterol Metabolism and Blood Lipoproteins Flashcards
what are the functions of cholesterol?
stabilizes cellular membranes primarily the plasma membrane
precursor for bile salts and steroids
precursor of cholesterol can be used for making ubiquinone, dolichol, cholecalciferol
what is ubiquinone used for?
isoprene antioxidant
what is dolichol used for?
glycoprotein synthesis
what is cholecalciferol?
the active form of vitamin D
what are the sources of cholesterol?
synthesized by most cells in the body like the liver and intestine
what is the starting material for cholesterol?
acetyl CoA
what are the dietary sources that contain cholesterol?
animal products like egg, red meat and liver
in cholesterol synthesis where do the carbons come from?
acetyl CoA
where do the first two stages of synthesis occur? where and what are the enzymes used in cholesterol synthesis?
in the cytosol; ER and the two enzymes are HMG CoA reductase and squalene synthase located on the cytoplasmic face of the ER
during cholesterol synthesis, how does the final stage occur?
with ER bound enzymes
where is the acetyl CoA for cholesterol synthesis formed?
in the mitochondrial matrix following glycolysis and it is transported to the cytosol by the citrate transport system
in the Fed state, what is made?
FAs and cholesterol and are transported using a citrate shuttle to get acetyl CoA out to the cytoplasm under insulin signaling
why is HMG CoA reductase important?
because of regulation the body will use and because its a target of drug therapy
what enzyme is used to form Acetyl CoA from Citrate?
citrate lyase and so note that acetyl CoA is the starting product for cholesterol synthesis
where do we see HMG-CoA reductase? where is it located?
in the first committed step of cholesterol synthesis which is also the site of regulation for cholesterol synthesis; it is located on the cytoplasmic face of the ER with catalytic domain and regulatory membrane domain
what is the effect of limiting HMG-CoA reductase?
Mevalonate cannot be produced but liver can use the HMG CoA to make ketone bodies during a fast
what is the only thing Mevalonate can be used to make?
cholesterol
liver synthesizes bile salts and the gallbladder holds and releases them, T/F?
T
what regulates HMG CoA reductase activity?
insulin dependent process and so cholesterol is made in addition to fatty acids by the liver, so for it to be activated under insulin it is dephosphorylated and phosphorylated when glucagon comes along shutting this pathway down
also note that DNA reductase under influence from bile salts and cholesterol turns on and off HMG-CoA reductase
what enzymes are responsible for the transcriptional control of cholesterol synthesis?
SREBP: sterol regulatory element binding protein
-enables gene transcription to take place
SCAP: SREBP cleavage-activating protein AND S2P: site 2 protease
how does transcriptional control of cholesterol synthesis work?
When cholesterol is high, cholesterol binds to SCAP. SREBP protein is intact and quiescent. When cholesterol is low, SCAP does not bind cholesterol, SREBP is activated, and S2P cleaves the DNA binding domain of SREBP. This signals DNA transcription.
what is the effect of cholesterol esterification? what part of the molecule is modified?
Increases the hydrophobicity of cholesterol, which increases is solubility in lipoprotein particles an in lipid droplets in the cytosol of cells.
The hydroxyl group at C-3 can be esterified with a fatty acid
what are the two main enzymes that esterify cholesterol?
Lecithin:cholesterol acyltransferase (LCAT) in blood
-esterifies cholesterol associated with HDL
Acyl:cholesterol acyltransferase (ACAT) in cells
-concentrated in cells that need to store cholesterol for steroid synthesis.
what is cholesterol a precursor for?
bile salts
vitamin D
steroid hormones
how often is cholesterol degraded?
a precursor for so many other molecules, that it is very rare that it ever needs to be degraded and eliminated.
One of the main “losses” of cholesterol occurs in the digestive tract with bile salts that are not resorbed properly.
what kind of effect does salt metabolism have on cholesterol metabolism
direct effect
what happens to patients who do not efficiently resorb bile salts?
must constantly resynthesize them from cholesterol.
These patients often have upregulated cholesterol synthesis.
what is Cytochrome P450 monooxygenase (7α-hydroxylase)?
first enzyme that takes a cholesterol molecule and moves it toward a bile salt by incorporating an -OH group first; also a rate limiting step in bile synthesis
also implicated in lipid digestion disorders because they are missing bile salts
what are primary bile salts?
first ones formed and so once released into digestive tract, they can be modified, forming the secondary bile salts.
OHs added to help make the molecule more soluble
what do bile salts do?
emulsifier that gelatinizes it; primary and secondary forms, resorbed in the colon (95%), cholesterol is the starting material with 7α-hydroxylase as key enzyme
know that testosterone, aldosterone, estradiol are examples of?
steroid hormones and note cytochrome P450 families named for location of where they put the oxygen
what are the two major classes of steroid hormones?
Corticosteroids: adrenal cortex
Sex steroids: gonads (and placenta during pregnancy)
what are five fundamental types of steroid hormones?
Glucocorticoids Mineralocorticoids Androgens Estrogens Progestogens
what are the major functions of steroid hormones?
Control metabolism Inflammation Immune function Salt and water balance Development of sexual characteristics Ability to withstand illness and/or injury
