Cholesterol Biosynthesis and Transport Genetics Part 1 Flashcards
cholesterol is a precursor for (3)
vitamin D
steroids
bile salts
cholesterol is necessary for — —
membrane stability
cholesterol is a major structural component of — —
myelin sheaths
myelin sheaths are synthesized by glial (what types of glial cells) cells and which surround axons in vertebrates
PNS: schwann cells
CNS: oligodendrocytes
what are nodes of ranvier?
non myelinated regions with a high concentration of Na+ channels which initiate depolarization of the membrane
all steroids contain the same four — —
hydrocarbon rings
the major portion of the molecule is — but the hydroxyl group is —
hydrophobic, hydrophilic
what two ways can cholesterol be absorbed?
dietary sources
synthesized de novo
what are the two main organs which synthesize cholesterol?
liver (70-80%) small intestine (10%)
cholesterol is also produced in the (2)
adrenal glands and gonads
why is cholesterol a critical component of cell membranes (~30%)?
it regulates membrane fluidity and has important functions in intracellular transport, cell signaling, and nerve conduction
cholesterol is the precursor for the biosynthesis of (3)
steroid hormones, bile acids, and vitamin D
an adults on a low cholesterol diet typically synthesizes about — mg of cholesterol on a daily basis
800 (de novo, liver)
LDL
most desirable
very high
under 100
over 190
HDL
undesirable
good, risk lowered
under 40
over 60
stage 1 of de novo biosynthesis of cholesterol
the synthesis of isopentenyl pyrophosphate
this stage becgins with the condensation of acetyl-coA and acetoacetyl-coA in the cytoplasm to form 3-hydroxyl-3-methylglutaryl coA (HMG-coA), which is then reduced to mevalonate by the enzyme HGM-coA reductase. mevalonate is then converted into isopentyl pyrophosphate
stage 2 of de novo biosynthesis of cholesterol
the condensation of 6 molecules of isopentyl pyrophosphate to form squalene
stage 3 of de novo biosynthesis of cholesterol
the cyclization of squalene to form the steroid 4-ring structure, which rearranges to form lanosterol. lanosterol is then converted into cholesterol
first committed step of cholesterol biosynthesis
HMG-coA is reduced by HMG-coA reductase to form mevalonate
in the cytosol, HGM-coA is converted into mevalonate whereas in the mitochondria, it is converted to — and —, which are further processed into — —
acetyl coA and acetoacetate
ketone bodies
what produces all of the acetyl coA?
fatty acid beta-oxidation
the source of carbon atoms in cholesterol are synthesized from
acetate
the rate of synthesis of reductase mRNA is controlled by the
sterol regulatory binding proteins (SREBP)
SREBP is a
transcription factor
this process is regulated by levels of cholesterol available by the — and — proteins that bind cholesterol
INGIG
SCAP
INSIG and SCAP act as — to tell us if we need to keep SREBP available
sensors
the rate of translation of reductase mRNA is inhibited by metabolites derived from — as well as — —
mevalonate
dietary cholesterol
degradation of the reductase is tightly controlled by —
lanosterol
phosphorylation of the enzyme decreases the activity of the
reductase
this enzyme, along with acetyl-coA carboxylase which catalyzes a similar committed step in fatty acid biosynthesis, is switched off by an — — — —
AMP-activated protein kinase
fatty acid and cholesterol biosynthesis cease when — is low in the cell
ATP
why does FA and cholesterol biosynthesis cease when ATP is low in the cell?
cholesterol and FA are not needed when ATP is low. these are ATP requiring steps, so they wont occur when ATP is low
synthesis of cholesterol and fatty acids is regulated by transcription factors — and —
SREBP 1 and SREBP 2
SREBP target genes are used in (4)
cholesterol metabolism
fatty acid metabolism
triglyceride synthesis
plasma lipoprotein metabolism
SREBP target genes in cholesterol metabolism (7)
LDL receptor HGM coA synthase HGM coA reductase farnesyl diphosphate synthase squalene synthase SREBP-2 lanosterol-14-alpha-demethylase (cyp51)
SREBP target genes in fatty acid metabolism (8)
acetyl coA carboxylase fatty acid synthase stearoyl coA desaturase-1 and 2 acyl-coA binding protein (diazepam) SREBP-1 ATP citrate lyase PPAR gamma acetyl coA synthetase
SREBP target genes in triglyceride synthesis (1)
glycerol-3-phosphate acyltranferase
SREBP target genes in plasma lipoprotein metabolism (2)
lipoprotein lipase HDL receptor (SRBI)
statins act by competitively inhibiting
HMG-coA reductase
by inhibiting HMG-coA reductase, the amount of — produced is reduced
mevalonate
reduced mevalonate ultimately leads to reduced — synthesis
cholesterol
when the liver can no longer produce cholesterol, levels in the blood will fall since most of the circulating cholesterol comes from
internal synthesis, rather than diet
cholesterol synthesis occurs mostly at — so statins with a short like are usually taken at — to maximize their benefit
night
statins inhibit the reabsorption of
ostetoclasts
statins inhibit the reabsorption of osteoclasts since they also inhibit the formation of prenylated proteins which is required for
osteoglastogenesis
what do statins ressemble?
the 3-hydroxy-3-methylglutaryl moiety recognized by HMG-coA reductase
statins act as a competitive inhibitor by preventing
HMG-coA reductase from producing HMG-coA
bisphosphonates are used for treating bone diseases such as — and —
osteoporosis
osteogenesis imperfecta
bisphosphonates inhibit
osteoclast resorption of bone
pyrophosphate is an inhibitor of
mineralization
what was the first bisphosphonate developed?
alendronate
zoledronate is a bisphosphonate used to treat
osteocronosis of the jaw
what is protein prenylation?
post-translational modification of proteins that adds a farnesyl or geranylgeranyl to the c-terminal cysteines of target proteins
the prenylation adds a — — to the target protein, which can serve to
hydrophobic molecule
anchor the protein to the membrane surface
what is the role of prenylation in osteoclast function?
prevents osteoclasts from resorption of bone
prenylation in osteoclast function
small GTPase localize to specific membrane compartments and assist in cytoskeleton rearrangement needs to form the sealing zone. this localization is dependent upon post-translational prenylation of these GTPases
bile salts are made in the — and stored in the — between meals
liver
gallbladder
after we eat and there are fats present in our digestive tracts, out hormones send. signal to our gallbladders to
release bile
bile salts aid in digestion by breaking down
fats
bile salts help absorb
fat-soluble vitamins
bile salts eliminate
waste products
