Cholesterol Flashcards
What is hypercholesterolemia?
high blood cholesterol; increases risk for heart disease and stroke; promotes plaque formation; blocks the flow of blood to the brain, heart other organs; plaques can break loose–causes heart attack or stroke
what is SREBP?
Sterol Regulatory Element Binding Protien; Regulates cholesterol biosynth pathway– activates transcription of gene for HMG-CoA Reductase–>increases chol synth; regulates and increases the transcription of the LDL receptor–>brings more chol into cell
what are all the plays involved in regulation of HMG-CoA Reductase
SREBP, Scap, Insig, S1P ad S2P
what is the role of Scap?
SREBP Cleavage Activating Protein cholesterol sensor; found in ER; binds to both SREBP and Insig
What is the role of insig?
Insulin Induced Gene; binds Scap in ER; retains SREBP/Scap in the ER when chol levels in the cell are sufficient
what is the role of S1/2P
site 1/2 protease; found in golgi; processes SREBP–snips (release SREBP from golgi membrane)– S1P snips the loop bw transription factor and regulatory element; S2P snips the intermembrane domain to release it form the golgi
Risk factors of hyperchol..emia
heredity–family history of heart disease; lack of exercise; diets high in sat fat; overweight/obese; high BP; smoking; diabetes
what is familial hyperchol..emia due from?
LDL receptor deficiency/mutation–>unresponsive receptor on cell sruface/lack of LDL–>have high chol in blood
symptoms of hyperchol..emia
none; xanthomas–> may only find out after recovering from heart attack in hospital
treatment of hetero FH
reduce blood chol–>reduce risk of atherosclerosis; reduce sat fat intake (less red meat); low fat dairy, no egg yolks; weight loss/exercise; only moderately successful; mainly use chol-lowering drugs: statins (results in ~60% reduced LDL-Chols
what are statins?
inhibit HMG-CoA reductase; thought to reduce chol synth which will decrease [chol]i; force more chol to be removed from the circulation; competitive inhibitor (bind to active site of enzyme)–taking advantage of partially working LDL receptor in hetero FH
treatment for homo FH
liver transplant; exercise, monitoring diet–> no effect; ezetimibe
what is the role of ezetimibe
binds to brush border of small int; inhibits absorption of chol; binds to receptor which brings chol–> reduces blood chol; commonly used with statin, additive effect on reducing blood chol
ezetimibe controversy
reduces LDL without a doubt; does not seem to decrease the events of cardiovascular problems (heart attacks); arterial wall thickness stays the same– plaque still builds up
what are bile acid sequestrants?
anion exchange resins; positively charged beads bind to negatively-charged BAs–> reduce absorptions of bile salts–>excreted; also inhibit absorption of fat sol vits (need a multi-vit supplement if taking)
how do BA sequestrants work?
Bile acids, when bound to resins can’t be recycled– the 2% that was excreted normally is increased– not enough BAs coming back to liver–> liver needs to use up chol to make Bas; increase more LDL receptors on cell surface when it gets low in liver cells–> bring more in from blood–>lower blood chol
what is LDL-apheresis?
Hooked up to IV –> blood is removed, ran through system of filters– >filters contain resins that have an affinity for apoB (LDL, VLDL, and chylomicrons contain them) –> contained –> blood is put back into you–> lower chol; very effective (80%); used every 2 weeks, and 3000$ per treatment
what is PCSK-9?
serine protease; also cleaves itself; produced and secreted by and from liver at the ER–> released into circulation
what do mutations in PCSK-9 cause?
low blood chol; increased LDL-receptors on cell surface–> increase chol uptake–> which will decrease plasma chol; mutations prevent the degradation of LDL-receptor
what is PCSK-9’s role?
binds to LDL-receptor which promotes LDL receptor degradation/prevents recycling to cell surface
can exploit the data collected on PCSK-9 mutations to understand how PCSK-9 plays into blood chol
can use Abs on nonmutated PCSK-9 to lower blood chol
PCSK-9 inhibitors pros and cons
very effective at lowering chol (LDL)–> 60%; patients 50% less likely to have stroke; must be given injection every 2-4 weeks; possible cognitive issues; high cost– 15,000$ per year; long term safety unknown
how are chylomicrons/ VLDLs produced?
particles of a TAG-rich core with a small content of cholesteryl esters, a surface monolayer of phospholipids and cholesterol and lipoproteins are produced in the intenstine/liver cells–> released into circulation
how is LDL made?
produced in circulati0n from VLDL; cholesteryl ester-rich core
mechanism of CM/VLDL assembly
microsomal triglyceride transfer protein (MTP)–> found in lumen of ER (inside of ER); function is dependent on binding to protein diphosphide isomerase (heterodimer)–> catalyzes transfer of TAG to CM/VLDL
functions of MTP
generation of lumenal lipid droplets; translation/translocation of apoB into ER lumen; cotranslational addition of TG to apoB; post-translational addition of TAG to fully translocated apoB
if not enough TAG is around, apoB degraded by the lysosome–always at the ready to form a lipoprotein; fasting–> not much TAG being consumed; apoB degraded
ya
what is the disease of mutation in MTP, what happens
abetalipoproteinemia; rare; impaired dietary fat absorption; absence of plasma liporpteins (CM, VLDL, LDL); low conc of TAG and chol; symptoms: failure to grow in infancy; fatty, pale stools (steatorrhea); neuro degeneration (balance and coordination problems); loss of vision;
what is NPC disease?
Niemann-Pick C Disease; fatal (no effective treatment), occurs 1/150 000; high incidence in Yarmouth Country, NS, involved neurodegeneration in children (like alzheimer’s); enlargement of liver; premature death; no affective treatment
cause of NPC disease
mutatins in the NPC1 (95%) and NPC2 genes (5%)
why might NPC disease affect the brain?
1/5 of the brain is cholesterol; lots of it is associated with myelin, which coats nerve fibres and is integral for nerve transmssion, learning, and memory
role of NPC1 or 2
proteins that bind chol present in lysosome; npc1 is in the plasma membrane and 2 is in the interior of the cell; npc2 graps chol, gives to npc1; npc1 flips it across the lysosomal membrane into the cytosol–>therefore either 1 or 2 can be defective and chol will accumulate in lysosome
describe how receptor-mediated endocytosis plays a role in absorption of cholesterol
LDL receptor (from synth in the ER, modified in the golgi) goes to the membrane and combines with LDl (apoB 100); membrane invaginates around the receptor and LDL particle, creating the endosome–> pH drops to 5 which causes hte receptor to dissociate from the LDL particle; the lysosome fuses with the endosome and the cholesteryl ester droplets do things lol idk
where are bile acids synthesized?
the liver
bile acids act as emulsifiers and are needed for chol excretion
ya
what is the RLS of bile acid synthesis catalyzed by?
7-alpha-hydroxylase
what regulates 7-a-hydroxylase?
bile acids inhibit, chol induces
what are the modified forms of bile acids?
primary bile acids +glycine/taurine
98% of bile acids are reabsorbed via enterohepatic circulation; stored in the gall bladder (bilirubin) until needed; 2% is excreted in feces
ya
why are bile acids necessary?
pancreatic lipase cannot degrade TAGs directly–need to be in special form; PL is sol. in water, while fats aren’t–>need to solubilize them by using BAs as an emulsifier
how do bile salts act as an emulsifier?
form micelles around the TAGs
emulsification of bile salts causes dietary fat to form small globules which greatly increases SA–>makes TAGs accessible to pancreatic lipase and accelerate the activity of PL
ya
what are gallstones?
solid particles that collect in gall bladder–>can range from the size of a salt grain to golf ball; normally, BSs keep chol solubilized but when there is to much chol and not enough BSs, chol ppts
what are the causes of gall stones?
high chol; overweight/obesity; age; bile salt deficiency
symptoms of gall stones?
abdominal pain after a fatty meal
treatment of gall stones?
sound waves–>sonification; gall bladder removal
what is the regulatory enzyme of chol synth?
HMG-CoA reductase; chol inhibits HMG-CoA R–CELLULAR chol levels (not blood levels) regulate chol synth
how does chol regulate HMG-CoA R activity?
through reductase phos and dephos, transcription of reductase gene, translation of reductase to mRNA, and degradation of reductase
what is SRE?
sterol regulatory/response element–>binds SREBP–>SREBP can then transcribe
describe the induced transcription of HMG-CoA R
A conf change in Scap causes Insig to dissociate; Scap and SREBP bubble off the ER membrane and go to the golgi; there, s1P cleaves the transmembrane loop between the domains; s2P then cleaves s that SREBP can be freed from teh golgi so SREBP can enter the nucleus, bind to SRE, and then activate transcription
hypercholesterolemia prevalence (hetero and homo)
1/500; homo 1/ 1 000 000
symptoms of abetalipoproteinemia and how to manage tehm (treatment)
symptoms: failure to grow in infancy; fatty, pale stools (steatorrhea); neuro degeneration (balance and coordination problems); loss of vision; manage symptoms by restriction of dietary fat
how can MTP be used to reduce high blood chol?
inhibit it
what is ApoB ASO?
Antisense oligonucleotide therapy for ApoB; create ApoB mRNA and then antisense mRNA which is complementary; causes RnaseH to degrade–>no ApoB–> reduced VLDL and LDL levels
what was the problem with ApoB ASO?
increased ALT and liver TG
