PHR 912 TOPIC 15 CHOLESTEROL

cholesterol

important steroid that makes membranes tight and is essential for the function of membranes

steroid structure

17 c ring with 3 6 mem rings and one 5 mem ring. rings a and b are fused variously and b/c and c/d are always trans fused

cholesterol structure

double bond at 5 and 6. has an oh on 3 with s sterochemistry and alipathic side chain. highly lipophilic

cholesterol functions

stabalize cell membranes, precursor for bile acids and steroid hormones and precursor for biosynthesis of ketone bodies, ubiquinone and cholecalciferol

steroid types and their uses

cholesterol- membrnae stability and precursor for steroid hormones and bile acids

steroid hormones- regualte growth, metabolism and reproduction

bile acids- lipid digestion and absorption

steroid hormones

chemical messengers that provide communication from one part of the body to another

what are the steroid hormones

sex hormones- androgens and estrogens

corticoadrenal hormones- corticoids

cholesterol complications

cholesterol deposition in arteries is associated with cardiovascular diseases and stroke

sources of cholesterol

diet; egg yolk and red meat

biosynthesized by most cells (esp. liver and intestinal cells)

not biosynthesized in plants

how to avoid excess of cholesterol

loose weight and excersise, diet high in fruits and veggies, cholesterol lowering drugs

what are the types of cholesterol lowering drugs

inhibitors of cholesterol biosynthesis, cholesterol binding and removing resins, cholesterol uptake inhibitors

when acetylk coa is converted to cholesterol where is this

cytosol

when cholesterol is converted to bile salts membranes steroid hormones and blood ipoproteins where is this

mitochondrial matrix

what can cholesterol come from

acetate

what is the precursor for cholesterol biosynthesis and where does it come from

acetyl coa which comes from breakdown of glucose, FA, or AA

what happens to citrate that has been carred into the mitochondria (from acetyl coa)

it is cleaved to oaa and acetyl coa by atp citrate lyase

tricarboxylate transport system purpose

acetyl coa cannot be transported though mito membrnae so it transports citrate and then it is cleaved in the cytosol back to oaa/malate/pyruvate and acetyl coa

what are the 3 phases of cholesterol biosynthesis

1) 3 step formation of the c6 metabolite mevalonate from 3 acetyl coa

2) 7 step conversion of mevalonate via c5 phosphorylated isoprene units which make squalene

3) cyclization of squalene and conversion into cholesterol (21steps)

phase 1 is called

hmg coa synthesis and hmg coa reductase

hmg coa synthesis steps

2 acetyl coa make acetoacetyl coa which combines with another acetyl coa to make hmg coa

hmg coa reductase

reduces hmg coa to mevalonate, RATE LIMITING STEP in cholesterol biosynthesis

which hmg coa is most effective and why

liver bc of bile acid production

what does hmg coa reductase require and what are the 2 steps

nadph, step 1- thioester to thioacetal 2- thioacetal to 1 alcohol

regualtion of hmg coa reductase

feedback regulation by cholesterol and bile acids and insulin (activates by dephosphorylation) and glucagon (inactivates by phosphoryaltion)

choelsterol lowering agents are called what and do what

statin drugs, inhibit hmg coa reductase

what is the key feature of statin drugs

lactone

mevastatin r 1 and 2

both h

lovastatin 1-r 1 and 2

1-ch3 2-h

pravastatin r 1 and 2

1-oh 2-h

simvastatin r1 and 2

both ch3

what are the 4 statin drugs and what do they do

pravastatin, simvastatin, lovastatin, mevastatin, hmg coa reductase inhibitors

what are the other statin drugs

fluvastatin, atorvastatin, cerivastatin, rosuvastatin

what is the moa for statin drugs

analouges of intermediates in the conversion of hmg coa to mevalonate, decreases the rate of cholesterol biosynthesis as COMPETETIVE inhibitor of hmg coa reductase, this inc the ldl receptor synthesis and uptake of ldl from blood

what is phase 2 of cholesterol biosynthesis

mevalonate to squalene

what are the steps of phase 2

mevalonate is phosphorylated by atp, decarboxylation to isopentenyl pyrophosphate which is now in equillibrium with dimethylallyl pyrophopshate, 2 isoprene unts make geranyl pyrophosphate and this combines with isopentyl pyrophosphate to make farnesyl pyrophosphate. 2 of these can then make squalene

what is phase 3

squalene to cholesterol

what are the 3 parts of phase 3

1- formation of squalene epoxide

2- cyclization to the tetracylic steroid skeleton and formation of lanosterol through hydride and methyl group shifts

3- 19 step sequence (remove 3 methyl, reposition the double bond, and saturate side chain double bond) finalizes cholesterol

step 1 of phase 3 (squalene epoixidase rxn)

uses nadph becuase the 2 h make the 2nd o into h2o

step 2 of phase 3

2,3-oxidocyclase makes lanosterol by squalene oxidocyclase

step 3 of phase 3

lanosterol to cholesterol which is 19 steps where 3 methyl groups are delted, double bond moves, and double bond on the side chain is saturated

cholesterol synthesized in the liver is converted to what

bile acids or ester

what does esterification do

increase lipopholicity, which is good for packaging into lipoproteins and lipid droplets

what are the enzymes that perform transesterification

LCAT (blood) lecitihin cholesterol acyltransferase

ACAT (liver) acyl cholesterol acyltransferase

cholesterol transport

highly insoluble so they are transported in lipoprotein complexes

biosynthetic transport from the liber sequence

cholesteryl ether> VLDL> IDL>LDL

how is dietary cholesterol transported

chylomicrons

what also plays an importnat role in transportation of cholesterol

HDL

what is the depository form of cholesterol in liver

bile acids or cholestryl eshers

chylomicrons

apo b48 that are synthesized in rough er

vldl

apo b100 that are synthesized in the liver

chylomicrons function and ho do they enter the blood and mature

lipoprotein that contains dietary lipids including dietary cholesterol, enter blood via lymphatic system and mature with apo c- activation of lpl and apo e- receptor recognition (these come from HDL)

how are chylomicrons broken down

though lpl they become remnants that can bind liver erceptors and enter liver through endocytosis, these eventually become lysosomes wihch can release free cholesterol

vldlfunction and what does it take up to mature

lipoprotein complex that channels lipids from the liver, takes up apo c and e from hdl to mature

what is the major purpose of lipoproteins

to transport triacylglycerols and deliver FA

what is the secondary function of lipoproteins and what can this do for lipoproteins

cholesterol delivery, cholesterol helps make them functional

ldl

bad cholesterol, made by vldl and idl, docks to ldl receptors of target cells and enter these cells via endocytosis, can reenter the liver and can be damged by oxidation and then needs to be taken up by scavengar recetors on macrophages

hdl

good cholesterol, helps retard atherosclerotic processes, interact with chylomicrons and vldl to exchange lipids and proteins

what does hdl do

takes up cholesterol from surface of cells and other lipoproteins and converts it to cholesteryl ethers

how are cholesteryl ethers returned to liver

reverse cholesterol transport

why are hdl high density

contain more proteins, less triacylglycerols per weight

what role do hdl have in maturing

transfer apo e and c to chylo and vldl

apo a on hdl

!!!stimulates LCAT to form cholesteryl esters

what are the different CETP inhibitors

anacetrapib, torcetrapib, dalcetrapib, and evacetrapib

what do cept inhibitors do

inhibit cholesteryl ester transfer protein (CEPT), supposed to raise hdl levels

what is the process for formation of ldl

vldl is degraded to idl and on to ldl, it transfers apo c and e back to hdl!!! so ldl no longer has apo E

ldl has a low content of ___ and a high content of ____

triacylglycerols, cholesteryl esters

how is cholesterol recycled

idl and ldl particles are endocytosed by liver

what is the most important and best characterized lipoprotein receptor

LDL receptor

where are ldl receptor biosynthesized

er and golgi complex

what does the ldl receptor recognize

apo E and apoB-100

what all does the ldl receptor bind to

ldl, vldl, idl and chylomicron reminants

ldl receptor is quite specific for

blood lipoproteins and scavenger receptor

endocytosis

after ligand binding, cell membrane invaginates forming first coated vesicles, then endosomes

coated vesicles

with clathrin

endosomes

without clathrin

endosome ph decreases by what and what does this cause

atp proton pumps, lipoproteins to dissociate from receptors

receptors are ___

recycled

what are the results of uptake and digestion of ldl

cholesterol biosynthesis decreases, cholesterol is used by cels, synthesis of ldl receptors decreases, and stimulation of ACAT activity to form cholesterol esters for storage

what all controls cholesterol metabolism

HMG coa reductase is the primary contol, rate of ldl receptor synthesis, and rate of cholesterol esterification by ACAT

hypocholesterolemia results from

overproduction or utilization of ldl

what does overproduction or utilization of ldl result from

high blood levels of ldl cholesterol, genetic defect or high cholesterol diet

what is the treatment for hypercholesterolemia

resins that bind bile acids in intestines and prevent their reuptake and hmg coa reductase inhibtors

what kind of disease is familial hypercholesterolemia and what is it caused by

genetic disease, caused by absence or deficency of functional LDL receptors

pcsk9 inhibitors name and function

proprotein convertase subtilisin/kexin type 9, newest drug in anti-cholesterol drug research

what does pcsk9 play a major role in and how

cholesterol homeostasis by binding to the ldl receptor and initiating its degredation

reduced ldl receptors lead to

hypercholesterolemia

inhibitors of pcsk9 are antibody or mrna drugs that do what

inhibit the degredation of ldl receptors

what are the inhibitors of pcsk9

alirocumab, evolocumab, and incilsiran

one type of familia hypercholesterolemia is caused by a mutation of

pcsk9 encoding gene leadering to a hyperreactive pcsk9 protein

LDL receptor related protein

similar to ldl receptor but less specific, binds a macroglobulin and tissue plasminogen activator (TPA)

what does LRP recognize

apoE of lipoproteins NOT LDL

what does LRP do and where is it and what is the synthesis not effected by vs is effected by

binds and clears chylomicron remnants and vldl from blood, most adundant in liver brain and placenta cells and the synthesis is not effected by cholesterol levels

what increases number of LRP receptors

insulin

scavenger recetors

last ditch defense!, nonspecific receptors occuring in membranes expecially macrophages

the macrophage SR binds various molecules inclsuing what

oxidized LDL

what scavenger recptor is for cholesterol loaded HDL

SR- B1 (liver)

superoxide radicals, NO and H2O2 cause what

oxidation of LDL

can cells remove oxidized LDL even long after intracellular cholesterol levels were elevated in SR

yes

when macrophages take up oxdized LDL they turn into

so-called foam cells

accumulation of these foam cells are earliest evidence of what

development of athersclerosis plaque in blood vessels (fatty streak)