Lipids and Lipoproteins Flashcards
What makes isoprenoids?
What is that made of?
What do isoprenoids make?
one isopentenyl pyrophosphate (IPP)
Three acetyl CoA
steroids, lipid-soluble vitamins, ubiquinone, and prenyl groups t
sources of acetyl coa?
oxidative decarbo of pyruvate, beta oxi of fatty acids, breakdown of aa
transport citrate shuttle
cholesterol is made of
sterane (allicyclic)
2 (a-coa) -> 27 c (w/ atp to make)
in plasma mem, so has OH
in bile acids/salts/ vit d/ steroid hormones
made and ingested, recycled or peed out
phase 1 - cholesterol synthesis
a-coa -> acetoacetyl coa + hmg-coa synthase -> hmg coa + HMGCOA REDUCTASE -> mevalonate -> isopentenyl pyrophasphate (IPP)
rate lim of cholesterol syn? what inhibits this, and what else does it affect?
HMG-COA REDUCTASE
inhibited by statin which can inhibit the making of lipid soluble vit, ubiquinone
phase II of cs
6 IPP -> squalene (open chain)-> lanosterol (cylic)-> cholesterol
what inhibits phase ii
antifungal agents - azoles, tamoxidfen (breast ca drug)
which has a higher affnity for the substrate - HMG-CoA reductase or statin? What else do statin effect besides the syn?
statin
good: transcription of LDL receptor, uptake of cholesterol via endocytosis
bad: Myotoxic side effects – depletion of muscle levels of ubiquinone (CoQ 10) - tired, then kills cells
regulators of HMG CoA reductase
Direct Inhibition – by free fatty acids, bile acids, oxysterols and statins
Covalent Modification:
low energy, high AMP, activate AMPK, phosphorylates
Insulin - dephosphorylating
Glucagon - phosphorylating it
transcription (mrna), translational (y-tocotrienol, oxylanosterols), post-trans - turnover, degrade enhanced by trans above
is HG CoA reductase active in phospho form or dephospho form
active in dephospho form.
what triggers translocation of srebp-scap complex to golgi? high keeps it where
low cholesterol
er mem with INSIG (keeps there)
what does srebp do? what does it bind to?
Up-regulation of enzymes in cholesterol Biosynthesis and LDL-Receptor (take in cells)
sterol regulatory element (SRE) in its promoter region of nucleus
lipoproteins functions?
transport and deliver TAGs , cholesterol homeostasis, targeting signals/ligands, activate various enzymes in lipid metabolism
size and density of lipoproteins
hdl, ldl, idl, vldl, chylomicron
order of highest density (small w/ most protein, least tag) to lowest (big w/ least protein, most tag)
Chylomicron markers
ApoB-48, ApoC-II, ApoE
VLDL markers
ApoB-100, ApoE, ApoC-II
made in liver, w tags and cholesterol
markers functions?
ApoB-48 - Facilitates transport
ApoE - Facilitates Uptake into liver, uptake into hepatocytes (HDL only)
ApoB-100 - uptake into cells
ApoA-I - Activates enzyme that esterifies cholesterol
ApoC-II - Activates capillary lipoprotein lipase
LDL markers
ApoB-100
HDL markers
ApoA-I
ApoC-II
ApoE
high protein and phospholipid content
chylomicron processing
in SI through lymph to blood
HDL gives ApoC-II and ApoE to mature chylomicron
releases ApoC-II, glycerol and free fatty acids
remnants endocytosed by liver via bind to ApoE receptor
what hydrolyzes TAG -> glycerol and free fatty acids from VLPL and chylomicrons? Can cause what disease if there is issues with it?
capillary lipoprotein lipase
Type I hyperlipoproteinemia
def in apoc-II (adult)or def lipoprotein lipase(infant), not able to hydrolyze TAGs in chylomicrons and VLDL
increase chlyomicrons and TAGs (>1000 mg/dL)
symp: xanthomas, abd p, acut pancreatitis
low fat diet
VLDL, IDL, and LDL Processing
vldl in liver to blood
releases ApoC-II to HDL, glycerol and free fatty acids, leaving IDL
ApOE to IDL receptors on liver
IDL
loses more glycerol and free fatty acids, leaving LDL
ApoB-100 to LDL receptors on peripheral tissues
What converts TAG -> glycerol and free fatty acids from IDL?
tissue lipoprotein lipases and hepatic lipoprotein lipases
deficiencies in LDL receptors on peripheral tissue is?
Type IIa (complete) type IIb (partially defective)
Increase chylomicrons; ldl (both), triacylglycerols and VLDL (IIb only)
what is the main carrier of cholesterol
LDL, 1500 cholesterol ester mol
apo b-100 recog by recpt in target cells
transport and denovo syn of cholesterol at sites
Uptake of LDL:Receptor-mediated Endocytosis
endocytoized -> vesicle, -> lysosome, ph breaks down into aa and cholesterol
what is it when receptors that are unable to release ldl cargo?
familial hypercholesterolemia
normally in endosome, reduced ph converts receptor from open into closed structure, releasing LDL
HDL processing
disk like HDL in liver, small intestin
gets chol from tissues, LCAT ((lecithin cholesterol acyl transferase) esterifies chol and enters HDL (sphere)
donates apoc-II/ApoE, esters, for tag, phospholipids
delivers to liver
what protein facilitates exchanges between HDL and the others?
cholesterol ester transfer protein, CETP
benefits of HDL
maturation of chylomicrons reverse cholesterol transport
HDL scavenges and removes LDL-cholesterol from periphery and transports it to liver where it can be recycled and processed
HDL-C levels increased by weight loss, exercise, and smoking cessation
antioxidant, anti-inflammatory, antithrombotic, and nitric oxide-inducing properties
Tangier disease
Loss of ABCA1 activity of cholesterol-transport protein
HDL deficiency, accumulation of cholesterol in macrophages, and premature atherosclerosis
ABCA1 binds to ApoA-I apoprotein component of HDL to facilitate transport of LDL
def in transport that supports cholesterol pickup by HDL
type II hyperlipoproteinemia
defects in LDL receptor resulting in defects inuptake of LDL via Receptor-mediated endocytosis
lots chol in blood
form oxidized LDL -> atherosclerosis
Impaired ability to recognize ApoB 100 on LDL
Xanthomas, corneal deposits in eyes, and angina pectoris
levels of cholesterol in T2 Hyperlipoproteinemia
Treatments?
Normal cholesterol 130-200 mg/dL
•Heterozygous – 300-500 mg/dL
•Homozygous – >800 mg/dL (die of CAD before teens)
Heterozygous respond to diet, statins and bile acid binding resins
Homozygous need LDL apheresis and liver transplantation
Plasma Cholesterol and Atherosclerosis
LDL-C in bv -> oxidized LDL (oxLDL) -> build in vessel wall ->endothelial injury and further influx ->Increased vascular permeability and leukocyte adhesion, inflam response ->macrophages engorge to form foam cells -> form plaques-> build up of foam cells, platelet adhesion, and recruitment of smooth muscle cells -> atherosclerosis -> MI
IDL markers
ApoB-100 and ApoE
