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9. Lipoprotein Metabolism and Clinical Correlation
BrownMed
91
Aerospace Engineering
1st Grade
10/07/2010

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Term
sources of cholesterol (2)
Definition
endogenous synthesis and animal products in diet
Term
cholesterol functions (3)
Definition
cell membranes, steroid hormones, bile acids
Term
cholesterol structure
Definition
steroid nucleus w/ hydrocarbon tail and FA tail
Term
lipoproteins transport (2)
Definition
cholesterol esters and triglyceride
Term
storage form of cholesterol?
Definition
CE; not found in cell membranes
Term
ACAT
Definition
acyl coa cholesterol acyltransferase - transfers long chain FFA (free fatty acids) to C3 carbon on cholesterol for CE storage in cells
Term
cholesterol synthesis
Definition
2acetyl coa> acetoacetyl coa+acetyl coa> HMG Coa> mevalonic acid >>>>>>>> cholesterol. 1. thiolase, 2. HMG coa synthase, 3. HMG coa reductase
Term
mevalonic acid
Definition
reactive O2 species
Term
rate limiting step in cholesterol synthesis (2)
Definition
HMG coa reductase; requires NADPH
Term
where do statins inhibit?
Definition
at HMG coa reductase, via competitive inhibition
Term
where does cholesterol synthesis occur?
Definition
10-20% in liver, but in all tissues
Term
gene expression of HMG coa reductase controlled by
Definition
insulin and SREBP - high cholesterol levels inhibit SREBP and vice versa, so increased cholesterol decreases stability of the enzyme and phosphorylation decreases its activity
Term
how much free cholesterol (FC) in gi tract excreted
Definition
50%; 50 sent back to liver
Term
cholesterol is metabolized to _____ by _____
Definition
bile acid (cholic acid); 7-alpha-hydroxylase. conjugated with glycine or taurine (ratio 3:1) to form bile salt, then secreted in bile to GI tract for micelle formation
Term
percent of bile salts excreted?
Definition
3%. 97% returned to liver via enterohepatic circulation
Term
what inhibits reabsorption of bile acids (2)
Definition
bile acid-binding resins, dietary fiber
Term
lipoprotein structure
Definition
shell = unesterified cholesterol, apoprotein and phospholipid. inside = TG and CE, fat-soluble vitamins. (function of lipoproteins is to carry these things around) apoproteins are SPECIFIC in binding and enzyme activation
Term
chylomicrons
Definition
90% TG, apoprotein B48, metabolized to CM-remnants
Term
VLDL
Definition
mostly TG but some CE; apoproteins B100 and E; metabolized to IDL and VLDL remnants
Term
function of apoprotein E
Definition
allows something to be taken up by the liver
Term
LDL
Definition
60% cholesterol (esters); apoprotein B100; metabolized FROM IDL and binds LDL receptor
Term
HDL
Definition
carries CE and proteins; apoproteins A C E; key in reverse cholesterol transport and synthesis of other lipoproteins
Term
CM remnant / IDL apoproteins
Definition
b48 and E / b100 and E
Term
chylomicrons from the intestine follow these pathways
Definition
intestine>mesenteric lymph>thoracic duct>blood > LipoProtein Lipase uses ApoCII as a cofactor to metabolize it > 1. CM-remnant goes to liver, which is mediated by ApoE. 2. CM-remnant enters as FFA into peripheral tissue.
Term
ApoE - what kinds of mutations?
Definition
autosomal recessive
Term
cholesterol ester transfer protein
Definition
HDL offers a CE in exchange for TG from VLDL, so that VLDL can make LDL
Term
IDL ___________ by (2) to become LDL
Definition
hydrolyzed; LPL and Hepatic Lipase
Term
VLDL - TG =
Definition
IDL
Term
HDL gives WHAT to VLDL for further cholesterol synthesis?
Definition
ApoCII and ApoE
Term
ApoCII / deficiency
Definition
cofactor for LipoProtein Lipase to break down cholesterol precursors / autosomal recessive
Term
VLDL synthesized how, regulated by what
Definition
synthesized in liver from TG; regulated by FFA influx, alcohol, drugs
Term
know VLDL>IDL>LDL diagram
Definition
Term
heparin sulfate
Definition
anchors LPL to capillary walls
Term
LPL
Definition
hydrolyzes TG from CM VLDL and IDL into FFA and glycerol
Term
2 isomers of LPL
Definition
adipose enzyme has high Km for excess storage, cardiac enzyme has small Km because heart prefers that type of energy. (active form is a dimer)
Term
regulation of LPL (2)
Definition
regulated by insulin, activated by fibrate drugs
Term
LPL deficiency
Definition
autosomal recessive: sky high chylomicrons/TG after birth. must restrict long chain fats in diet
Term
LDL delivers cholesterol to tissues by
Definition
apoB100 binding to LDL receptor (LDLR) and endocytosis
Term
foam cells
Definition
in endothelial plaques = oxidized LDL taken up by scavenger receptor macrophages
Term
HL acts on LDL to form
Definition
small, dense LDL
Term
Lp(a)
Definition
modified LDL w/ Apo(a) linked to ApoB100 via disulfide bond; correlates with CVD because apo(a) is homologous to plasminogen and promotes thrombosis
Term
LDL receptor / regulation
Definition
glycoprotein binds apoB100 and apoE, not apoB48. ligand binding causes endocytosis. gene expression controlled by SREBP (like HMG Coa Reductase)
Term
LDL Receptor-Related Protein (LRP)
Definition
4LDLR that binds ApoE enriched particles (CM and VLDL remnants), NOT LDL
Term
Familial Hypercholesterolemia
Definition
LDLR mutation
Term
nHDL
Definition
= nascent HDL = in liver/intestines. contains PL and ApoAI. acquires free cholesterol from cells via ABCA1. LCAT forms CE+PL to make mature HDL (FC+PL>CE)
Term
ApoAI
Definition
structural protein, LCAT cofactor (LCAT fuses CE and phospholipids to make mature HDL from nHDL and FC - FC+PL>CE), binds SR-B1 on liver, adrenal, gonads
Term
SR-B1
Definition
HDL receptor = scavenger receptor B1. ApoAI binds it on the liver, adrenal, gonads, and then it accepts CE from mature HDL
Term
ApoCI
Definition
inhibits CETP (cholesterol ester transfer protein, which exchanges CE for TG with HDL to make LDL from IDL) and HL (hepatic lipase, which hydrolyzes IDL to LDL along with LPL=lipoprotein lipase), stimulates LCAT (which forms mature HDL from CE and PL)
Term
HL (2) / regulation
Definition
1. hydrolyzes IDL to LDL along with LPL; 2. TG hydrolysis produces small HDL3 from larger HDL2 - acts on HDL to remove TG, PL, and may increase clearance. (this enzyme is cleared by kidney). INSULIN inhibits this enzyme.
Term
ABC1
Definition
ATP binding cassette transporter: transports FC out of cells to be picked up by HDL
Term
B48
Definition
attaches to CM, synthesized in the intestine, structural function
Term
ApoE
Definition
attaches to CM remnants, VLDL, IDL; synthesized in liver/anywhere; is a ligand for LDLR and CM remnant receptor
Term
B100
Definition
attaches to VLDL, IDL, LDL; synthesized in liver; is LDLR ligand and also structural
Term
ApoAI, ApoAII
Definition
attach to HDL (CM), synthesized in liver and intestine, structural protein and also cofactor for LCAT and HL
Term
ApoCII
Definition
lipoprotein: HDL>CM, VLDL, IDL. synthesized in liver, is LPL cofactor
Term
CM
Definition
source: small intestine (diet), destination: tissues (remnant to liver), function: transport exogenous TG
Term
VLDL
Definition
source: liver, destination: tissues (converted to IDL), function: transport endogenous TG
Term
LDL
Definition
source: IDL, destination: tissues and liver, function: transport cholesterol
Term
HDL
Definition
source: liver, destination: tissues and liver, function: reverse cholesterol transport
Term
fasting sample eliminates
Definition
CM
Term
total cholesterol indicates
Definition
LDL
Term
triglyceride measurement indicates
Definition
CM and VLDL
Term
how is HDL measured?
Definition
directly, after precipitation of ApoB100-containing proteins (VLDL, IDL, LDL)
Term
T/F: LDL in a standard lipid profile is an estimation
Definition
true
Term
LDL=
Definition
TC-HDL-TG/5
Term
TG restriction for fasting lipid profile
Definition
<400mg/dl, but best at <250mg/dl
Term
friedewald equation
Definition
LDL=TC-HDL-TG/5
Term
TC, TG, HDL, LDL standard values
Definition
TC<200, TG<150, HDL>40, LDL<130
Term
Type I lipoprotein disorder
Definition
elevated chylomicrons because can't make VLDL because of mutation in LPL gene
Term
type IIa lipoprotein disorder
Definition
familial hypercholesterolemia - elevated LDL
Term
type IIB lipoprotein disorder
Definition
familial combined hyperlipidemia - elevated LDL and VLDL
Term
lipoprotein disorders associated with premature vascular disease
Definition
II, III, IV
Term
lipoprotein disorders associated with pancreatitis
Definition
type V
Term
remnant receptor disease
Definition
ApoE defect
Term
ApoA1 defect
Definition
very small HDL
Term
factors affecting LDL blood levels (5)
Definition
increased VLDL synthesis, down-regulation of LDLR, increased ApoE-containing particles that compete for the LDLR, defective or decreased expression of LDLR, defective ApoB100
Term
increased VLDL synthesis (3)
Definition
familial combined hyperlipidemia, polygenic familial hypertriglyceridemia, dietary FFA
Term
familial combined hyperlipidemia
Definition
autosomal dominant 1/200, type II disorder, elevated LDL and VLDL
Term
familial dysbetalipoproteinemia
Definition
increased ApoE-containing particles competing for LDLR
Term
down-regulation of LDLR (2)
Definition
diet, FFA influx
Term
familial hypercholesterolemia
Definition
defective or decreased expression of LDLR (doesn't affect triglycerides)
Term
defective ApoB100
Definition
another form of familial hypercholesterolemia
Term
excess calories, fat, cholesterol -> (2)
Definition
1. increased TG/cholesterol to liver > downregulation of LDLR and overproduction of VLDL, 2. obesity with increased insulin resistance > increased HDL catabolism, decreased LPL activity, VLDL overproduction
Term
dietary management of lipid disorders (4)
Definition
reduce saturated fat and cholesterol; fiber and plant sterols inhibit cholesterol absorption; substitute w/ things like olive oil; exercise and restrict calories to prevent obesity
Term
medical therapy for lipid disorders (5)
Definition
bile acid sequestrants, cholesterol absorption inhibitors, hmg coa reductase inhibitors, niacin, fibrates
Term
bile acid sequestrants
Definition
"resins" decrease reabsorption of bile acids so more cholesterol is excreted; significant GI side effects
Term
cholesterol absorption inhibitors
Definition
intracellular action
Term
hmg coa reductase inhibitors
Definition
"statins" upregulate LDL receptors (mechanism?); low but serious side effects
Term
niacin as treatment for lipid disorders
Definition
inhibits VLDL secretion; annoying side effects
Term
fibrates as treatment for lipid disorders
Definition
reduce triglycerides via LPL
Term
metabolic syndrome
Definition
high TG, TC, LDL, fasting glucose, low HDL
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