092614 lipids Flashcards
fates of cholesterol
some examples:
sex hormones
mineralcorticoids
glucocorticoids
vitamin D
primary bile acids
how is cholesterol cytotoxic?
excess cholesterol can lead to:
formation of cholesterol crystals
triggering of apoptosis
formation of toxic oxysterols
disruption of membrane domains that are crucial for fxn of enzymes and signaling molecules
contribute to machanisms that promote atherosclerosis
four steps of cholesterol synthesis
three acetates condense to make mevalonate
mevalonate converted to phosphorylated 5-C isoprene
six isoprenes polymerize to make 30-C linear squalene
squalene cyclizes to make four rings which are modified to make cholesterol
how is mevalonate made from acetyl-coA
2 acetyl coAs form acetyoacetyl-coA
then acetyl-coA and acetoacetyl-coA combine, in a step catalyzed by HMG-coA synthase, to form beta hydroxyl beta methylglutaryl-coA (HMG-coA)
HMG-coA and 2 NADPH, in a step catalyzed by HMG-coA reductase, form mevalonate
what is the rate limiting step in cholesterol synthesis
HMG-coA reductase
where is most cholesterol made
liver. then it is exported as bile acids, biliary cholesterol, or cholesteryl esters.
cholesteryl esters are the storage form of cholesterol
how are cholesteryl esters different from cholesterol
they are more non-polar than cholesterol b/c they have a fatty acid esterified to the oxygen
what happens to cholesteryl esters?
they are transported in lipoproteins to other tissues or stored in the liver
apolipoproteins
proteins on the surface of a lipoprotein particle, which is used to carry lipids through plasma
what does the interior of lipoprotein particles contain
cholesterol, triglycerides, cholesteryl esters
what does the surface of lipoprotein particles contain
apolipoproteins and phospholipid monolayer
which lipoproteins are atherogenic (found in plaques)
VLDL VLDL remnants IDL LDL Lp (A)
what is a chylomicron made of primarily?
triglycerides
which lipoproteins have the highest content of triacylglycerls
chylomicrons
which kind of lipoproteins have the highest content of proteins and phospholipids
HDL
what are the core lipids of HDL?
cholesteryl ester
are apolipoproteins exchangeable or non-exchangeable
can be exchangeable and non-exchangeable
in the case of LDL-they are non-exchangeable
what can apolipoproteins do?
they can change conformation to adjust to changing lipid contents and metabolic states of the lipoproteins
they can activate or inhibit plasma enzymes
they serve as ligands for cell surface receptors
NPC1L1 does what
mediates intestinal cholesterol absorption
called Niemann Pick C1 Like 1 protein
ABCG5/G8 does what
export plant sterols back into the intestinal lumen
they are ATP-binding cassette (ABC) half transporters
exogenous pathway
dietary fats are packaged into chylomicrons
in the blodstream, lipoprotein lipase releases free fatty acids from the chylomicrons to give to the adipose tissue and muscle.
remnants of chylomicrons are taken up by liver. liver can use these remnants to make bile acids and cholesterol to release back to the intestine
sitosterolemia
autosomal recessive disorder with mutations in either of the genes that encode ABCG5 and ABCG8
result is that they absorb unusually large amounts of plant sterols, and because they fail to excrete these dietary sterols into the bile, they accumulate plant sterols in the blood and tissues
accumulation of plant sterols is associated with tendon and subcutnaoues xanthomas and increased risk of premature coronary heart disease
chylomicrons’ main apolipoprotein is
B-48
how long do chylomicrons remain in the blood after a fat-containing meal?
3-6 hours
role of ApoC-II in a chylomicron
activates lipoprotein lipase to allow free fatty acid release for fuel in adipose tissue, heart, skeletal musc
lipoprotein lipase
found on capillary endothelium in heart, skel musc, adipose tissue, mammary gland, etc
required for hydrolysis of fatty acids derived from triglycerides of chylomicrons and VLDL so that the fatty acids can be delivered to tissues
what do you get when lipoprotein lipase works on a chylomicron or VLDL?
shrunken triglyceride-rich particle (chylomicron remnants, IDL, and LDL). cholesterol, phospholipids, and apolipoproteins are transferred to HDL
when is LDL transcriptionally activated?
when glucose levels in plasma are elevated and the release of insulin is stimulated
during prolonged fasting, what would LPL activity be?
LPL activity of adipose tissue falls to prevent storage of fatty acids
when chylomicrons are depleted of their dietary triglyceride through LPL, what happens to their remnants?
remnants go to liver to release dietary cholesterol.
endocytosed at the liver through a process that requires apoE as a ligand for hepatic receptors like LDL receptor or the LDL receptor-related protein (LRP)
LRP’s significance
backup receptor for the uptake of apoE enriched remnants of chylomicrons and VLDL
VLDL does what
transport endogenous lipids that the liver makes
VLDL is made by the liver when triglyceride production is stimulated by an increased flux of free fatty acids or by increased de novo synthesis of fatty acids by the liver
cholesteryl esters and triglycerides from excess fatty acids and cholesterol are packed into the core of VLDL and exported to peripheral tissues
apolipoproteins of chylomicrons are acquired from where
some are made by intestinal epithelial cells and others are acquired from HDL after chylomicrons have been secreted into the lymph and enter plasma
microsomal tryglyceride transfer protein does what
it transfers triglyceride to the VLDL core (after being made in the ER, triglyceride is transferred by MTP to newly made apoB-100 to make VLDL
also transfers triglyceride to chylomicrons in intestine
pts with dysfunctional MTP have what happen
they fail to make any of the apoB-containing lipoproteins (chylomicrons, VLDL, LDL)
causes abetalipoproteinemia (fat in stool, vitamin deficiency, developmental delays)
cholesterol ester
storage form of cholesterol
endogenous cholesterol in excess of need for membrane synthesis is metabolized to cholesterol ester by what
ACAT (acyl-CoA cholesterol acyltransferase)
an important regulator of cellular cholesterol pool that serves as substrate for bile acid and steroid hormone production
ACAT-2 is found where
intestine and liver, where cellular free cholesterol is esterified before triglyceride-rich lipoproteins (chylomicrons and VLDL) are assembled
ACAT-1 is found where
macrophages including foam cells
role of apoC-II in VLDL
same as for chylomicron-activates lipoprotein lipase
VLDL have what two fates (their half life is less than 30 minutes)
40-60% are celared from plasma by the liver via LDL receptors and LRP which recognize ligands-apoB100 and apoE-on the remnants
LPL and hepatic lipase convert the remainder of the remnants/IDL to LDL by removing additional triglyceride
just about all LDL particles in the plasma are derived from
VLDL
LDL is enriched in
cholesterol or cholesteryl esters
what determines LDL production
rate of removal of VLDL remnants
LDL does what
deposits cholesterol in peripheral tissues
what enables binding of LDL to LDL receptor
apoB-100
what is the most effective way to modulate plasma LDL levels?
manipulation of hepatic LDL receptor gene expression (because the liver expresses a large complement of LDL receptors and is responsible for removing 75% of all LDL in the plasma)
what other tissues have LDL receptors other than the liver?
muscle and adipose tissue
half life of LDL
2.5 days
most common cause of autosomal dominant hypercholesterolemia
mutation of LDL receptor gene
regulation of LDL receptor expression is mediated by
transcription factors called sterol regulatory element binding proteins (SREBPs) and SREBP cleavage activating protein (Scap)
proprotein convertase subtilisin/kexin type 9 (PCSK9)
serine protease that decreases the steady state level of expression of LDL receptor on the hepatocyte cell membrane (binds to the EGF-A domain of LDLR and causes internalization and targeting to lysosome)
high interest in this as a cholesterol lowering target!
lipoprotein (a) or Lp(a) is
an LDL-like particle where apoB-100 is covalently bound to apolipoprotein(a)
half life in ciruclation is 3-4 days
a risk factor for CV disease
what will LDL do eventually in peripheral tissues if HDL can’t kick in?
will eventually deposit cholesterol in peripheral tissues
HDL is good cholesterol in that it will do the opposite-it will take cholesterol from peripheral tissues and take it back to liver for excretion via bile
how is HDL athero-protective
anti oxidant anti thrombotic reduces vascular adhesion molecules on endothelium stimulates endothelial repair promotes endothelial fxn lowers inflam stabilizes atherosclerotic plaques
most abundant proteins in HDL
HDL in general has a lot of protein!
apoA-I is most abundant
ApoA-II is second most abundant
(HDL also has C apolipoproteins and lecithin-cholesterol acyl transferase)
ApoA-I mutations can
cause HDL deficiency
reduce capacity of apoA-I to activate LCAT
ATP binding cassette transporter (ABCA1) does what
helps release free cholesterol to apoA-I to make discoidal HDL (promotes efflux of cellular phospholipid and cholesterol to lipid-free apoA-I)
where is ATP binding cassette transporter (ABCA1) expressed
it’s a membrane transporter expressed in liver, intestine, macrophages, brain, other tissues
loss of fxn mutations of ABCA1 result in what disease
Tangier disease-extremely low levels of HDL
majority of prebeta-HDL (discoidal HDL) formation occurs where
liver and intestine (also the sites of apoA-I synthesis and ABCA1 expression)
where is lecithin-cholesterol acyl transferase (LCAT) found
secreted by liver, circulates in blood and at times associated with HDL
lecithin-cholesterol acyl transferase (LCAT) ‘s fxn is
to help form the cholesterol ester core of HDL-after free cholesterol is acquired by the prebeta HDL, the free cholesterol is esterified by LCAT
how does discoidal HDL become spherical?
through esterification of cholesterols–because esterified cholesterol is more hydrophobic and moves into the core to plump up the HDL
apoA-I on HDL activates
LCAT
ABCG1 does what
transfers cholesterol to spherical HDL
expressed in spleen, thymus, lung and brain, liver and macrophages
contributes to HDL remodeling
alters distribution of cholesterol on cells’ membranes and allows its removal by HDL
cholesteryl ester transfer protein (CETP)
exchanges lipid btwn LDL and HDL-promotes transfer of cholesterol ester from HDL to VLDL, IDL and LDL in exchange for triglyceride
scavenger receptor BI (SR-BI)
HDL receptor-a good receptor
expressed in liver, ovaries, testes, adrenal glands
endothelial lipase
hydrolyzes HDL phospholipids, generating smaller HDL particles that are catabolized faster
modifies HDL to such an extent that it binds less to SR-BI
selective uptake in the case of HDL binding to SR-BI
only lipid is transferred to cells (entire HDL particle is not internalized)
enterohepatic circulation of cholesterol
in liver, cholesterol is secreted into bile either directly or after conversion to bile acids (cholesterol is converted to bile acids by cholesterol 7alpha hydroxylase)
however, only 5% of the bile salts are actually lost in feces–the rest gets reabsorbed by the intestines (this reabsorbed portion goes back to the liver by ENTEROHEPATIC CIRCULATION-so the bile salts are recycled)
regulation of cholesterol synthesis and transport
covalent modification of HMG-coA reductase
transcriptional regulation of HMG-coA gene
activation of ACAT
transcriptional regulation of LDL receptor
AMP dependent protein kinase regulates cholesterol metabolism how
when AMP rises, the kinase phosphorylates HMG-coA reductase, leading to decreased activity of HMG-coA reductase and decreased cholesterol synthesis
SREBPs (sterol regulatory element binding proteins)
longer-term regulation of HMG-coA reductase through transcriptional control
this protein activates transcription of HMG-CoA reductase and LDL receptor
when cellular sterol levels are high, SREBP is not active
do oxidized LDL bind to the same receptors as non-oxidized?
no, oxidized is taken up by scavenger receptors not LDL receptors
