Lipoproteins - Abali 2/19/16 Flashcards
total cholesterol calculation
Friedwald equation and application
LDL + HDL + VLDL
*where VLDL = triacylglycerol/5
LDL cholesterol = total chol - HDL chol - (total triglycerides/5)
blood lipid levels (norms)
mg/dl
total lipid = 400-800
triacylglycerol = 40-160 (male), 35-135 (female)
total chol = 120-210
chol (free) = <160 - >240
phospholipids = 150-380
fatty acids = 8-14
cholesterol
- definition
- where synthesized
- transport
27-C four-ringed, hydrophobic molecule synthesized by virtually all cells
- esp liver, intestine, adrenal cortex, repro tissues
- transported in plasma in lipoproteins
- typically in esterified form (+ FA; not as free chol)
cholesterol fx
- structural component of membranes
- abundant in myelin sheaths of CNS
- precursor of
- bile salts
- 5 classes of steroid hormones (mineralocorticoids, glucocorticoids, androgens, estrogens, progestins)
- vitamin D
cholesterol and link to cardiac pathologies
stem from regulation of amt of cholesterol in the serum and the propensity of LDL to accumulate in arterial walls (stroke, MI, etc)
cholesterol structure
- four fused hydrocarbon rings (“steroid nucleus” A-D)
- 8C branched chain “tail” at C17 (D ring)
- OH group at C3 (A ring)
- double bond between C5=C6 (B ring)
**reactive sites for esterification and redox rxns**
- when esterified: FA attached to C3
- more hydrophobic than free/unesterified chol
sources of liver cholesterol
- de novo synthesis in liver: VLDL (endogenous pathway of lipoprotein metab)
- diet cholesterol: chylomicrons from intestine (exogenous pathway of lipoprotein metab)
- synthesis in extrahepatic tissues (via HDL and LDL)
**each of the lipoproteins fx to transport cholesterol to/from peripheral tissues and liver
exit of cholesterol from liver
liver moves cholesterol out via…
- secretion of VLDL
- free cholesterol secretion in bile
- conversion of chol into bile acids/salts
only mechanism body has to eliminate cholesterol:
excretion of bile acids (and derivative bile salts) in feces
cholesterol biosynthesis
- location
- C, cofactor, energy?, enzyme
know pathway [written]
- takes place in almost all cell types in cytosol
- major organs of de novo synth
- liver
- intestines
- honorable mention: adrenal cortex, testes/ovaries, fetus
- all C sourced from acetyl CoA
- major cofactor: NADPH
- ATP consumed
- major step catalyzed by HMG-CoA reductase
rate limiting step of chol synthesis
committed step catalyzed by HMG-CoA reductase
HMG CoA → mevalonic acid + free CoA
- uses 2 NADPH
- HMG-CoA reductase expression inhibited by cholesterol (feedback inhib)
(mevalonic acid → squalene, folds up → lanosterol → cholesterol)
fates of mevalonic acid (besides cholesterol synthesis)
also makes terpenes/isoprenoids/isoprenes
- farnesyl pyrophostphate, geranylgeranyl phyrophosphate: conjugated with proteins, serve as lipid anchors (ex. ras)
- dolichol pyrophosphate: req for dolichol pathway of N-linked posttransl glycosylation
- ubiquinones: reduced to ubiquinols like Coenzyme Q, donate e to etc in oxphos
fates of cholesterol
- bile acids
- steroid hormones
- cholesterol esters
- modified proteins like hedgehog
- vitamin D
esterification of cholesterol
whats the point?
enzymes involved
esterification makes chol more hydrophobic : makes it easier to package, store, transport
- ACAT (liver) : acyl CoA cholesterol acyl transferase
- free cholesterol (from diet/de novo synth)→ cholesteryl esters
- hydrophobic, cant be incorp’d into membranes or transported through them
- stored in lipid droplets in cytosol of hepatocytes and steroid-producing cells
- LCAT (bound to HDL in blood) : lecithin cholesterol acyl transferase
- cholesterol → cholesteryl esters
- uses FA from phospholipid lecithin (such as phosphatidyl choline) to esterify cholesterol in peripheral tissues
- esters stored in HDL, taken to liver
regulatory effects of excess cholesterol
rising intracellular chol concentration…
- reduces action of HMG-CoA reductase on two fronts
- stimulates proteolysis of existing HMG-CoA reductase
- downregulates HMG-CoA reductase gene expression by downregulating RNA poly II activity
- RNA poly II activity also stim by insulin (growth signal), inhib by glucagon (to save acetyl CoA for TCA cycle)
- activates ACAT
* shuttles existing chol to esters for storage - inhibits uptake of chol into liver cells
liver is the main clearinghouse!
short term hormonal regulation of chol synthesis
(effect of insulin and glucagon)
HMGR (HMG CoA reductase) is the main target
- has an active form (not P’d), and an inactive form (P’d)
conditions of low energy/low glucose
- glucagon and epi (in effort to raise glucose levels and prevent it from being drawn off in acetyl CoA for chol synth) stimulate the inhibitor of PPI-1 (phosphoprotein phosphatase inhibitor-1)
- __when active, PPI-1 inhibits phosphoprotein phosphatase (req for glycogen synth)
- lower PPI-1 means more PP means more glycogen synth!
- i.e. high [AMP], glucagon, sterols upregulate AMPK (AMP-activated protein kinase), which phosphorylates and deactivates HMGR
conditions of high energy/high glucose
- insulin stimulates removate of phosphate via HMGR-phosphatase, which dephosphorylates inactive HMGR and makes it active
long term effects of intracell chol levels on HMGR transcription effected via tf SREBP
long term hormonal regulation of chol synthesis
transcriptional regulation via SREBP2
(SREBP: sterol regulatory element binding protein)
- SREBP2 is a cholesterol sensor in ER; main regulator of HMG-CoA reductase activity
low chol in ER
- vesicles with SREBP2 move to Golgi → proteases cleave SREBP2 → N-term moves to nucleus and enhances transcription of genes (including HMG-CoA reductase, LDL receptors)
high chol in ER
- no tf action of SREBP2 fragment
statins
(indication, mech of action)
(competitive) HMG-CoA reductase inhibitors
reduce risk of heart disease (CAD, MI)
ex. lovastatin
mechanism of action
- HMG-CoA analogs, competitively bind to HMG-CoA reductase and block chol synth
- lower levels of de novo synth in liver (and size of liver chol pool) trigger more efficient retrieval of LDL-cholesterol by liver
- how? upregulation of LDL receptors (number and/or activity) on hepatocytes!
hepatic cholesterol homeostasis: summary
- 4 regulatory mechs
- regulation of HMG-CoA reductase (HMGR) activity and levels
- transcription (long term)
- proteolytic degradation (high intracell chol)
- hormonal reg (short term)
- insulin (upreg)
- glucagon (downreg)
- regulation of excess free intracell chol via ACAT
- regulation of plasma chol via…
- LDL-mediated uptake
- HDL-mediated reverse transport (periph tissues back to liver)
- inhibition of chol synth by drugs (statins: competitive inhibitors of HMGR)
cholesterol dysregulation
LDL levels linked to incidence of coronary artery disease
- high LDL linked to atherosclerosis
- oxidized LDL : plaque : can rupture and resulting clot can block blood flow
- overall…
- narrowing of artery walls
- lower blood/oxygen supply to heart
- MI
- death
xanthomas
cutaneous deposition of lipidosis
collection of cholesterol-laden foam cells deposited at…
- hands and feet : tendon xanthomas : hypercholesterolemia + NO hypertriglyceridema
- over joints : tuberous xanthomas : hypercholesterolemia + YES hypertriglyceridema
- under skin (eyelid) : xanthelasmas
SLOS
Smith-Lemli-Opitz Syndrome
(chol deficiency due to mutation)
metabolic disorder caused by mutation in DHCR7 (7-dehydrocholesterol reductase) on chromosome 11 (req for chol synth)
- pt with SLOS unable to make sufficient chol for normal growth and devpt
-
facial features
- microcephaly, ptosis (drooping eyelid), broad nasal bridge, upturned nose, micrognathia (undersized jaw), cleft palate
-
limb anomalies
- short thumbs, polydactyly, syndactyly of second/third toes (most reported clinical finding)
lipids in the blood
either FA associated with albumin or lipoprotein (lipid + protein)
lipoprotein structure
surface
1. amphipathic lipids: phospholipids, unesterified cholesterol
2. proteins: lipoproteins
anhydrous core
1. triacylglycerols (aka TAG, TG)
2. cholesteryl esters (aka CE)
*during transport, each class of lipoproteins undergoes change in coposition*
apolipoproteins
- definition (“apo”)
- function
lipid-binding proteins in blood resp for transport of PL, C (surface); TAGs, CE (anhydrous core) between organs
- “apo” = protein in lipid-free form
functions
- recognition sites or ligands for receptors
- structural components
- activators or coenzymes for enzymes involved in lipid metab
classification of lipoproteins
placed into general classes on basis of
- electrophoretic mobility
- density
- tissue of origin
- average composition of lipoprotein
broad particle classes: chylomicron, VLDL, LDL, HDL
size/density of lipoproteins
chylomicrons
- lowest density, largest size.
- highest % lipid, lowest % protein.
progression moving down list: more dense, higher protein:lipid ratio
VLDL
LDL
HDL
general phases of lipoprotein metabolism
1. processing: changes in composition of surgace and core components during transit : conversion to remnant form
2. clearance from blood: in liver and other tissues via receptor-mediated endocytosis
classification of apolipoproteins
- several fx (ex. recognition sites for receptors, acrivators/coenzymes of metabolic enzymes), but not all fx are known
- some are req structural components of lipoproteins, others are transferred freely between liproporteins
-
divided by structure and fx into 5 major classes: A, B, C, D, E
- most classes have subclasses (I, II, etc)
chylomicron (CM) snapshot
- source
- fx
- major apolipoproteins
- source: intestine
- fx: transport of dietary TAG
- major apolipoproteins: B48, CII, CIII, E
very low density lipoprotiens (VLDL) snapshot
- source
- fx
- major apolipoproteins
- source: liver
- fx: transport of endogenously synth’d TAG
- major apolipoproteins: B100, CII, CIII, E
low density lipoprotein (LDL) snapshot
- source
- fx
- major apolipoproteins
- source: formed in circ by partial brakdown of IDL
- fx: delivers cholesterol to periph tissues
- major apolipoproteins: B100
high density lipoprotein (HDL) snapshot
- source
- fx
- major apolipoproteins
- source: liver
-
fx: removed “used” chol from tissues and takes it to liver (reverse transport)
- “reservoir” for apoproteins donated from other lipoproteins
- major apolipoproteins: AI, AII, CII, CIII, E
3 pathways for lipoprotein metabolism
1. exogenous pathway: originates in intestine, involves dietary lipids (in chylomicrons)
2. endogenous pathway: originates in liver, involves mostly de novo synthesized lipids (in VLDL, LDL, IDL)
3. reverse cholesterol transport pathway: deals largely with cholesterol (in HDL) from peripheral tissues
enzymes for TAG metabolism
TAG → FAs + glycerol
- lipoprotein lipase
- hepatic lipase
3 key apoproteins found in “reservoir”
“reservoir” = HDL
- holds, loses, regains apoCII, apoCIII, apoE as needed
1. apo CII: lipoprotein lipase activator (essential cofactor for LPL)
- synth in liver, held on HDL
- essential cofactor for lipoprotein lipase (key for reducing TAG content, changing TAG:CE ratio of anhydrous core, altering particle shape)
2. apo CIII: lipoprotein lipase inhibitor
3. apo E: ligand for receptor-mediated clearance of chylomicrons by liver
- synth in liver, picked up from HDL by chylomicrons
- once on chylomicron remnants (and/or VLDL/IDL remnants), binds to LRP1 (LDL receptor-related protein 1) on hepatocytes
- remnants undergo endocytosis
lipoprotein lipase
(basic fx and what happens to products)
cleaves FAs from TAGs in anhydrous core of lipoproteins [cofactor: apoCII on CM, VLDL)
- drops TAG content (changes TAG:CE ratio)
- alters particle shape
what happens to liberated FAs?
- can be taken up by adipose for storage in resynth’d TAGs
- can be taken to metabolically active periph tissues for use as energy
apo C-II
lipoprotein lipase activator (essential cofactor for LPL)
- synth in liver, held on HDL
- essential cofactor for lipoprotein lipase (key for reducing TAG content, changing TAG:CE ratio of anhydrous core, altering particle shape)
apo C-III
lipoprotein lipase inhibitor
apo E
ligand for receptor-mediated clearance of chylomicrons by liver
- synth in liver, picked up from HDL by chylomicrons
- once on chylomicron remnants (and/or VLDL/IDL remnants), binds to LRP1 (LDL receptor-related protein 1) on hepatocytes
- remnants undergo endocytosis
lipoprotein lipase
(location, specifics of fx and products)
location: attached to endothelial cells in blood cap walls via interaction with GAGs
fx: acts on chylomicrons and VLDLs, catalyzes hydrolysis of TAGs → FAs + glycerol
- cofactor: apoCII (on lipoprotein)
product fates: 80% taken up, 20% shuttled back to liver indirectly
- if immediately taken up: stored (adipose), used (muscle, heart)
- if not: long chain FAs are transported by serum albumin until taken up
hepatic lipase
- source/location
- fx
source/location: synth in hepatocytes
- primarily found on liver endothelial cells, HSPG (heparin sulfate proteoglycan) in space of Disse
- transported from liver to cap endothelium of adrenals, ovaries, testes : releases lipids from lipoproteins for use
fx: phospholipase (also has triglyceride hydrolase activity)
- final CM processing: hydrolyzes triglycerides, excess surface PL
- completes IDL→LDL processing
- helps convert HDL2→HDL3 (removes triglyceride and phospholipid from HDL2)
exogenous pathway
processing of dietary cholesterol
- sources
- stepwise processing & locations
- sourced from foods derived from animals only
processing
- intestinal lumen: cholesteryl esters are hydrolyzed, chol and other sterols are packaged → mixed micelles containing bile salts, fatty acids, monoglycerides
- jejunum: epithelial cells pick up via indiscriminate binding to NPC1L1 (Niemann-Pick C1-Like protein 1) : most sterols expelled, chol retained
- intestinal epithelial cells: use MTP (microsomal triglyceride transfer protein) to assemble CM from apoB48 + TAG + PL + C + CM
-
transit to liver: CM exported into lymphatic system : thoracic duct to subclavian vein
- in blood: pick up apoCII (LPL cofactor) and apoE (needed for CM remnant endocytosis) - mostly from HDL
-
in blood: LPL (on endothelial surface) removes TAGs [cofactor: apoCII]
- CM remnant dissociates from LPL, return apoCII to HDL
-
into liver: CM remnants enter space of Disse, where HL (hepatic lipase) removes more TAGs.
- apoE binds to LRP1 (LDL receptor-related protein 1) on hepatyctes → endocytosis.
-
in liver: lysosomes degrade CM remnants
- dietary chol either repackaged in VLDLs and sent out or converted to bile salts
- dietary chol inhibits liver chol synth
how do fat soluble vitamins get into liver?
A, D, E, K absorbed in small intestine, transported with CM to liver
fasting blood sample
- what’s measured, what’s not (why?)
total TG = TG inside all lipoproteins (CM, CM remnants, VLDL, IDL, LDL, HDL)
fasting blood sample = VLDL, IDL, LDL, HDL
- CM clearance t1/2 after meal = minutes, so fasting blood sample is taken to avoid contamination by CM and CM remnants
- after overnight fast, very little CM and CM remnants in blood
endogenous pathway1
metabolism of VLDL
(FAs to VLDL remnants/IDL)
- VLDL synthesized in liver from FAs
- some FA synth by liver from excess carbs, lots received on blood
- FAs esterified into TAGs → TAGs packaged into VLDLs → VLDLs released into blood (t1/2 = hours)
- nascent VLDL contains apoB100, apoE, apoCII
- additional apoE and apoCII donated from HDL
-
apoCII is cofactor for LDL : degrades TAGs in VLDL and delivers liver-origin FAs to adipose and other tissues
- LPL action on VLDL → VLDL remnant (aka IDL)
- apoE is ligand for LRP1 receptor : 50% IDL moves into liver
- rest of IDL converted to LDL (with B100)
endogenous pathway2
(VLDL remnants/IDL to LDL)
VLDL remnants = IDL (with apoE, apoB100) : TAG transport and LDL precursor
- approx 50% IDL removed from circ via apoE-LRP1/endocytosis
- other 50% IDL converted to LDL, stay in circ
- LPL and HL (hepatic lipase) remove TAGs and PLs → enrich CE content during processing into LDL
endogenous pathway3
LDL delivery
LDL (with B100) : cholesterol transport (major carrier in blood) and delivery
- apoB100 acts as ligand for LDL receptors in cells throughout body (“unlocks doors” in cells for chol delivery)
- LDL t1/2 = days, so comprises most of what you see in a fasting sample
endogenous pathway4
LDL clearance from blood
- 2/3 of LDL in circ taken up by liver via apoB100 binding to LDL receptor
-
1/3 of LDL taken up by peripheral tissues (mostly) via apoB100 binding to LDL receptor
- significant source of chol for peripheral tissues (supplement endog synth)
*LDL receptor (and apoB100 binding) is not the only means of LDL clearance from blood!
endogenous pathway5
regulation of LDL receptors and chol intake
hepatocytes and periph cells display LDL receptors based on their need for chol
- SREBP2 senses chol in ER membrane and upregulates LDL receptor synth (or not)
- once LDL is endocytosed, lysosomal acid lipase hydrolyzes TAG and CE in lysosomes
- LDL receptors can be recycled back into pl membrane to repeat
regulation (key part of chol-dependent LDL receptor # reg)
- liver secretes enzyme PCSK9 into blood, signals LDL receptors not to recycle to pl mem; favors lysosomal degradation
endogenous pathway6
non-LDL-receptor-mediated LDL clearance
macrophases and some endothelial cell types possess SR-A (scavenger receptor)
-
SR-A: lower affinity (for LDL), but broader specificity (can bind normal and damaged LDL)
- greater affinity for oxidized/damaged LDL
- endocytosed particles taken to lysosome : free cholesterol released into cytosol
accounts for good chunks of LDL uptake in intestine and spleen
endogenous pathway
summary
- VLDL syntehsized in liver with apoB100, apoCII and apoE from HDL
- VLDL moves through circ until it associates with LPL [cofactor: apoCII] : TAG hydrolyzed, FA liberated to local tissues (stored as fat/used as egy) : VLDL shrinks → IDL → LDL (apoCII returned to HDL)
- some LDL heads back to liver (via apoE), some LDL returns apoE to HDL and hits extrahepatic tissues via LDL-receptor and SR-A
LDL is the route through which chol is transported from liver to tissues (supplements small amt of endog synth chol)
apoB100 synth
case of differential post-translational mRNA editing
-
apoB mRNA is made in liver and small intestine
- in sm int only, CAA (Glu) C deaminated → U
- intestine makes a truncated version of the transcript, apoB48 - incorp into chylomicrons
- liver makes full-length version of transcript, apoB100 - incorp into VLDL
reverse cholesterol transport pathway
removes excess chol from peripheral tissues and returns it to liver (body’s chol “clearinghouse”) via HDL
chol from liver → tissues: chol transport
chol from tissues → liver, then: reverse chol transport
- liver: makes apoAI (LCAT activator), secreted into blood
- in blood: lipid + apoAI = HDL (apoAI is signature HDL protein, makes up 70% of apoprotein in HDL)
- later on in blood: + apoAII (activator of HL), apoCII, apoCIII, apoE
fx
- circulating reservoir of apolipoproteins
- apoCII - cofactor for LPL
- apoE - ligand for receptormediated endo of remnants (VLDL remnants/IDLS and CM remnants)
CETP
cholesterol ester transfer protein
- secreted from liver, circulates in plasma (bound mainly to HDL)
- promotes redistribution of CE, TG, and PL (to lesser extent) between pl lipoproteins
- overall effect: net mass transfer of…
- CE: from HDL to VLDL
- TG: from VLDL to HDL
- reduction in HDL size/chol content : “remodeling”
following CETP action, HP removes TGs from HDL
HDL synthesis
1. liver/intestine: apoAI + PL + C = nascent HDL
-
key apoprotein: apoAI to start
- poorly lipidated: PL (phosphatidylcholine) and C
- apoAII, apoE, apoCs aquired later in circ
- disc shaped
2. ABC A1 (ATP-Binding Cassette transporter A1) enriches HDL with PL (phosphatidylcholine) and C [both from pl mem] → discoidal nascent HDL
3. C loaded onto HDL is immediately esterified by LCAT [transfers FA from phosphatidylcholine to C; cofactor: apoAI] → more hydrophobic CE (sequestered in anhydrous core)
- discoidal nascent HDL picks up more CE via LCAT → relatively CE-poor HDL3 → relatively CE-rich HDL2
- CETP pulls the CE/TG swap between HDL/VLDL : keeps product inhibition of LCAT off
- VLDLs are catabolized to LDL → CEs on VLDL ultimately taken up by liver!
4. CE taken up by liver via SR-B1 (scavenger receptor B1) which binds HDL : selective uptake of CE from HDL particle
- HL (since it can degrade TG and PL) helps convert HDL2 → HDL3 [activated by apoAII]
5. ultimately, HDL is degraded by liver
- chol either excreted in bile salts or repackaged in VLDL for distribution to tissues
cholesterol synthesis in liver: regulation
regulated based on…
- chol arriving through HDL
- brought from periph cells, which add it to HDL
- dietary chol returned by CM remnants
CAD
coronary artery disease
- leading cause of natural death in the world
- correlated with levels of plasma chol/TG-containing particles
- steady state levels in circ can be influenced by…
- genetic factors
- diet
- obesity
hyperlipidemia
either primary or secondary
- primary: can result from single inherited gene defect or combo of genetic and environmental factors
- secondary: result of metabolic disorder (DM, obesity, hypothyroidism, 1 biliary cirrhosis)
tx strategies: dietary intervention + drugs
hypertriglyceridemia
- criteria
- prevalence
- risks
- risk factors
total fasting pl TG > 150 mg/dl
due to abnormally high CM, VLDL, or both (either formed at high rate or removed at low rate)
- USA: 1/3 of adult pop has it, 0.2% has severe/v severe
-
risks
- __increased risk for CVD
- v severe hyper TGemia
- pancreatitis
- eruptive and tuberous xanthomas
-
risk factors:
- insulin resistance (obese/DM2), hypothyroidism, alcoholism, meds, pregnancy, genetic predisp
familial hyperchylomicronemia
Type I
lipoprotein lipase deficiency or apoCII deficiency
-
pathologic presence of chylomicrons after 12-14h fasting [fasting TG > 1000 mg/dl]
- creamy supnernatant when refrigerated
- features: eruptive xanthomata, lipemia retinalis, hepatosplenomegaly, focal neurologic symptoms (ex. irritability), recurrent epigastric pain with increased risk of pancreatitis
- key distinguishing features
- initial manifestation during childhood
- biochemically-demonstrated deficiency of LPL (or homozygous gene muts), apoCII
- low population prevalence (1/10M)
familial chylomicronemia
vs
primary mixed hyperlipidemia
manifestation
- FC: initial manifestation during childhood
- PMH: adulthood
function issue
- FC: biochemically-demonstrated deficiency of LPL, apoCII, or homozygous gene muts
- PMH: less severefx deficits, infrequent detection of gene mut
prevalence
- FC: low population prevalence (1/10M)
- PMH: more prevalent (1/1K)
extras: PMH has secondary factors more often and shows a greater elevation of total chol
treating pancreatitis in familiar hyperchylomicronemia
drop food intake : reduces production of CM (from dietary TG) and VLDL (from dietary TG and de novo synth from carbs)
- dropping pl TG < 500 mg/dl virtually eliminates repeat risk of hyperTGemia-induced pancreatitis
familial dysbetalipoproteinemia
Type III
dys (bad) beta (B100)
apoE deficiency
- overproduction or underutilization of IDL : increased IDL → increased TG (250-400) and chol (250-400)
- also see elevated plasma LDL (due to interrupted processing of VLDL)
- prevalence: 1-2/20K
-
features: xanthomas, accelerated coronary and periph vascular disease by middle age
- tuberous or tuberoeruptive xanthomata on extensor surfaces of extremities
- planar or palmarcrease xanthomata
- increased risk of CVD
- typically homozygotic for binding-defective apoE
- phenotypic expression usually requires: obesity, DM2, hypothyroidism
-
diagnosis
- increased VLDL-C:TG ratio
- apoE homozygosity
familial combined hyperbetalipoproteinemia
Type IIB
defects in synthesis, processing, or fx of LDL receptors
- relatively common: prevalence 2-5%
- autosomal dom with variable penetrance
- increased VLDL and LDL, decreased HDL
- VLDL increased → elevated serum TAG (500) and C
- excess TAG in liver/sm int can cause overproduction and delayed lipolysis of VLDLs and CMs
- increased CETP activity!
- increased CETP activity leads to rapid formation of small LDL particles → also high levels of small HDL particles
- see high LDL levels in these pts
- small HDL are renally excreted: see low HDL, apoAI levels in these pts
treatment for hypertriglyceridemia
- lifestyle mods
* weight loss, exercise, diest low in sat FAs, avoding excess alcohol - drugs to normalize pl TAG
- diabetes? wt control via exog insulin
- hypothyroidism? levothyroxine
- statin: drops VLDL production
- fibrate: activate PPARalpha tfs → increasedLPL activity, increased rate of FA beta-ox
- nicotinic acid (niacin/vitB3): activates niacin receptor 1 → inhibits lipolysis and release of FAs from adipose tissue
manifestations of primary hypercholesterolemia
v high levels of chol in blood
- high risk of developing CAD due to devpt of atherosclerosis
- buildup in other tissues: xanthomas contain chol-laden foam cells (location dependent on dylipidemia cause)
- hyperchol with no hyperTG : tendon xanthomas (Achilles tendons and tendons in hands/fingers)
- hyperchol with hyperTG : tuberous xanthoma (over joints)
- under skin (ex. eyelids): xanthelasma
atherosclerotic plaque devpt
- formation of fatty streak
- streak becomes altered to fibrous plaque
- plaque becomes altered to complicated lesion
fatty streak formation
- recruitment of monocyte macrophages to subendothelial space, infiltration of oxidized LDLs
- oxidized LDLs picked up by macrophages → foam cells → release cytokines and growth factors, leading to more infiltration, new cell division → fatty streak! (normal: form/spontaneously dissolve)
progression to fatty streak lesion
- further recruitment of monocyte-macrophages from plasma, sm muscle proliferation, collagen synth. elastin fibers begin to accumulate
progression to fibrous lesion
- lesion beings to extend into lumen. necrosis of foam cells, migration of smooth muscle cells through, some of which accumulate lipid droplets
progression to complicated lesion
- endothelial cell layer covering lesion lost → surface becomes thrombogenic, throbus forms. cellular debris, calcification, chol crystals form
can lead to complete occlusion (infarction) or disruption of plaque and thrombosis at distant site (stroke)
role of Lp(a)
highly-heritable independent, causal risk factor for atherosclerosis/ MI
- circulating abnormal variant of LDL
- Lp(a) is a lipoprotein made of: apo(a) molecule covalently linked by disulfide bond to apoB100
- certain SNPs of LPA gene might have higher CV risk levels
familial hypercholesterolemia
(hyperbetalipoproteinemia)
Type II
homo vs heterozygous
defects in synthesis, processing, fx of LDL receptors
- block in LDL degradation → elevated LDL with normal VLDL levels
- increased serum chol (>400) but normal TGs
- ischemic heart disease greatly accelerated
homozygous familial hypercholesterolemia
- low prevalence: 1/1M
- usually two alleles for defective LDL-receptor
- sometimes homozygous loss of fx muts for apoB100
- usually 10x lDL chol and without treatment, heart attacks in teens/twenties
heterozygous familial hypercholesterolemia
- most have mutant allele for LDL receptor
- 5% mutant apoB100
- 2% overactive PCSK9
- usually 2x LDL chol and without treatment, CAD before late 50s
apoA1 deficiency
complete loss of plasma apoAI, normal levels of LDL and TAG
- HDL collection/reverse transport of chol is interrupted bc you cant make normal HDL
- nonesterified chol is randomly deposited in excess (ex. cornea, vessels)
- features: xanthomas, mild to moderate corneal opacification/clouding
why is low HDL a bad thing?
- low HDL is most common lipoprotein abnormality among pts with CAD, component trait of metabolic syndrome
- most common genetic disorder: hypoalphalipoproteinemia (FHA) - HDL levels below 10th percentile and FHx of low HDL
LCAT deficiency
complete deficiency = familial LCAT
partial deficiency = fish-eye disease
reduced HDL, reduced apoAI, elevated TAGs, decreased LDL
- free chol greatly increased in plasma and periph tissues because it cant be converted to CE → inability to form mature HDL particles
- features: early onset corneal opacifications (v striking)
Tangier disease
familial alphalipoprotein dificiency
ABCA1 deficiency
autosomal recessive, loss of fx muts in ABCA1
- impaired ABCA1 : cant make mature HDL → cant pick up chol from tissues and bring it to liver → chol accumulation in tissues
- features: enlarged orange tonsils, hepatomegaly, splenomegaly, occasionally mild corneal opacification
fd
mechanism of action of statins
(how do they lower plasma chol?)
- statins are competitive inhibitors of HMG CoA reductase
- reduces de novo synthesis of chol in liver
- prompts liver to upregulate LDL receptors on hepatocytes
- decreased de novo synth + increased efficiency of LDL uptake from plasma = normalized liver chol + lowered plasma chol
ezetimibe
inhibits absorption of dietary chol in intestine
- competitive inhibitor of Niemann-Pick C1-like 1 protein in brush border cells (involved in chol abs)
- stimulates upregulation of liver LDL receptor expression
bile acid binding resins
ex. cholestryamine
- increases shunting of chol and bile acids into feces
- resins act as binding agents in intestine to sequester bile acids from normal reabs via enterohepatic circ
- accelerated loss of bile → liver taps into pool of chol to make more
- liver looks to restore chol by increasing de novo synthesis and increaseing LDL receptor expression → decrease in plasma LDL
nicotinic acid (form of vit B3)
inhibits mobilization of FFA from periph adipose tissue to the liver
can lower plasma TG, raise plasma HDL, drop plasma LDL
fibrate drugs
activate PPARalpha tfs → increased LPL activity
(+ apoAI, apoAII, - apoCIII inhibitor of lipolysis)
and
increased rate of FA beta-ox
