01-06 Hyperlipoproteinemia Flashcards
ApoA1
—particle
—biochemistry
—particles: HDL
—biochemistry: activates LCAT which converts HDL to HDL2 by esterifying cholesterol in the HDL molecule
ApoB48
—particle
—biochemistry
—particles: chylomicrons
—biochemistry: interacts with a B receptor
ApoB100
—particle
—biochemistry
—clinical utility
—particles: VLDL, ILDL, LDL
—biochemistry: interacts with LDLR
ApoCII
—particle
—biochemistry
—particles: VLDL
—biochemistry: activates LPL
ApoE
—particle
—biochemistry
—particles: HDL, VLDL, chylomicrons
—biochemistry: required for receptor binding
Apo(a)
—particle
—biochemistry
—clinical utility
—particles: lipoprotein (a)
—biochemistry: links to B100
LPL
—site of synth
—MOA
—stimulus
—synth’d in liver
—catalyzes the hydrolysis of TG’s into phospholipids and glycerol, for entry into cells.
—insulin and contact w/ ApoCII
HL
—acts on which particles?
—MOA?
—located where?
HEPATIC LIPASE
It acts on LDL and HDL borne triglycerides.
1) on the endothelium within the liver
2) functions much like LPL – but for liver cells only
—Converts HDL 2 to HDL 3
LCAT
—location
—fxn
lecithin cholesterol acyl transferase
—transfers acyl groups from lecithin to cholesterol
to create cholesterol esters.
1) made in the liver
2) Interacts with with apoAI on HDL.
3) converts HDL1 to HDL 2 and HDL 2 to HDL 3
CETP
—fxn
—site of action
cholesterol ester transferase protein
—converts cholesterol esters back to cholesterol for delivery to the liver
—Acts within the HDL particle
SCAP
—fxn
—mechanism
SREBP Cleavage Activating Protein
1) Acts as a sensor for intracellular sterols
2) With low intracellular steroids, it binds to SREB-2 to allow S1 and S2 to cleave of SREBP-2’s N terminal segment, which is then activated
3) SCAP is therefore activated by low cholesterol diets cholesterol binding resins niacin statins
SREBP
sterol responsive element binding protein
1) transcription activating factor
2) on the ER
3) released by protein cleavage
4) acts at the nucleus.
SREBP2
controls genes for de novo cholesterol synthesis, such as (HMGCoA reductase) ;
activated when cytoplasmic levels of cholesterol are low
(as occurs due to treatment for high cholesterol)
Steps in responding to low intracellular [sterol] w/ SREPB
1) SCAP is Modified in Golgi & binds to SREBP
2) SREPB, bound to SCAP relocates to ER; acted on by S1P and S2P (scissors) to release N terminal
3) N terminal of SREBP-2 acts as a transcription actor, increases LDLR
4) increased # of LDLRs on cell surfaces leads to incr uptake of LDL
ABC1
—fxn
ATP binding casette protein 1 transfers cholesterol and phospholipids to the cell membrane for pickup by HDL particles
—In the absence of ABC1, cholesterol does not move from the cytoplasm to the outer leaflet of the cell membrane and is therefore unable to interact with the Apo1 of HDL
LDLR
LDLreceptor interacts with the B100 apoplipoprotein to recognize LDL particles
PCSK-9
Paraprotein Convertase Subtilisin/Kexin 9
- secreted protein Binds to LDL R
- Targets LDLR for degradation
- if you mutate/inhibit or decr the [PCSK-9] you ↑ number of LDLR on cell surface
- *novel drug target
PPAR System
PPAR = peroxisome proliferation activating receptor-α
—involved in energy homeostasis
—system of PPAR-α, -∆, (catabolic) and -γ (anabolic)
PPAR-α Specifically:
—target of fibrates (e.g. gemfibrizol)
—together w/ RXR it attracts coactivators
—key determinant of VLDL synthesis: induces transcription of genes that facilitate lipid metab
Equation for total cholesterol?
Total* = LDL* + VLDL + HDL*
- measured
- VLDL = TG/5
- ** calculated from these other numbers
What is “non-HDL” cholesterol and how do we calculate it?
—Benefits?
“non-HDL” = total - HDL
—includes: LDL, IDL (known atherogens), VLDL (possible atherogen), ApoB and lipoproteins
—no need to fast before blood draw
—maybe be better at predicting risk in DM2 or FCH
Why do you need to fast before lipid panel?
Triglycerides —> VLDL estimate & LDL_calc
Interpreting the chilled tube test
White on top = chylos —should be absent w/ fasting sample —otherwise = excess chylos Fluid in middle = serum —should be translucent —if cloudy = excess VLDL GEL RBCs
1° Causes of chylomicron excess + presentation
LPL deficiency & apoCII deficiency
—both very rare, recessive conditions
—both cause: TGs 1000-2000mg/dL, pancreatitis, eruptive xanthomas
1° Causes of VLDL excess + presentation
Familial hypertriglyceridemia
—common (1%) dominant inheritance
—TGs 250-1000 & pancreatitis
FCH: see separate card
FCH
Causes both VLDL & LDL excess
—dom. inher
—thought to be due to excessive VLDL synth
—↑ chol, TGs, VLDL and LDL
—variable presentation: eruptive and tuberous xanthomas, ASCVD,
1° Causes of ILDL excess + presentation
remnant removal dz (familial dysbetalipoproteinemia, Hyperbetalipoproteinemia)
—super rare, recessive condition
—must have ApoE2
—cholesterol is = to TG which is abnl (usu TGs < chol when fasting)
—palmar and tuberous xanthomas; ASCVD
