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L14 Cholesterol ADME (A= Absorption (Ch. Transport
Free C does NOT…
L14 Cholesterol ADME
A= Absorption
Ch. Transport
- Free C does NOT actually diffuse across plasma membs well
~ into (C)s = C transporters (NPC1) [fac diffu]
~ out of (C)s = ABCs (ATP-bining cassettes)
□ pump ch: active transport
~Exocytosed/endocytosed in LPs [package it to shuttle these things]
- Loaded into HDLs
~ ABCA1
~ HDLs are prod empty & float around in plasma
~ keep floating around until it is full & then gets taken up by a liver
- Esterification further regs this
~ Ch. has a mobile & stable form: mobile→ch., esterify it to pin it down
Ch into (C)s → NPC1
- Niemann-Pick disease, type C1 (NPC1) [conc grad]
- Ch. transporter?
~ functions more like a Rs [form an endozyme: a vesicle]
~ creates an chol. endosome
- Inhibited by intera(C)ullar sterols (& drugs)
- (also ebola Rs)
Ch. storage /liberation
- Absorbable & usable & mobile ⇌ Storable & transportable & unreactive
- Ch. acyltransferases (LCAT/ACAT)
- Ch. esterases [breaks ester linkage, liberates free ch.]
Ch. out of (C)s → ABCs
- ATP-Binding Cassette transporters [they punch a ch. sized hole in the memb & pump ch. out of (C)s
~use ATP to get it out of cells
- ABCA1: into HDLs [so we can move it elsewhere]
- ABCG5/8: into gut lumen/bile [present in our gut & liver]
Absorption
- Poorly absorbed (30-50% of dietary ch.) - ineffecient
~ largely absorbed source is biliary secretion, not diet)
- Must be de-esterised (ch. esterases)
- Must be solubilised (bile salts)
- Transported across apical memb
~ Ch. transporter (NPC1)
~ competition by plant sterols [competitively inhibits NPC1, so don't absorb as much]
- Packed into CMs (or used by enterocyte)
~ Re-esterified (mostly) by ACAT [stick a FA on it]
~ Assembly reqs microsomal transport prot (MTP1) [essential for loading C;. into chylomicrons]
-
Uses/Essential for life
- As a constituent of CM + lipid rafts
- As a regulator of gene exp
~ mods the flexibility & modurity(?) of musc membs
- As a regulator of fetal dev
Defects in ch. synth:
- Lethal, or cause dev abnormalities
~ if bad: miscarriage
- Smith-Lemli-Opitz syndrome (7-dehydroch. reductase deficiency): cerebral dysgenesis & dysmyelinisation, cataracts cleft palate [migratory cells], congenital heart defect, adrenal insuficiency, liver disease
~ lose ability to metabolise ch. properly: everyth tht ch. does, we don't get
- treatment? ⇈dietary ch.
Lipid rafts & signal transduction
- (C) signalling
- A ch.-enriched microdomain in CM
- Creates a niche for Rs- essential for signal transduction
- Ch. is the "glue tht holds lipid rafts 2gth"
~ If lose glue then lose niche & lose platform for (C) signalling
- G prot coupled Rs
Ch.
- Can get ch. from anything we eat
- Exogenous: dietary ch. absorbed by GIT (minor)
~ we have an exog source of ch. in our diet (unless vegetarian)
~ Ester linkage: O & C : holds it 2gth
~ esterifed ch. is less mobile: most of what we consume
~ in order to absorb it we need to chop up
- Endogenous:
~ ch. formed in body (major)
~ Mevalonate pathway- synthesized from ace coa
□ Rate limiting step: whether or not we convert ace coa to mevalonate
~ Ubiquitous but regulated [process happens all time & in every (C) in bod but regulated: can ⇈ it when not enough ch., & can ⇊ when too much ch.
- Moved around in LP
~ not H2O sol
~ LDLP
~ diff functions of the 3 diff LP
- Can't be catabolized!
~ can buid it up but cant break it down
~ lack of break down ezms
Numbers
- whole body: 140g
- Brain: 23% [has lots of membs & myelin]
- Plasma memb: 85%
- Endocytotic vesicles: 10%
- Mitochondria & nuc: 4.5%
- ER: 0.5%
ADME
- Absorption
- Distribution
- Metabolism
- Excretion
Numbers
- in = 1.5g/day
- out = 1.5g/day
- Diet: 0.5g/day [tend to absorb tht much no matter how much you eat]
- Synth: 1g/day [we synth this much]
M = Mevalonate pathway
- ch. is prod by the M pathway
- Imp:
~HMG-CoA reductase
~Mevalonate
~ Ch.
~ can anabolise into: Bile salts, Vit D, Steroids
- This ch. can then be used for things except for breaking down
A useful building block!
- Hormones: testosterone, cortisol, aldosterone, estrogen
We produce, from ch.:
Bile salts:
- prod in liver [steroids prod every cell but not bile salts]
- stored in gall
bladder
- squirted into duodenum [1st bit of small intestines, detergents to emulsify them]
- essential for fat absorption [emulsifies ch.]
Vit D
- Synth in skin: 7-dehydroch. + UV → D3 (cholecalciferol)
~ by UV hitting ur skin
- Not a vit at all
- Activated n liver → kidneys
- Essential for Ca2+ absorption
How is intra(C)ullar ch. regulated?
- Ch. overload exerts -ve feedback
- Reg pathway homeostatically
- in 3 lvls:
~ Synth: inhibition of HMG-CoA-reductase activity
~ Uptake: reduced LDL-Rs (LDLR) expression [stop taking up LDL]
~ Storage: stimulates acyl CoA: cholesterol acyl transferase (ACAT) [we store more of it as ch. esters]
The LDL Rs pathway
- when have too much ch in cells, then we stop ch. synth & ⇈ activity of storage of ch. esters
- Inhibit act. of HMG-reductase: stops us from prod any more ch.
HMG-CoA: drug industry
- HMG-CoA → Mevalonate
- Statins: diffuses into every celll & stops M pathway by inhibiting HMG-CoA
- by doing this: then can knock out 95% of ur ch. production
-
E= Ch. excretion
- How we get rid of it: liver dumping it into guts
- BSEP (bile salt export pump)
- ~95% of bile acids are re-taken up in ileum by ASBT (apical Na-dependent bile salt transporter)
- Only ~5% ends up in toilets bc we use those bile salts to..
Learning Outcomes
- List biological uses for cholesterol
- Describe cholesterol absorption, transport & excretion
~ Name the carriers usd in cholesterol transport
- Outline the synth & metabolism of cholesterol
- Discuss cholesterol homeostasis & reg of (C) cholesterol
- Discuss the LDL Rs pathway