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Foundational Sciences I-II > Cholesterol > Flashcards

Cholesterol Flashcards

1
Q

Dietary Sterols

plant sterols > phytosterols (_____ most common)

_____ (shrimp, crabs)
eggs (yolk)

_____ (egg nog, pecan pie, etc.)

A

sitosterol
seafood
holiday foods

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2
Q

USDA view on Cholesterol

2015 Report
Cholesterol Limit _____ from 2015 Dietary Guidelines. The advisory panel has decided to eliminate warnings about dietary cholesterol, According to the report, “cholesterol is not a nutrient of concern for _____.”

A

removed

overconsumption

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3
Q

Dietary Sterols: Normal Physiology REWATCH

In humans- Cholesterol cannot be broken down
into its _____ EVER

So we shuttle de novo synthesized and dietary cholesterol
BUT

Cholesterol is the precursor to _____, _____, _____- so we can’t live without it

A

component parts
hormones
bile
Vitamin D3

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4
Q

Intestinal Absorption of Cholesterol

 Cholesterol absorption by intestinal cells (enterocytes) is a key _____ in sterol metabolism.

 The less we absorb the more we need to synthesize- not a _____

A

regulatory point

bad thing

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5
Q

Intestinal Absorption of Cholesterol

More dietary cholesterol we take in; the more cholesterol delivered to liver; absorb 20-80%, the vast majority goes into making _____

excreted; but 95% of bile returns to the _____(lose very little bulk cholesterol in biliary excretion)

regulate, based on the level of the _____ (the less we absorb, the more we have to synthesize > much easier to control the _____ than to control the _____ of cholesterol)

A 
bile
liver
enterocytes
synthesis
absorption
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6
Q

_____ protein family necessary to regulate cholesterol absorption

• _____ Trans-membrane domains
• Couple ATP hydrolysis to the transport of
excess or unwanted _____ or _____ from enterocyte back into gut lumen.
• Mutations in genes encoding these proteins results in _____

• Sitosterolemia –leads to accumulation of cholesterol and phytosterols in enterocytes and bloodstream- formation of _____.

A

adenosine triphosphate (ATP) binding cassette (ABC) protein

6
cholesterol
plant sterols
sitosterolemia

artherosclerotic plaque

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7
Q

Intestinal Absorption of Cholesterol

Transport out of the enterocyte into gut lumen is mediated by members of the ATP binding cassette protein family, _____ and _____

55% of intestinal pool enters blood through enterocytes by _____ or via _____

A

ABCG5
ABCG8
diffusion
Niemann-Pick C1-like 1 protein (NPC1L1)

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8
Q

Intestinal Absorption of Cholesterol

_____ takes chol from lumen of SI into the enterocyte

as cholesterol enters in intestine; NPC1L1 takes into enterocyte (repackages) and transports into the blood

these two transporters act in concert in order to maintain homeostasis

drug: _____; inhibits NPC1L1, inhibit chol uptake > lowering chol bc you’re not _____; decreasing dietary cholesterol > now forcing the liver to _____ the cholesterol (which is easier to regulate)

A

NPC1L1
ezetimibe
absorbing
synthesize

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9
Q

Cholesterol
• Cholesterol- a _____ nucleus consisting of _____ fused rings.
• It is _____ due to the OH group on the #3 carbon and a hydrocarbon chain on C#17.
• Sterols are the precursors to biologically active compounds including, _____, hormones and _____.

high levels of free cholesterol (crystallize out, which attracts _____ > formation of plaque)

A 
steroid
four
amphipathic
bile acids
vitamin D

hydroxyapatite

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10
Q

Features and Stages of Cholesterol Synthesis

  • Mostly in _____
  • Synthesis Rxns occur in _____ and _____
  • Primary intermediate is the _____ unit
  • All 27 carbons are provided by _____ units
  • _____-reducing equivalent
  • _____-energy soucr
A 
liver
cytosol
ER
isoprene
acetate
NADPH
ATP
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11
Q

Features and Stages of Cholesterol Synthesis

STAGE 1 - condensation of 3 acetate units to form _____.

STAGE 2 - polymerization of 6, 5-carbon isoprene units to form linear _____.

STAGE 3 - _____ of squalene to form sterol ring and ultimately cholesterol.

A

mevalonate
squalene
cyclization

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12
Q

Features and Stages of Cholesterol Synthesis

entire structure derived from _____; from cytosolic acetyl CoA (may need breakdown of glucose/protein to have chol synthesis > more likely to be synthesized during a _____ stage (regulated by insulin + glucagon)

A

acetate

“fed”

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13
Q

Stage 1 of Cholesterol Synthesis

reverse reaction for FA > reaction for _____ synthesis

ketone body synthesis is within the _____; chol biosynthesis is _____

source of acetyl-CoA > high _____, _____ inhibited > citrate leaves the mitochondria > gives you elevated _____ in the cytosol

A 
ketone body synthesis
mitochondria
cytosol
blood glucose
pyruvate dehydrogenase
acetyl CoA
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14
Q

Regulated Step of Biosynthesis-HMGCoA Reductase

_____- cholesterol lowering drugs

Competitive inhibitor of _____.
 Lowers serum cholesterol by approx. _____.
 Side-effects; liver
problems, muscle pain, etc.

HMGCoA Reductase = _____ (2 NADPH’S)

statin’s prevent the synthesis of _____; bind the active site and competitively inhibit

A

statins
HMG CoA Reductase
50%

regulating step
mevalonate

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15
Q

Stage 2 Cholesterol Synthesis

Stage 2
• Activated _____ polymerize to form _____
• The 30C squalene molecule is synthesized from 6 molecules of 5 C _____
• Addition of the _____ keeps the molecules water soluble and drives subsequent reactions

A

isoprene units
squalene
isopentyl pyrophosphates
phosphate groups

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16
Q

Cholesterol intermediates provide proteins with lipid anchors

activated isoprenes: head to tail _____ > lose their phosphate groups to get a _____ and _____; these both are anchors for lipid proteins (and chol intermediates

converted to squalene, loses two more phosphates; linear squalene is very _____

A

condensation
fernesyl pyrophosphate
geranyl pyrophosphate
unstable

17
Q

Cholesterol intermediates necessary to synthesize Ubiquinone and Dolichols

 Ubiquinone- needed to synthesize _____- component of e-transport chain in mitochondria

 Dolichol involved in _____ of proteins as Dolichyl-phosphate

 Inhibition of cholesterol biosynthesis by _____ has critical side effects

A

coenzyme Q
N-glycosylation
statins

18
Q

Stage 3 Cholesterol Synthesis

squalene monooxygenase is _____ enzyme > makes the squalene cyclize

squalene is a precursor to chol (22 steps required)

3 _____ > mevalonate > phosphorylated with 3 diff _____ > activated isoprenes > _____ > squalene > _____ (22 steps downfield)

A 
ER-associated
Acetyl CoA
ATP
head-to-tail condensation
cholesterol
19
Q

Esterification increase cholesterol’s hydrophobicity

following synthesis cholesterol is _____ (more _____)

storage form: _____

esterification catalyzed by _____ (requires an _____, often _____)

A 
esterified
hydrophobic
cholesterol esters
ACAT (acyl cholesterol acyl transferase)
activated fatty acyl chain (linoleic)
20
Q

Malformation syndromes due to inborn errors of cholesterol metabolism

Three genes linked to altered cholesterol biosynthesis

Smith-Lemli- Optiz (SLO); deficiency in _____ activity

 Conradi-Hunermann-Happle; deficiency in _____ activity

 CHILD syndrome; deficiency in _____.

All 3 show craniofacial abnormalities; specifically _____

A

7-dehydro reductase
delta8, delta7 isomerase
NADPH sterol dehydrogenase
cleft palate

21
Q

Regulation of Cholesterol Metabolism via HMG-CoA Reductase

Regulation 
Systemic \_\_\_\_\_
Feedback 
\_\_\_\_\_ 
Gene expression
A

hormones

proteolysis

22
Q

Regulation of Cholesterol Metabolism via HMG-CoA Reductase

anabolic/cytosolic > activated in response to _____ insulin and _____ glucagon

inhibited by the reverse (high _____/_____ insulin

HMG-CoA reductase (both _____ tagged) step

high cholesterol > ACAT _____ and esterifies for storage (do not want free chol around)

high cholesterol > HMG-CoA Reduct is _____ (and becomes _____)

A

high
low
glucagon
low

ER

activated
inhibited
inactive

23
Q

Regulation of Cholesterol Metabolism via HMG-CoA Reductase cont.

AMP-Protein Kinase acts as an _____; cholesterol synthesis _____ when ATP levels are low and the AMP-PK is active

this regulation occurs at the level of _____

A

energy sensor
decreases
phosphorylation

24
Q

Control of HMGCoA reductase expression

Rate of HMG CoA reductase mRNA synthesis is controlled by _____ (transcription factors).

  1. SREBPs enhance HMGCoAR transcription by binding to _____ upstream of the gene.
  2. SREBPS is bound to _____ in the ER when cholesterol levels are _____
  3. As cholesterol levels _____ the SREBP:SCAP complex is transported to _____.
  4. In golgi _____ proteolytic cleavages occur releasing the _____
  5. This N-terminal component binds to the _____ activating transcription.
  6. _____ cholesterol SCAP- SREBP cannot translocate to golgi

This process contains some of the most _____ metabolic processes

Sterol-regulatory element binding protein – (transcription factor). Activates expression of over _____ involved in synthesis and uptake of Cholesterol, TAGs, fatty acids and NADPH

A 
SREBPs (transcription factors)
SRE (sterol-regulatory element)
SCAP
high
decrease
golgi
two
N-terminal transcription factor domain
SRE
high

highly regulated
30 genes

25
Q

Cholesterol is the precursor for bile acids

• Synthesized in _____, stored in _____ released into _____.
• Aids in digestion of fats through formation of biliary micelle in process of _____.
• Greater than 95 % of bile is reabsorbed and returns to _____.

A 
liver
gall bladder
small intestine
emulsification
liver
26
Q

Bile acid/salt formation and recycling

The conjugation of _____ or _____ to bile acids makes them bile salts- thus they become more _____

Bacteria deconjugate bile salts- and 95% of bile acids recirculate via _____

A

glycine
taurine
amphiphilic

enterohepatic circulation

27
Q

Bile acid/salt formation and recycling

one step to know: cholesterol is catalyzed by _____ > _____ (prcursor for 20 diff compounds) > this step is feedback inhibited by _____

conjugated to glycine/taurine they become _____ (become MORE amphiphilic)

as we take in a meal > release of bile acids (from _____) > formation biliary micelles; in intestine, bacteria _____ bile acids (remove glycine/taurine)

only 5% of bile is excreted in feces, 95% recirculates to the _____ (drugs that increase the amount of bile acids that are excreted also aid in _____ (can remove more than 5%))

A

7 alpha hydrolase
7 alpha hydroxycholesterol
bile acids

amphiphilic

CCK
deconjugate

liver
total body cholesterol

28
Q

Steroid hormone synthesis

all steroid hormone synthesis within the _____ glands

enzyme that catalyzes formation of prenenonlone (precursor to cortisol, corticosterone, testosterone) = _____

A

endocrine

cholesterol desmolase

29
Q

Synthesis of Vitamin D

Benefits; increased absorption of _____ and _____, healthy bone.

Excess-_____, weak muscles.

Both _____ and _____ are available from diet

A

calcium
phosphorus

kidney stones

cholecalciferol (D3)
calciferol (D2)

30
Q

Take home lessons

 Dietary cholesterol absorption utilizes _____ and _____ transporters

 Cholesterol synthesis is _____, _____, utilizes NADPH with _____ serving as donor of all Carbons.

 Regulated step is _____

 Intermediates of the biosynthetic pathway are necessary for other cellular functions

 Cholesterol CANNOT be _____ into component
parts.

A

NPC1L1
ABC

anabolic
cytosolic
acetyl CoA
HMGCoA Reductase

degraded

Foundational Sciences I-II (14 decks)

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