06a: Cholesterol Flashcards by Nuna H

Desirable total cholesterol level.

Under 200 mg/dL blood

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“High” total cholesterol level.

Over 240 mg/dL blood

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Cholesterol is (consumed/synthesized).

Both

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Cholesterol, a (polar/nonpolar) molecule, biosynthesis occurs in (X) cells.

Amphipathic

X = all

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Rate-limiting step in cholesterol biosynthesis is conversion of (X) to (Y), carried out by (Z).

X = HMG CoA
Y = mevalonate
Z = HMG CoA reductase

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Regulation of cholesterol synthesis can be controlled by changing (amount/activity) of (X) enzyme.

Both/either;

X = HMG CoA Reductase

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SREBP-SCAP, aka (X), up-regulation of cholesterol does so by eventually (increasing/decreasing) (Y).

X = Sterol regulatory element binding protein (SREBP) cleavage activating protein;

Increasing;
Y = transcription of HMG CoA reductase

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Up-regulation of cholesterol: (X) moves from (ER/Golgi) to (ER/Golgi), where (Y) undergoes proteolytic cleavage.

X = SREPB-SCAP
ER to Golgi;
Y = SREBP

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Up-regulation of cholesterol: In (ER/Golgi), (X) is proteolytically cleaved to release (Y), which then does what?

Golgi;
X = SREBP
Y = DNA binding domain

Binds to SRE in nucleus and enhances HMG CoA reductase transcription

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(Up/down)-regulation of cholesterol: SREBP-SCAP is maintained in (Y) location via (Z).

Down-regulation
Y = ER
Z = interaction with Insig (membrane protein)

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Down-regulation of cholesterol: (X) binds (Y) to facilitate its interaction with Insig.

X = cholesterol
Y = SCAP

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Cholesterol can be up-regulated by (X) hormones and down-regulated by (Y) hormones.

X = insulin and thyroxine
Y = glucagon and glucocorticoids

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Under (low/high) cholesterol conditions, (X) enzyme can bind to (Y), leading to ubiquination and proteosomal degradation of enzyme.

High;
X = HMG CoA reductase
Y = Insig

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Under high cholesterol conditions, (phosphorylation/dephosphorylation) of (X) by (Y) will (activate/inactivate) it.

Phosphorylation;
X = HMG CoA Reductase
Y = AMPK (AMP-activated protein kinase)
Inactivate

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The action of statins is (X). The (raised/lower) intracellular cholesterol levels then causes (increase/decrease) expression of (Y) receptors.

X = inhibit HMG CoA reductase (lowering synthesis of cholesterol)
Lower;
Increase;
Y = LDL

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Statins cause (increase/decrease) expression of LDL receptors. This is to allow (increase/decrease) cellular uptake of (X).

Increase;
Increase;
X = LDL (and thus cholesterol from extracellular sources)

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Cholesterol is metabolized in body by (X) enzyme.

Cannot be metabolized! Only eliminated

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Cholesterol is eliminated from body in which way(s)?

Conversion to bile acids and bile salts (to feces)

2. Solubilized into bile (to intestine)

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Bile (acids/salts) can be made into bile (acids/salts) by adding (X). Where does this occur?

Acids; salts
X = glycine or taurine

Liver

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Bile (salts/acids) are secreted into bile, contains (organic/inorganic) compounds.

Salts only

Both

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About (X)% of bile salts and acids are lost in fecal excretion daily. Where does the rest go?

X = 3 (0.5g);

Efficiently reabsorbed/reused

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The (X) number of carbons of cholesterol are derived from (Y). And reducing equivalents provided by (Z).

X = 27;
Y = Acetyl CoA
Z = NADPH

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Cholesterol: (X) is the membrane component and (Y) is the storage/transport form.

X = free cholesterol
Y = cholesteryl ester

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ACAT enzyme, aka (X), converts cholesterol to (Y).

X = Acyl CoA:cholesterol acyltransferase;
Y = cholesteryl ester

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Statin structure is critical in explaining their function of (X). What do they resemble?

X = inhibiting HMG CoA reductase HMG CoA

T/F: Statins pause cholesterol biosynthesis at the mevalonate step.

False - HMG CoA; mevalonate not produced (you would need to reduce HMG CoA)

Plasma lipoproteins transport (X) throughout body. They have (polar/nonpolar) core and (polar/nonpolar) shell. What are the general contents of the core/shell?

X = cholesterol and triacylglycerols Nonpolar (cholesteryl esters and triacylglycerols); Relatively more polar (phospholipids, free cholesterol, proteins)

(X) on lipoproteins function as ligands for cell receptors/enzyme cofactors.

X = Apolipoproteins

List classes of lipoproteins, from largest to smallest in size. Star the primary ones.

1. Chylomicron* 2. VLDL* 3. IDL 4. LDL 5. HDL

Fat absorption and production of (X) lipoproteins occurs in which location of digestive tract?

X = chylomicron; | Jejunum

Resorption of bile salts occurs in which location of digestive tract? Their destination is (X).

Ileum | X = liver

Fat breakdown/absorption: Large lipid droplet mixes with (X), which breaks it down into (Y).

``` X = bile salts Y = micelles ```

Fat breakdown/absorption: Micelles are acted on by (X) to produce (Y), which transport across (Z) cells.

``` X = pancreatic lipase Y = monoglyceride/FA Z = intestinal mucosal cells ```

Fat breakdown/absorption: (X) lipoprotein is packaged with (Y) prior to transport (into/out of) intestinal mucosal cell.

``` X = chylomicron; Y = cholesteryl ester and triacylglycerol Out of (and into lymphatic system) ```

Chylomicron origin is (X). It carries (endogenous/exogenous) lipids. Its key function is (Y).

X = intestine; Exogenous (dietary) Y = delivery of dietary TAG to cells

T/F: VLDLs are the least dense lipoproteins.

False - chylomicrons

Chylomicron contain Apo-(X). Star the ones transferred to/from (Y).

X = A1*, B48, CII*, E* Y = HDL

Chylomicron loses (X) apolipoprotein(s) and the remnant lipoprotein is recognized by (Y) apolipoprotein receptor on (Z).

``` X = Apo-A1 (to HDL) and Apo-CII Y = ApoE Z = liver ```

Contents of chylomicron, (X), broken down into (Y) and (Z). Where is the destination of each?

``` X = TAG Y = MAG (liver) Z = 2 FA (cells) ```

Contents of chylomicron, (X), are acted on by (Y) enzyme, which is located in/on (Z).

``` X = TAG Y = lipoprotein lipase (LPL) Z = endothelial cells (capillary lining) ```

After passing through blood, the chylomicron remnant will be recognized, by its (X). Then what?

X = Apo-E protein Recepor-mediated endocytosis into liver

LPL requires (X) as cofactor.

X = Apo-CII

T/F: Chylomicron loses both size and spherical shape as TAG is lost.

False - size lost, but shape retained

VLDL origin is (X). It carries (endogenous/exogenous) lipids. Its key function is (Y).

X = Liver Endogenous (non-dietary); Y = delivery of non-dietary TAG to cells

VLDL contains Apo-(X). Star the ones transferred to/from (Y).

``` X = B-100, C-II*, E* Y = HDL ```

Contents of VLDL, (X), are acted on by (Y). The remnant particle is (Z).

``` X = TAG Y = LPL Z = IDL ```

VLDL remnant particle (X) has which fate?

X = IDL 1. 50% converted to LDL 2. 50% taken up by liver

VLDL remnant particle has which apolipoproteins?

Apo-E and Apo-B100 (Apo-CII transferred to HDL)

LDL origin is (X). It carries (endogenous/exogenous) lipids. Its key function is (Y).

X = IDL catabolism in plasma Endogenous Y = delivery of cholesterol to cells

(X) lipoprotein carries most, (Y) fraction, of all plasma cholesterol.

``` X = LDL Y = 2/3 ```

LDL contains Apo-(X). How many of each protein per LDL molecule?

X = B100 1 molecule per LDL

LDL delivers its cargo, (X), to (Y) by which mechanism?

``` X = cholesterol Y = liver or other cells ``` Receptor-mediated endocytosis of LDL (binds to LDL receptor)

LDL receptor is activated by (X).

X = Apo-B100

What's the final fate of LDL?

Destruction in liver and extra-hepatic tissues via endocytosis (and lysosomal digestion)

Internalization of LDL results in its degradation by (X) enzymes. List the components of LDL and which enzyme(s) responsible for their degradation.

X = lysosomal enzymes 1. TAG (lipase) 2. Cholesteryl ester (esterase) 3. LDL receptors (recycled to plasma membrane)

Upon degradation of LDL in cell, (X) leaves the lysosome and regulates which three things?

X = cholesterol; 1. Suppress HMG CoA reductase 2. Increases ACAT (Acyl CoA:cholesterol acyltransferase) 3. Decreases surface LDL receptors

In FH (familial hypercholesterolemia), most common mutation is in (X). It's inherited in (Y) fashion.

``` X = LDL receptor gene Y = autosomal dominant (with gene dosage effect) ```

FH (familial hypercholesterolemia) is characterized by which symptoms?

1. deposition of cholesterol in tendons and arteries 2. elevated plasma cholesterol and LDL 3. accelerated development of atherosclerosis

Total cholesterol in homozygous FH patient is (X) times (lower/higher) than normal.

X = nearly 4; Higher (175 mg/dL versus 678 mg/dL)

Total LDL in homozygous FH patient is (X) times (lower/higher) than normal.

X = nearly 6 Higher (110 mg/dL versus 625 mg/dL)

Homozygous FH patients have (X) LDL receptors. And an (increase/decrease) in LDL receptors with heterozygosity increases typical age for (Y) in these patients.

X = ZERO Increase; Y = MI (Typical age is 20 yo for homozygotes)

HDL is made from (X), manufactured by/from (Y).

X = discs; Y = liver, intestine or chylomicron remnants

What is the composition of HDL discs?

1. Phospholipids 2. Free cholesterol 3. Protein (apolipoproteins)

LCAT enzyme, aka (X), acts on (Y), its major substrate.

X = Lecithin:cholesterol acyltransferase Y = HDL discs

LCAT enzyme recognizes (X), which is found on (Y) lipoprotein. What's the function of LCAT?

``` X = Apo-A1 Y = HDL ``` Esterification of free cholesterol (into unsaturated cholesteryl ester)

What's the fate of cholesteryl esters in HDL?

Transferred to other lipoproteins (IDL, VLDL, LDL)

Cholesteryl ester transfer protein (CETP) functions to:

1. Transfer cholesteryl esters from HDL to other lipoproteins 2. Transfer TAG and phospholipids from other lipoproteins to HDL

HDL contains Apo-(X). It's a circulating reservoir of which apolipoproteins? (Star them)

X = A-1, C-II*, E*

Key function of HDL.

Reverse cholesterol transport (from periphery to liver) by facilitating removal of free cholesterol from peripheral cells

Risk of developing atherosclerosis is directly related to (X) levels and inversely related to (Y) levels. What's a healthy ratio?

``` X = plasma LDL cholesterol Y = plasma HDL cholesterol ``` LDL/HDL less than 3.5

T/F: atherosclerosis typically occurs in small arteries and arterioles.

False - large and medium

Atherosclerosis first begins by injury to arterial (X), which allows migration of (Y) to (Z). What are some risk factors for this injury?

``` X = endothelium Y = LDL particles Z = intima ``` Smoking, HT, diabetes, hypercholesterolemia

Atherosclerosis: once (X) lipoproteins migrate to intima, some undergo (Y) by (Z).

``` X = LDL Y = oxidation Z = free radicals ```

Atherosclerosis: the oxidized (X) prompt (Y) to do what?

``` X = LDL Y = endothelial cells ``` Secrete molecules that attract monocytes to intima (accumulation)

Atherosclerosis: which role(s) to macrophages play in disease development?

1. engulf oxidized LDL (become large foam cells) | 2. Foam cells stimulate migration/proliferation of smooth muscle cells from media to intima

T/F: In development of atherosclerosis, only macrophages ingest oxidized LDL particles.

False - foam cells and smooth muscle cells also

Fatty streaks (early atherosclerotic lesion) is formed from (X). And a (Y) formed from (Z) covers this fatty streak.

``` X = foam cells Y = fibrous cap Z = smooth muscle cells ```

Atherosclerosis: (X), forming fibrous cap, secrete extracellular components, such as (Y), to stabilize the lesion.

``` X = smooth muscle cells Y = collagen ```

Atherosclerosis: Accumulation of lipid-laden cells underneath (X) layer of artery eventually forms a (Y). The real issues is if (Y) ruptures...

``` X = intima Y = fibro-fatty atheroma (plaque) ``` Thrombus forms (partial/complete obstruction of lumen)

Cholestryramine sequesters (X), (decreasing/increasing) its elimination in stool. This will (raise/lower) serum cholesterol.

X = bile salts; Increasing; Lower (increased demand to produce bile salts)

NPC1L1 transporter allows uptake of (X) in (Y) location. Inhibition of this transporter would have which effect on serum LDL?

``` X = dietary cholesterol Y = intestine ``` Decreases LDL

Describe steps that explain effect that inhibition of NPC1L1 transporter has on serum LDL.

1. Decrease (dietary) CE in chylomicrons 2. Decrease in CE returned to liver (and thus in hepatic cholesterol stores) 3. Decrease amount VLDL produced 4. Increase LDL receptors and uptake of LDL 5. Decrease circulating LDL

Mipomersen Drug for homozygous FH patients targets silencing of which apolipoproteins?

B100

Aside from mutation in LDL-receptor, which other mutation(s) can cause FH?

ApoB100 or protease PCSK9 mutations

A 2015 FDA approved drug for FH patients aims to (stimulate/inhibit) (X). What's the normal function of (X)?

Inhibit; X = PCSK9 protease Targets and degrades LDL receptor during its incorporation into cell (prevents its recycling after lysosomal degradation)