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Flashcards in Lipoprotein Biochemistry - Sahoo Deck (86)

What's the difference between a simple and mixed triglyceride? Which is more common in nature?

Simple TGs: Same fatty acid in all 3 positions. Mixed TGs: 2 or 3 different fatty acids. Most naturally-occurring TGs are Mixed.


What can an elevated TG level predict independent of other risk factors?

-Risk of CV disease -Pancreatitis if several elevated (>1000mg/dL)


Name 5 functions of cholesterol.

1) Essential cell membrane component 2) Important and enriched in lipid rafts 3) Reduces membrane fluidity* 4) Precursor for bile acids and steroid hormones 5) Covalent modification of embryonic signaling proteins *From what I can find, this helps make the cell membrane a little more structurally rigid (in a good way), and makes it less permeable to small water-soluble compounds that would otherwise diffuse into the cell.


Name 5 classes of compounds derived from cholesterol and at least one specific compound in each class.

1) Androgens - Androsterone, Testosterone 2) Estrogens - Estradiol, Estriol, Estrone 3) Mineralocorticoids - Aldosterone, Corticosterone 4) Glucocorticoids - Cortisol 5) (Primary & Secondary) Bile Acids - Cholic acid (1°), Deoxycholic acid (2°)


Name 5 ways in which excessive cholesterol is cytotoxic.

1) Cholesterol crystal formation 2) Triggering apoptotic pathways 3) Forming toxic oxysterols 4) Disruption of functional & signaling membrane domains 5) Promotes atherosclerosis


Name the 4 major steps of cholesterol synthesis and the number of carbon atoms in each major compound

1) 3x Acetate (2C) --> Mevalonate (6C) 2) Mevalonate --> phosphorylated Isoprene (5C) 3) 6x Isoprene --> Squalene (30C) 4) Squalene --> Cholesterol (27C)


Name 3 substeps in the formation of mevalonate from acetyl-CoA and the enzymes that catalyze them.

1) 2 Acetyl-CoA → Acetoacetyl-CoA

   via acetyl-CoA acyl transferase

2) Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA

   via HMG-CoA synthase

3) HMG-CoA + 2 NADPH → Mevalonate

   via HMG-CoA reductase*

   Rate-Limiting Step of Cholesterol Synthesis


Name 3 substeps in the conversion of mevalonate to isoprene.

1) Stepwise transfer of 3 PO43- from ATP to mevalonate.

2) Decarboxylation and hydrolysis forms the 5C isoprene

   -Introduces a double bond

3) There are actually 2 isoprenes, which can isomerize back and forth

   -Difference is location of double bond




Name 3 substeps in the formation of squalene from isoprene units.

1) 2 isoprene → geranyl pyrophosphate

   -one of each isoprene isomer is needed

2) geranyl pyrophosphate + isoprene → farnesyl pyrophosphate

3) 2 farnesyl pyrophosphate → squalene

   -squalene is phosphate-free


Name 3 substeps in the conversion of squalene to cholesterol and the enzymes that perform each step.

1) squalene + NADPH + O2 → squalene 2,3-epoxide

   via squalene monooxygenase

2) squalene 2,3-epoxide → lanosterol

   via cyclase

3) lanosterol → cholesterol

   multistep - specifics not listed


Where does cholesterol synthesis diverge between animals and plants and fungi?

The fate of squalene 2,3-epoxide differs.

Animal: Lanosterol → Cholesterol

Plants, Fungi: Stigmasterol, Ergosterol


1) Where is most cholesterol synthesized in the body?

2) In what forms?

3) What forms are later converted from cholesterol in other tissues?

1) Liver

2) Bile acids, Biliary Cholesterol, Cholesteryl Esters

3) Other tissues form steroid hormones, some others


How do bile acids work?

They surround fat droplets and help to emulsify them. This increases the surface area available for attack by lipases.


Which are more non-polar: cholesterol or cholesterol esters? What is a consequence of this?

Cholesterol esters. The added hydrophibicity makes then unable to enter membranes.


Which LP class contains the most:

1) Protein

2) Phospholipids

3) Free Chol

4) Chol esters (CEs)

5) TGs

1) Protein: HDL

2) Phospholipids: HDL

3) Free Chol: VLDL/LDL

4) Chol esters (CEs): LDL

5) TGs: Chylomicrons


What is the surface of a lipoprotein particle composed of?

What is the interior composed of?

Surface: apolipoproteins, phospholipid monolayer

Interior: cholesterol, cholesterol esters, TGs


A lipoprotein's density is [directly, inversely] related to its size.



Name the major subclasses of lipoproteins in order of increasing density.

1) Chylomicrons

2) VLDLs

3) VLDL remnants

4) IDLs

5) LDLs

6) Lp(A)

7) HDLs


Name the identifying apolipoprotein (apoLP) and a major function/characteristic of:

1) Chylomicrons

2) VLDLs

3) IDLs

4) LDLs

5) Lp(A)

6) HDLs

1) Chylomicrons: apoB-48, C, E; delivers chol & TGs from gut to tissues & liver

2) VLDLs: apoB-100, C, E; made in liver and delivers TG to tissues as fatty acids

3) IDLs: apoB-100, some C, E; short-lived LP between VLDL and LDL

4) LDLs: apoB-100 ONLY; stays in circulation longest

5) Lp(A): apo(a), apoB-100; an odd LDL-like particle - apo(A) is structurally sim(ilar to plasminogen

6) HDLs: apoA-I & apoA-II, C, E; generally good


Which LP class contains the least:

1) Protein

2) Phospholipids

3) Free Chol

4) Chol esters (CEs)

5) TGs

1) Protein: Chylomicrons

2) Phospholipids: Chylomicrons

3) Free Chol: Chylomicrons/HDL

4) Chol esters (CEs): Chylomicrons

5) TGs: HDL


Name 4 functions of apolipoproteins.

1) Help solubilize the LP particle in the circulation

2) Change conformation to adjust to changing lipid contents, compositions, and metabolic states

3) Can activate or inhibit plasma enzymes

4) Serve as ligands for cell surface receptors


Name the function(s) of:

1) ApoA-I

2) ApoA-II

3) ApoB-48

4) ApoB-100

1) ApoA-I: Activates LCAT, interacts with ABC transporter

2) ApoA-II: Inhibits LCAT, structural

3) ApoB-48: Chol & TG transport and clearance

4) ApoB-100: Binds LDL receptor to deliver endogenous chol


Which ApoLPs are most strongly associated with

1) increased risk of atherosclerosis?

2) decreased risk of atherosclerosis?

Increased risk: apoB-100, apo(a)

Decreased risk: apoA-I


How are triacylglycerols taken up by the gut? Where is this process mirrored?

In short, they are broken down, absorbed, then reformed.

In detail: bile salts emusify the fats, forming mixed micelles that are attacked by lipases. The lipases degrade TGs into fatty acids (FAs), which are taken up by the mucosa and converted back into TGs. 

The process is mirrored in the capillaries: LP lipase converts TGs into FAs + glycerol, which are taken up by cells. Cells can resesterify these back into TGs (or utilize them as fuel).


What lipoprotein are TGs taken up in the gut packaged into for transport?



What protein mediates the absorption of cholesterol in the intestine? What drug inhibits this protein?

Protein: NPC1L1 (Neimann-Pick C1-Like 1 protein)

Drug: ezetimibe


Which transporters prevent the assimilation of plant sterols into the body by channeling them back into the intestinal lumen?

What disease results from mutations in these proteins?

How is it inherited?

What symptoms to these patients show?

Transporters: ABCG5 and ABCG8

Disease: Sitosterolemia

Inheritance: Autosomal recessive

Sxs: Accumulation of plant sterols in blood & tissues, associated with tendon & subQ xanthomas and markedly increased risk of premature CHD.


When can chylomicrons be detected in plasma?

Elevated for 3-6 hours after eating a fat-containing meal. No chylomicrons remain after a fast of 10-12 hours, except in patients with disorders in chylomicron metabolism.


What is the % fat content of a chylomicron?

What % of this is dietary TGs?

98-99% fat

85% TGs


What gives apoB-48 its name?

48% of the MW of apoB-100


What apoLP activates lipoprotein lipase (LPL), allowing lipoproteins to release free fatty acids for fuel to adipose tissue, heart, and skeletal muscle?



Where is lipoprotein lipase (LPL) located?

LPL is bound to capillary endothelium in various tissues. Lipolysis therefore takes place at the vascular endothelial surface.

(Heart, skeletal muscle, adipose tissue, mammary glands, others.)


What is the conseqence of LPL deficiency?

Lethal in mice: die of severe hypertriglyceridemia


1. How is LPL regulated?

2. What are LPLs cofactors?

3. Which of these cofactors allows for measurement of LPL?

1. Increased plasma glucose and insulin release upregulate LPL transcription to facilitate FA storage in adipocytes.

Conversely, LPL activity of adipose tissue falls during prolonged fasting or in diabetic ketoacidosis, preventing FA storage.

2. ApoC-II and heparin

3. Heparin, given IV, will displace LPL activity into the plasma, allowing its measurement



What happens to chylomicrons after they are depleted of dietary TG via LPL activity in the body tissues? What ligand:receptor interaction is necessary for this?

Chylomicron remnants go to the liver. There:

  • apoE acts as a ligand for LDL receptor or the related LRP to stimulates endocytosis
  • ApoB-48 is degraded
  • dietary cholesterol is released into the liver


What is LRP? What is it for?

LDL receptor-related protein.

It is the backup receptor (behind LDLR) responsible for uptake and clearance of chylomicron remnants and VLDL.


ApoE deficiency causes what disease? What is a consequence of this?

Type III hyperlipoproteinemia

Increased TGs and cholesterol in the plasma due to impeded clearance of remnants


What LP particle is produced by the liver for transporting endogenous lipids? What stimulates the liver to synthesize this particle?

Particle: VLDLs

Stimulation: Increased flux of free FAs or increased de novo FA synthesis in liver


What apoLPs do VLDLs contain? Where are these proteins synthesized?

ApoB-100, apoC-I, apoC-II, apoC-III, apoE.

All constituitively synthesized in the liver.


Other than fat, excess of what food type can also be converted into TGs by the liver?



1) What enzyme transports newly synthesized TGs from the ER to sites of VLDL and chylomicron formation?

2) What is at these sites?

1) Microsomal tryglyceride transfer protein (MTP)

2) apoB-100 (VLDLs) or apoB-48 (chylomicrons)


1) A defect in microsomal tryglyceride transfer protein (MTP) causes what disease?

2) What is the pathophysiology of this disease?

3) What symptoms do patients with this disease exhibit?

1) abetalipoproteinemia

2) failure to produce any apoB-containing LP particles (chylomicrons, VLDLs, LDLs) - unable to concentrate TGs within these particles to form them

3) vitamin deficiency, steatorrhea, developmental delays


Which enzyme esterifies free cholesterol into cholesterol esters (CEs)?

Why bother making the CEs at all?

Acyl-CoA:cholesterol Acyltransferase (ACAT)

Better storage


Which isoform of ACAT is located in the intestine and the liver?

What does it do in the intestine?

Why might it be medically important?


Regulates the absorption of dietary cholesterol

Due to its function, is a potential pharmacological target for reducing blood cholesterol


In what tissues is the ACAT-1 isoform located?

1) Macrophages (including foam cells)

2) Adrenocortical cells

3) Skin sebaceous glands


In what ways are VLDLs and chylomicrons similar?

1) Both used to transport TGs to adipose tissue and muscle

2) In both, apoC-II activates LPL to release FFAs

(Think of chylomicrons as mainly for the exogenous pathway and VLDLs mainly for the endogenous pathway)


How is IDL formed?

IDL is essentially the TG-depleted remnants of VLDL


What is the half-life of VLDL remnants / IDL? What are the two fates possible for this lipoprotein?

t1/2 < 30min

Fate 1: 40-60% are cleared from plasma by liver via LDLR and LRP

Fate 2: LPL and hepatic lipase (HL) convert the remainder of remnants/ID to LDL by further TG removal. Virtually all LDL is derived from VLDL remnants.


What determines the rate of LDL production?

What is enriched in LDLs?

What's the major apoLP in LDL?

The rate of VLDL remnant clearance - the remainder of remnants that escape uptake become LDLs

Cholesterol is considered to be enriched in LDLs because TG has been removed.

ApoB-100 is the major apoLP


In the formation of LDL, which apoLP facilitates the removal of residual TG by hepatic lipase?



What receptor mediates the clearance of LDL particles?

What apoLP is the ligand for this receptor?

Why is this interaction clinically significant?

Receptor: LDL receptors

Ligand: ApoB-100

Significance: manipulation of hepatic LDL receptor gene expression is the most effective way of modulating plasma LDL levels


Name two conditions in which LDL become atherogenic.

1) Modification by oxidation

2) Uptake by macrophage scavenger receptors


True or False:

LDLs can carry cholesterol from the liver to muscle and adipose tissue like chylomicrons and VLDLs can.



How does the half-life of an LP correlate with its density?

The trend appears to be: as density increases, t1/2 increases.

Chylomicrons: 5-20min

VLDL: 30min-1hr

LDL: 2.5days


After endocytosis of LDL particles, what are the fates of the endosomal components?

1) After lysosomal fusion, apoB-100 and CEs are degrades to release amino acids, FAs, and cholesterol.

2) The LDL receptor, however, is segregated into vesicles and recycled to the cell surface.


Mutations in what protein are the most common cause of autosomal dominant hypercholesterolemia?

LDL Receptor (LDLR) - Over 900 known mutations


Name two endogenous hormones that can lower LDL levels. How do they accomplish this?

1) Thyroxine & estrogen

2) Enhancement of LDLR gene expression - increases LDL uptake


What is single most effective:

1) dietary alteration

2) pharmacological treatment

for hypercholesterolemia?

3) How do they both work?

1) Eat fewer saturated fats and cholesterol

2) Statins

3) Enhancing hepatic LDLR expression

[one would assume less cholesterol/fat itself would also help...]


What transcription factors mediate the regulation of LDLR expression?

Sterol Regulatory Element Binding Proteins (SREBPs)


SREBP cleavage activating protein (Scap)

[Nested acronyms should be illegal]


1) What serine protease descreases the expression of LDLR on hepatocytes?

2) How does the LDLR get downregulated, specifically?

3) Given the above, what would a gain-of-function mutation in this protease dispose a patient to?

4) How about a loss-of-function mutation?

1) Protease: Proprotein convertase subtilisin/kexin type 9 (PCSK9)

2) How: PCSK9 binds LDLR, and the complex of the two is internalized and targeted to the lysosome for degradation.

3) Gain: Less LDLR means more LDL. More LDL and cholesterol in plasma → increased risk of CHD

4) Loss: More LDLR means lower LDL cholesterol levels and protection from CHD.


Name a protein that, when mutated, causes autosomal dominant hypercholesteremia that isn't LDLR.

PCSK9 (Gain-of-function mutation)



1) What the hell is it?

2) What is its identifying apoLP?

3) Good or Bad?

4) Why?

5) Half-life?


1) What: An LDL-like particle

2) ApoLP: apo(a), which is covalently bound to apoB-100.

3) Bad.

4) Not discussed - may have anti-fibrinolytic qualities

5) t1/2: 3-4 days


What protein is apo(a) highly homologous to?

What structural domain causes apo(a) to vary in size?


A variable number of kringle IV repeats.


Name 7 ways in which HDL is atheroprotective.

1) Anti-oxidant

2) Anti-thrombotic

3) Anti-inflammatory

4) Reduces endothelial expression of adhesion molecules

5) Stimulates endothelial repair

6) Promotes endothelial function

7) Stabilizes atherosclerotic plaques




In general, LDL (deposits / removes) cholesterol (in / from) the periphery. In contrast, HDL generally (deposits / removes) cholesterol (in / from) the periphery.

In general, LDL (deposits / removes) cholesterol (in / from) the periphery. In contrast, HDL generally (deposits / removes) cholesterol (in / from) the periphery.


What are the most abundant apoLPs in HDLs?

1) ApoA-I (70% of protein)

2) ApoA-II (20% of protein)

3) ApoC

4) Lecithin-cholesterol acyl transferases (LCAT)


A loss-of-function mutation in what gene might cause HDL deficiency?

What risk would this present?

apoA-I gene.

Risk of accelerated atherogenesis.

(Conversely, a gain-of-function mutation likely protects against atherogenesis.)


1) What transporter promotes the release of cellular phospholipids and cholesterol to join apoA-I and form HDL?

2) What form of HDL is produced this way?

1) ATP binding cassette transporter (ABCA1)

2) Discoidal HDL, not spherical HDL


1) Mutations in ABCA1 cause what rare disease?

2) What is the pathophysiology?

3) What clinical symptoms are seen?

4) Are plasma cholesterol levels low or high?

1) Tangier disease

2) Defective ABCA1 results in severely reduced cholesterol efflux to apoA-I. Pooly-lipidated nascent HDL is rapidly metabolized, resulting to markedly reduced HDL levels and cholersterol deposition in various tissues (liver, speen, tonsils, peripheral neurons)

3) Enlarged spleens & tonsils. Tonsils are orange from carotenoid accumulation. 

4) Notably, plasma cholesterol levels are very low.


1) What is another name for discoidal HDL?

2) Where is the majority of discoidal HDL formed?

3) What's godd about discoidal HDL?

1) preß-HDL

2) Liver and intestine

3) It's a cholesterol sponge that can acquire free, unesterified cholesterol from tissue cell membranes, including arterial wall macrophages.


1) What protein is important in the generation of spherical HDL from discoidal HDL?

2) How does it accomplish this?

3) What apoLP on HDL activates this protein again?

1) Lecithin-Cholesterol Acyl Transferase (LCAT)

2) LCAT associates with HDL and esterifies free cholesterol that is acquired by discoidal HDL. The hydrophobic CEs move to the core of the HDL particle, increasing its size and eventually making it spherical.

3) apoA-I


1) What protein promotes the release of cholesterol to already-spherical HDL?

2) In what tisses is it found?

3) What remodeling processes does this assist in?

1) ABCG1

2) Spleen, thymus, lung, brain, liver, and macrophages

3) HDL remodeling and alteration of cholesterol distribution on "donor" cell membranes.


Why is HDL remodeling important?

It influences the metabolism, function, and plasma concentrations of HDL.


1) What does cholesterol ester transfer protein (CETP) do?

2) Is CETP activity beneficial or harmful? Why?

1) Promotes the transfer of CEs from HDL to VLDL, IDL, and LDL in exchange for TGs.

2) Harmful. Inceased CETP means more CEs moved into LDL-like particles, which can deposit those CEs into tissues and cause atherogenesis. A known Japanese population of CETP deficient people have reduced CAD risk.


Name 4 functions Phospholipid Transfer Protein (PLTP).

1) Transfer of excess free cholesterol and phospholipids from cylomicrons and VLDLs to HDL

2) Needed for maximal activity of LCAT

3) Major role in generating preß-HDL (discoidal HDL)

4) Promotes phospholipid efflux to preformed HDL


1) What is the function of Hepatic Lipase (HL)?

2) When does HL act?

3) How do androgens and estrogens affect HL gene expression?

1) Function: Hydrolyzes TGs and phospholipids to generate smaller spherical HDL particles. These smaller particles can recirculate and soak up additional free cholesterol.

2) When: After CETP and PLTP action, the TG-enriched HDL is a better substrate for HL.

3) Androgens: increase HL activity; thus, men often have lower HDL-cholesterol levels than women

    Estogens: reduce HL activity, but the increase is minor compared to the increase in men from androgens.


1) What protein hydrolyzes HDL phospholipids?

2) What is the result of this hydrolysis?

3) Is this protein therefore atherogenic or atheroprotective?

4) What apoLP may inhibit this protein's activity?

1) Endothelial Lipase (EL)

2) Generates smaller HDL particles that are catabolized faster

3) Atherogenic. EL overexpression has been seen to reduce apoA-I and HDL-C levels to almost zero

4) ApoA-II may inhibit EL activity (HDL with ApoA-II are catabolized more slowly)


1) What is the function of Scavenger Receptor BI (SR-BI)?

2) Is SR-BI atherogenic or atheroprotective?


1) A major HDL receptor. It plays a critical role in maintaining plasma cholesterol levels and acts to deliver cholesterol to the adrenal cortex and gonads to support steroidogenesis.

2) Atheroprotective.


How does the transfer process of HDL components via SR-BI occur? What happens to the HDL after transfer?

-ONLY lipid is trasnferred to cells

-The entire HDL particle is NOT internalized

After transfer, HDL can recirculate to pick up more cholesterol


During HDL catabolism, how are apoA-I and apoA-II degraded? Where?

They are degraded synchronously, in the liver and kidney.


What enzyme initiates the conversion of cholesterol to bile acids?

cholesterol 7ɑ-hydroxylase


1) What is the fate of most bile acids?

2) What happens to the remainder of bile acids?

3) How is this important pharmacologically?

1) Most bile acids are reabsorbed, returned to the liver via the portal vein, and resecreted.

2) A small amount is lost in the stool, which provides a means of cholesterol elimination

3) Agents that bind bile salts and prevent their reabsorption are used to treat high blood cholesterol.


Name 4 regulatory mechanisms for the synthesis and transport of cholesterol.

1) Covalent modification of HMG-CoA reductase

2) Transcriptional regulation of HMG-CoA reductase gene

3) Activation of ACAT (increases esterification for storage)

4) Transcriptional regulation of the LDL Receptor


How do the following proteins affect the activity of HMG-CoA Reductase?

1) AMP-dependent protein kinase (AMPK)

2) Glucagon

3) Epinephrine

4) Insulin

Do they provide short or long-term regulation?

1) AMPK: phosphorylation, decreased activity

2) Glucagon: Cascades lead to phosphorylation, decreased activity

3) Epinephrine: Cascades lead to phosphorylation, decreased activity

4) Insulin: Cascades lead to dephosphorylation, increased activity

Covalent modification (phosphorylation) provides short-term regulation


1) What transcription factors control long-term regulation of HMG-CoA Reductase?

2) How are these transcription factors activated?

3) What other genes do these transcription factors upregulate?

1) Sterol regulatory element-binding proteins (SREBPs) and SREBP cleavage activating protein (Scap, which inhibits SREBP)

2) High cellular sterol levels: Sterol-bound Scap binds SREBP in ER and holds it there

Low cellular sterol levels: Scap/SREBPcomplex cleaved, SREBP moves to nucleus and activates transcription

3) LDL Receptor, others



What sorts of feedback regulation of cholesterol synthesis and metabolism might you expect in a cell after it binds and internalizes an LDL particle?

- Decreased HMG-CoA activity

- Decreased LDL receptor expression

- Increased expression of storage enzymes