RX413 - PDA2 E4: Lipids & anti-hyperlipidemia therapy 1

What are lipoproteins?

Macromolecular vesicles that serve as molecular carriers for lipid transport

What is on the surface of lipoproteins?

phospholipid monolayer embedded with cholesterol

What is in the core of lipoproteins?

Triglycerides and cholesteryl esters

What are apolipoproteins?

Stabilize the structure of lipoproteins

Serve as the ligand for receptors of lipoproteins or co-factors of enzymes

What are the 5 major lipoproteins?

Chylomicron (CM)

Very-low-density lipoprotein (VLDL)

Intermediate density lipoprotein (IDL)

Low-density lipoprotein (LDL)

High-density lipoprotein (HDL)

Rank the 5 major lipoproteins from least dense to most dense

HDL

LDL

IDL

VLDL

CM

Which lipoprotein has the highest protein content?

HDL

Which lipoprotein has the highest cholesterol content?

LDL

Which lipoprotein has the highest triglyceride content?

CM

Which apolipoproteins are important for receptor-mediated uptake of lipoproteins?

ApoB and ApoE

What apolipoproteins are unique to LDL?

ApoB100

Which apolipoprotein does HDL lack?

ApoB

Which apolipoprotein is required for the formation of HDL?

ApoA

Where are the protein components of lipoproteins synthesized in CM and VLDL?

Rough ER

What happens in the smooth ER during the assembly of lipoproteins in CM and VLDL

MTP incorporates lipids

What are the unique features of CM?

ApoB48

Made in enterocytes

What are the unique features of VLDL?

ApoB100

Made in hepatocytes

Why does CM have a different ApoB than VLDL despite coming from the same gene?

Enterocytes express ApoB editing complex-1 which turns cytosine to uridine which causes a premature stop codon

Translated protein is smaller

mRNA editing does not happen in hepatocytes so full ApoB100 is translated and incorporated into VLDL

Where does ApoC-II come from? Where does it go?

Transferred from HDL to CM and VLDL

What does ApoC-II do?

Bind to and activate LPL on surface of endothelial cells

What does LPL do?

Breakdown triglycerides but not cholesteryl esters

What happens to CM and VLDL after hydrolysis of triglycerides?

Depleted of TG but rich in cholesteryl → loose affinity for LPL

Bind to circulating HDL and exchanges their ApoB for ApoE

What are the resulting particles of apolipoprotein exchange?

VLDL remnants (IDL) and CM remnants

If a patient has a genetic deficit of lipoprotein lipase, what is likely the main phenotype on plasma lipid levels?

• Increased LDL-cholesterol in blood

• Decreased HDL-cholesterol in blood

• Decreased TG in blood

• Increase TG in blood?

Increase TG in blood

If a patient has a genetic deficit of ApoC-II, what is likely the main phenotype on plasma lipid levels?

• Increased LDL-cholesterol in blood

• Decreased HDL-cholesterol in blood

• Decreased TG in blood

• Increase TG in blood?

Increased TG in blood

What is the space of Disse

Between hepatic sinusoidal endothelium and the basolateral plasma membrane of the hepatocytes

Where are CM remnants and IDL sequestrated?

Space of Disse

What prepares CM remnants and IDL by optimizing the triglyceride content?

Hepatic Lipase (HL)

What 3 things does ApoE interact with for receptor-mediated uptake of remnant particles?

LDL receptor (LDL-R)

LDL receptor-related receptor (LRP)

Heparan sulfate proteoglycans (HSPG)

What clears ApoB48-containing remnants?

By liver

which remnant is not fully cleared by hepatocytes?

VLDL

What happens to remaining IDL after clearance?

Concerted to LDL

What is left on the membrane of VLDL after ApoE and ApoC-II are transferred back to HDL?

ApoB-100

What happens to IDL particles once they bind to LDL-R?

LDL-R take them into the cell where lysosomes turn cholesterol esters into free cholesterol. LDL receptors are then recycled back onto the cell surface

What does PCSK9 do?

Directs LDL-R to degradation

What happens to LDL not cleared by LDL-R?

Migrate to bind to proteoglycans and oxidize which induces cellular damages

If a patient has a genetic deficit of LDL-R, what is likely the main phenotype of plasma lipid levels?

Increase cholesterol in liver

How is HDL formed?

ApoA-I secreted from liver and incorporated in nascent HDL particles

Cholesterol from macrophages esterified by LCAT forming mature HDLs

What does HDL regulate?

Cholesterol homeostasis

What is unique to HDL function?

Reverse cholesterol transport

• Carries excess cholesterol from periphery back to liver for excretion in the bile

What is HDL a reservoir for?

Exchangeable apolipoproteins for metabolism of ApoB-containing lipoproteins

If a patient has a genetic deficit of ApoA-I, what is likely the main phenotype on plasma lipid levels?

Decreased HDL-cholesterol in blood

What is the only organ that can eliminate cholesterol?

Liver

Where does the major of cholesterol come from in hepatocytes?

De novo synthesis that requires HMG-CoA reductase

What is the RLS of cholesterol biosynthesis?

HMG-CoA reductase

What does cytosolic cholesterol do?

Decrease activity of HMG-CoA reductase

Activate ACAT

Decrease LDL-R

What does ACAT do?

Convert cholesterol into water soluble (Easier to get rid of)

What would inhibiting HMG-CoA reductase result in?

Decrease of LDL