Atherosclerosis Lecture 1/26/23

Total cholesterol is mixture of....

LDL and HDL

Chylomicrons (carrying the fat) then gets hydrolyzed by ________ and converts into chylomicron remnants. This will also sub-produce free fatty acids that will go to the tissues.

LPL

Second possible pathway: IDL can be further hydrolyzed by LPL or HL to create _________.

LDL

Once LDL is created from IDL, it can either attach itself to the liver via its __________ mediated receptors or go to peripheral tissues.

ApoB

One possible pathway: Receptors on IDL are ________ mediated and can attach to the liver.

ApoE

The Chylomicron remnants have receptors on its surface that are __________ mediated which can then attach to the liver.

ApoE

What is atherosclerosis?

The build-up of fats, cholesterol, and other substances in and on the artery walls.

What are triglycerides?

The stored form of fat -muscles use it as an energy source

The liver produces _________ which can then be hydrolyzed by LPL to create IDL. Two pathways are possible after this step.

VLDL

Which type of lipoprotein is bad at high levels?

VLDL and LDL

What is liver and cholesterol production?

We make our own cholesterol via the liver (800-1500 mg a day) to contribute to Vitamin D, steroid hormones, etc.

What is PCSK9?

a protein that degrades LDL receptors on the liver

What is in the core of lipoproteins?

triglycerides and cholesterol ester

Fatty streak (accumulation of LDL) develops due to _________ endothelium or direct binding to extracellular matrix.

"leaky"

What are the 3 types of autosomal dominant hypercholesterolemia (ADH)?

- ADH-1: receptor has an issue being translocated to the cell membrane (can't clear LDL from the blood) -ADH-2: ApoB receptor is abnormal so it can't be recognized by the receptor so receptor cannot physically pick up LDL -ADH-3: Patients have a gain of function of PCSK-9 protein that circulates the blood and bind to the LDL receptor. Degradation occurs

What are two important enzymes in lipoprotein metabolism?

- Lipoprotein Lipase (LPL) - Hepatic Lipase (HL)

What does the inflammatory response do?

- Monocytes become macrophages that ingest lipids becoming foam cells - White blood cells migrate to area - Smooth muscle cells accumulate

What are stable plaques?

- asymptomatic - thick fibrous caps that partially block vessels (rich in smooth muscle and extracellular matrix) - do NOT tend to form clots or emboli

What are unstable plaques?

- have thin fibrous caps that may completely block the artery (rich in macrophages and foam cells) - plaque can rupture and cause a clot (thrombus) to form - clot may end up in the heart or brain - cause thromboembolism

What are functions of cholesterol?

1) Maintaining the structure and fluidity of membranes with changing temperature 2) Serving as a precursor for steroid synthesis 3) Formation of bile acids/salts 4) Synthesis of Vitamin D

What are the name of the locations most likely to have development of plaque formation (3)?

1. Carotid bifurcation 2. proximal renal arteries 3. left descending coronary artery

Where do plasmid lipids go (2)?

1. Clearance by liver and other tissues 2. Oxidation and formation of atherosclerotic plaque

Where are three locations plasma lipids can come from?

1. Dietary Lipids 2. Export from Liver 3. High Cellular, Energy State

What do apolipoproteins do?

1. Structural integrity/support 2. Act as ligands for receptors (i.e. tells the lipoprotein where to go) 3. Transport H2O insoluble material

What are the 4 lipoprotein types?

1. VLDL (very low density lipoprotein) 2. IDL (intermediate density lipoprotein) 3. LDL (low density lipoprotein) 4. HDL (high density lipoprotein)

Normal range of LDL should be

< 100 mg/dL

Normal range of triglycerides should be

< 150 mg/dL

Normal range of total cholesterol should be

< 200 mg/dL

Normal range of HDL should be

>50 mg/dL

Apo-lipoproteins serve what important function in cholesterol metabolism? A. transport of dietary fats from the digestive tract into the blood B. oxidize of LDL during plaque formation C. receptor recognition and cholesterol uptake into tissue D. recognition by lipoprotein lipase to release FreeFattyAcids

A. transport of dietary fats from the digestive tract into the blood C. receptor recognition and cholesterol uptake into tissue D. recognition by lipoprotein lipase to release FreeFattyAcids

Atherosclerosis is also a major contributor to __________________________________________ (CHF).

Congestive Heart Failure

Which type of lipoprotein is good at high levels?

HDL

Acetyl CoA is converted to ________________ in liver cholesterol synthesis.

HMG-CoA

What step in liver cholesterol synthesis do statins inhibit?

HMG-CoA --> Mevalonate

Describe plaque formation: Once the inner wall of an artery is damaged, blood cells and other substances may gather at the injury site and build up in the inner lining of the artery. Over time, fats, cholesterols and other substances also collect on the inner walls of the heart arteries. This buildup is called plaque. Monocytes are converted to Macrophages. What happens next?

Macrophages in atherosclerotic lesions actively participate in lipoprotein ingestion and accumulation giving rise to foam cells filled with lipid droplets. Accumulation of foam cells contributes to lipid storage and atherosclerotic plaque growth

In order to reduce LDL levels, we want to produce drugs that will target and inhibit/inactivate ___________.

PCSK9

What are the proteins in lipoproteins?

apolipoproteins

What does thrombus do?

block blood flow causing tissue/organ ischemia

What is thrombus formation?

blood clot that remains attached to the vessel wall

What is lipoprotein lipase (LPL) important for?

catalyzes hydrolysis of various lipids on lipoprotein particles and turns them into smaller remnants that are more rapidly cleared

Once we digest fat, it gets absorbed into the intestine. The intestine then gets rid of the fat through a carrier called ______________.

chylomicrons

What is hepatic lipase (HL) important for?

essential for LDL production and redistribution in HDL fraction. In its absence, VLDL becomes very elevated.

Initially, atheroma growth is outward (maintain lumen radius) but later an eccentric plaque can result from a healing response which are more ___________________ significant.

hemodynamically

A gain of function of PCSK9 will ultimately result in...

higher LDL blood levels

As lipase hydrolyzes VLDL to IDL to LDL, the triglyceride content decreases while cholesterol __________________.

increases (this is why LDL is really bad at high levels)

What is in the outer layer of lipoproteins?

phospholipids, proteins, NON-ester cholesterol

Calcification (deposition of Ca salts) of the plaque develops as a result of ________________.

inflammation

The fibrous cap separates the artery lumen from the thrombogenic core of the plaque and as such is the final barrier to thrombus formation. Thus if the fibrous cap is broken open, what happens to thrombus formation?

it is stimulated

The death of macrophages leads to formation of ______________.

lipid rich, necrotic core

Most endogenous cholesterol is formed in the _________.

liver

Loss of function PCSK9 leads to...

lower LDL blood levels (hypocholesterolemia)

As lipase hydrolyzes VLDL to IDL to LDL, the size is getting bigger or smaller?

smaller

Atherosclerosis is the underlying cause for MOST cases of ____________________________ (coronary arteries), ischemic stroke (cerebral arteries), and peripheral arterial disease.

myocardial infarction

What state of LDL triggers an inflammatory response?

oxidative LDL

What do statins do?

reduce cholesterol in blood

Fats first accumulation can occur in the coronary arteries as early as ______________________.

the 1st decade

What is a lipoprotein?

the transport form of fat and cholesterol in the circulation

Why is HDL (ApoA-I mediated) good at high levels?

they pick up extra cholesterol in the body and bring it back to the liver to be excreted

Erosion of atherosclerotic plaque can trigger rapid ____________ formation.

thrombus

When does LDL become a problem?

when it becomes oxidized because it will create macrophages and form foam cells (atherosclerosis)

Plaque formation is most likely to occur where?

where a vessel or artery branches off (arterial bifurcations) due to disturbed hydrodynamics