Cardiovascular Nutrition and Hyperlipidemia

Question 1

What molecules are on the outer surface of lipoprotein particles?

Answer 1

Apolipoproteins, phospholipids

Question 2

What molecules are in the inner core of lipoprotein particles?

Answer 2

Triglycerides and cholesteryl esters

Question 3

What apoprotein is on LDL and other atherogenic lipoproteins?

Answer 3

ApoB

Question 4

What apoprotein is on HDL and other antiatherogenic lipoproteins?

Answer 4

ApoAI

Question 5

Describe the endogenous pathway of VLDL and LDL cholesterol transport

Answer 5

Liver secretes VLDL (composed of cholesterol, triglycerides)
VLDL gets hydrolyzes to IDL and triglycerides
IDL can be taken up via LDL-receptor into liver or hydrolyzed to form LDL particles
LDL particles (primarily cholesterol) are normally taken up by liver, but can also get modified (glycosylated), allowing them to be taken up by macrophages (foam cells) and be atherogenic

Question 6

How is LDL metabolized in hepatocytes?

Answer 6

Apo B on LDL binds LDL receptors and LDL/LDL-R complex is internalized in clathrin-coated vesicles
Vesicles fuse with endosome, complex dissociates
Free LDL-Rs recycle back to surface
Free LDL particles are transported to lysosomes and degraded

Question 7

What protein targets LDL receptor and traps it with the LDL particle, inducing lysosomal degradation?

Answer 7

PCSK9

Question 8

What occurs if there is a gain of function mutation in PCSK9?

Answer 8

Lack of LDL-Rs will result in build up of LDL in blood stream where it will get taken up by macrophages and promote atherogenesis

Question 9

What is the defining characteristic of familial hypercholesterolemia (FH)?

Answer 9

High LDL cholesterol levels, causing premature CAD

Question 10

What is the most common genetic defect causing FH?

Answer 10

LDL-receptor

Question 11

What are physical findings of FH?

Answer 11

Thickened Achilles tendon
Xanthelasmas - nonspecific cholesterol deposits that encircle eye
Arcus - grayish blue ring along surface of cornea, diagnostic of FH!

Question 12

What usually causes familial combined hyperlipidemia (FCH)?

Answer 12

Overproduction of ApoB-100

Question 13

What is deficient when someone has Apo-E2 homozygosity?

Answer 13

IDL particles cannot be cleared efficiently by the liver from the circulation
Remnant particles can build up and be pro-atherogenic

Question 14

In addition to Apo-E2 homozygosity, what is needed to develop full clinical presentation of Type III hyperlipidemia?

Answer 14

Metabolic abnormality like T2DM

Question 15

What are physical findings of Type III hyperlipidemia?

Answer 15

Yellow streaks in palmar creases

Tuberous xanthomas

Question 16

How are dietary triglycerides metabolized? (step by step)

Answer 16

Triglycerides catabolized to free fatty acids by lipases
FFAs are re-esterified and packaged as chylomicrons
Chylomicrons are hydrolyzed by lipoprotein lipase (LPL) to FFAs and chylomicron remnants (CMR)
CMR can be directly removed by hepatocytes or, when in excess, be taken up by macrophages in vascular wall –> foam cell –> atherosclerosis

Question 17

What metabolic consequences occur when you have hypertriglyceridemia? (step by step)

Answer 17

Hypertriglyceridemia causes excess VLDL secretion
Higher VLDL-TG output activates cholesteryl ester transfer protein (CETP) that exchanges TG from VLDL for CE from HDL or LDL
This results in TG-enrichment of LDL and HDL
TG content within these particles is hydrolyzed by HTGL resulting in small, dense cholesterol rich LDL and HDL particles

Question 18

Why are small, dense HDL and LDL bad?

Answer 18

Small HDL: particles more rapidly cleared by kidneys, cannot exert anti-atherosclerotic effect

Small LDL: decreased affinity for LDL-R, will remain in circulation longer –> increased atherogenicity

Question 19

What is a normal triglyceride level?

Answer 19

<150

Question 20

What are physical signs of high triglycerides?

Answer 20

Creamy layer in refrigerated plasma
Cutaneous xanthomas
Creamy retinal layer
Tuberous xanthomas and yellow streaking on palm

Question 21

What is the process of reverse cholesterol transport?

Answer 21

HDL takes lipids (free cholesterol) from vascular macrophages, mediated by ABCA1 protein
Free cholesterol on HDL gets esterified into cholesteryl ester (CE) by LCAT
HDL can do 3 things with CE:
- Deliver CE to hepatocytes via LDL-R
- Donate CE to LDL, VLDL in exchange for TG by CETP
- Donate CE to steroidogenic tissues (ovaries, testes)

Question 22

What occurs if you have defect in ABCA1?

Answer 22

Lipid accumulation in macrophages

Causes yellow-orange tonsils seen in Tnagier Disease

Question 23

What occurs if you have defect in LCAT?

Answer 23

Lipids accumulate in eye and kidney, causing corneal opacification and/or renal failure

Question 24

Why are saturated fats particularly bad for cholesterol?

Answer 24

Inhibits LDL receptor activity

Prothrombotic and proinflammatory