Lipid Metabolism 3 & 4

What functions in the uptake of LDL

A type of macrophage called foam cells

What is a byproduct of LDL uptake

Atherosclerotic plaque

A high level of oxidized LDL means an increase in...

free radicals

What cholesterol is increased, what happens to LDL

It gets oxidized

What causes atherosclerotic plaque buildup?

Foam cells

If there is an LDL receptor mutation, what happens to blood cholesterol

Blood cholesterol increases, causing hyper cholesterimea

Which region of the LDL receptor binds LDL?

Region 1

Where are the "hotspots" for mutations in regards to familial hypercholesterolemia?

At ligand binding genes

Type IIa hyperlipidemia has a deficiency in what receptor? And what is elevated?

LDL-receptor is deficient
LDL levels are elevated

Why are LDL levels elevated in Type IIA hyperlipidemia?

Because LDL cannot go into the liver. The liver thinks we are in a deficit because of this, and continues to produce LDL

Type IIb hyperlipidemia has a deficiency in what receptor? What apolipoprotein is increased? And what is elevated?

LDL-receptor is deficient
ApoB is increased
LDL, VDL, and TG are elevated, but remain below 1000mg/dl

Why does LDL-R deficiency increase LDL?

LDL cannot enter the liver. Liver thinks we do not have enough LDL because it doesn't have enough LDL. It makes more LDL

An increase in ApoB causes an increase in liver biosynthesis of...

VLDL

Why does a high VLDL mean a high TG?

Because VLDL is TG rich, the more VLDL there is, the more TG there is

A genetic analysis suggests familial hypercholesterolemia, type II. It is a disorder caused by a deficiency of LDL receptors. Which of the following best describes patients with type II?

A. LDL and LDL-R interaction leads to premature degradation of LDL
B. Cholesterol synthesis increases in the liver

B. Cholesterol synthesis increases in the liver

Name the 5 consequences that occur when you have deficient LDL receptors

1. Cannot incorporate LDL into the cells
2. Reduces cholesterol in the cells
3. Feedback inhibition is reduced
4. Cholesterol biosynthesis is increased
5. More LDL

What is the so-called good cholesterol?

HDL

Where is HDL located?

In the blood

What is the major apolipoprotein of HDL?

ApoA

What is the function of Lecithin Cholesterol Acyl Transferase?

Converts free cholesterol into cholesteryl ester, which is then sequestered into the core of a lipoprotein particle, eventually making the newly synthesized HDL

What enzyme converts free cholesterol into cholesteryl ester, which is then sequestered into the core of a lipoprotein particle, eventually making the newly synthesized HDL?

Lecithin Cholesterol Acyl Transferase

What is the function of Cholesterol Exchange Transfer Protein?

Facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from VLDL or LDL and exchanges them for cholesteryl esters from HDL, and vice versa

Describe the 3 consequences of Lecithin Cholesterol Acyl Transferase deficiency in both HDL and LDL

1. Lack of cholesterol esterification
2. Accumulation of unesterified cholesterol in the peripheral tissues
3. Marked corneal opacification and increased risk of renal failure

How does fish-eye disease occur?

Through a partial LCAT deficiency (affects HDL only)

What does LCAT put on the cholesterol when activated along with ApoA1

LCAT replaces alcohol group with FA

What is the function of Cholesterol Ester Transfer Protein?

To trade the TG in VLDL to an HDL and trade the CE in the HDL to the VLDL

What functions to trade the TG in VLDL with the CE in HDL?

Cholesterol Ester Transfer Protein (CETP)

What does a CETP enzyme deficiency lead to?

High HDL Cholesterol

Why is VLDL-TG less affected than HDL-CE with a CETP enzyme deficiency?

There are other ways of removing the TG within the VLDL

What is the function of CETP?

Moves CE from HDL to VLDL and TG from VLDL to HDL

What is the function of LCAT?

Makes CE before CETP transfers

What is the function of PLTP?

Transfers excess phospholipid from TG rich remnants to HDL (also some cholestrol)

What is the function of ApoC-II

Activator of LP Lipase

What is the function of ApoC-III

Inhbitor of LP Lipase

What is the function of ApoA-I

Activator (co-factor) for LCAT and cofactor for ABC-1

What is the function of ApoA-II

Inhibitor of LCAT and ABC-1

What is the Activator of LP Lipase

ApoC-II

What is the Inhbitor of LP Lipase

ApoC-III

What is the Activator (co-factor) for LCAT and cofactor for ABC-1

ApoA-I

What is the Inhibitor of LCAT and ABC-1

ApoA-II

Type 1 hyperlipidemia means a deficiency in what and elevated what?

LPL or C-II and elevated chylomicrons

What is the function of ApoB-100?

LDL receptor in the liver and periphery tissues and VLDL construction

What is the function of ApoC?

Functions with LRP (liver)

What is the function of ApoC and ApoB-100 together?

Clears IDL

What is the function of ApoB-48?

Chylomicron construction

Type 1 hyperlipidemia is a deficiency in what with elevated what?

Deficiency in LPL (Type 1A) or C-II (type 1B)
And elevated chylomicrons

Type IIa Hyperlipidemia is a deficiency in what with elevated what?

Deficiency in LDL-R and elevated LDL only

Type II b Hyperlipidemia is a deficiency in what (along with increased what) with elevated what?

LDL-R (with increased ApoB) and elevated LDL, VLDL, and TG (<1000mg/dl)

Type III Hyperlipidemia is a deficiency in what along with elevated what?

Deficiency in ApoE and elevated IDL

Why does Type I Hyperlipidemia lead to elevated chylomicron levels?

Because of the deficiency in LPL or ApoC-II, the body cannot digest TG in in chylomicrons to make FA, and thus chylomicrons accumulate

What is the difference between patients with Type IIb and Type III hyperlipidemia?

Both have elevated total total cholesterol and TG levels, but patients with Type III hyperlipidemia have elevated IDL BUT NOT elevated LDL or VLDL

What happens in Type IV hyperlipidemia?

There is VLDL overproduction, leading to elevated VLDL levels

What happens in Type V hyperlipidemia?

LPL is low and VLDL is high, thus chylomicrons and VLDL are elevated

What happens in Tangier disease?

Mutations in the ABC1 transport prevent cholesterol from exiting the cell, leading to cholesterol accumulation and low levels of HDL

Why is partial LCAT deficiency cause such a strong fisheye reaction?

LDL is providing the cholesterol, however the HDL has the problem in this case, and cannot pick up the cholesterol

Why does full LCAT deficiency cause a partial fisheye reaction?

In this case, the full deficiency affects both LDL and HDL, thus LDL is not providing the cholesterol and HDL is not picking up the cholesterol

What is the function of LP Lipase?

Degrades 2 legs of TG

When HDL goes down, what happens to apolipoprotein?

It also goes down, because HDL stores apolipoprotein

What is the name for Type I hyperlipidemia?

Hyperlipoproteinemia/hyperchylomicronemia

What is the type of hyperlipidemia that represents hyperlipoproteinemia/hyperchylomicronemia?

Type I

What is the name for Type IIa hyperlipidemia?

Hypercholesterolemia

What is the type of hyperlipidemia that represents hypercholesterolemia?

Type IIa

What is the name for Type IIb hyperlipidemia?

Familial combined hypercholesterolemia

What is the name for Type III hyperlipidemia?

Familial dysbetalipoproteinemia

What is the name for Type IV hyperlipidemia?

Familial hyperlipidemias

What is the name for Type V hyperlipidemia?

Hypertriglyceridemia with chylomicronemia

What is the type of hyperlipidemia that represents Familial combined hypercholesterolemia?

Type IIb

What is the type of hyperlipidemia that represents Familial dysbetalipoproteinemia?

Type III

What is the type of hyperlipidemia that represents Familial hyperlipidemias?

Type IV

What is the type of hyperlipidemia that represents Hypertriglyceridemia with chylomicronemia?

Type V

What is the type of hyperlipidemia that represents hypoalphalipoproteinemia?

Tangier's Disease

What is another name for Tangier's disease?

Hypoalphalipoproteinemia

Name 3 risk factors for atherosclerosis

1. Genetics
2. Oxidation of LDL
3. High Lipoprotein (a)

What does Lp(a) inhibit the formation of? And why is that bad?

Lp(a) inhibits the formation of plasminogen, which is the main protein component of blood clots

Name 5 facts about lipoprotein (a)

1. Risk factor for CHD (10x greater than LDL)
2. Highly variable in genetics
3. Structurally similar to plasminogen
4. Reduced fibrinolysis (fibrinolysis prevents blood clots from getting bigger and being dangerous to an individual)
5. Promotes plaque formation

What two pathways do we need eicosanoids for?

COX and LOX pathways

What is the most common precursor of eicosanoids?

Arachidonic acid

Name 3 groups eicosanoids

Prostaglandin
Thromboxane
Leukotriene

Where are omega 3 acids found?

In fish oil

Where are omega 6 acids found?

Seed oils and mainly animal meat

True/False: Hydrocortisone is an NSAID

False, it is a corticosteroid

True/False: Aspirin is not an NSAID

False, it is an NSAID

What is the function of corticosteroids?

To inhibit eicosanoid metabolism, specifically the step involving bradykinin and angiotensin

Which pathway do NSAIDs block?

The COX pathway

How many double bonds does COX use from arachidonic acid?

2 double bonds

What is the COX pathway involved with?

Clotting stuff, and also deals with fever, pain, etc.

What is the LOX pathway involved with?

Lung stuff, ie inflammatory response in lungs

When arachadonic acid goes through the LOX pathway it makes...

Leukotrienes

When arachadonic acid goes through the COX pathway it makes...

Thromboxases and postaglandins

True/False: Alpha linoleic acid is related to Omega 3

True

True/False: Linoleic acid is related to Omega 6

True

How is linoleate related to the active form of arachidonic acid?

Linoleate makes arachidonic acid that combines with membrane phospholipid to become active form of arachidonic acid by means of phospholipase A2

How is phospholipase A2 inhibited?

By glucocorticoids

How does arachidonic acid become a leukotriene

It becomes HPETE by means of lipoxygenase and then becomes a leukotriene

How does arachidonic acid become a thromboxane or prostaglandin?

It becomes PGG2 by means of cyclooxygenase, then becomes either thromboxane or prostaglandin

What does PGE2 refer to? (2 is in subscript)

Omega 6

What does PGE3 refer to? (3 is in subscript)

Omega 3

What are the 2 functions of prostaglycin?

1. Inhibit platelet aggregation
2. Cause vasodilation

Where are postaglycins produced?

Vascular endothelial cells

Where are Thromboxanes produced?

Platelet cells