Lecture 34: Cholesterol and Lipoprotein Metabolism Flashcards Preview

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Flashcards in Lecture 34: Cholesterol and Lipoprotein Metabolism Deck (45):
1

What are the types of lipoprotein disorders?

Think about the TYPE of lipoprotein that is elevated
1. Familial Chylomicronemia Syndrome (FCS; Type I)
-mutation in ApoC2 or LPL
2. Familial Hypercholesteremia (FH; type IIa)
-mutation in LDLR
a. Familial Defective ApoB-100, FDB (nothing for LDL to bind to liver with)
b. autosomal dominant hypercholesterolemia, ADH3 = gain of function for PCSK9 which downregulates LDLR
3. Familial Combined Hyperlipidemia (FCHL)
-unknown mutation that leads to increase in VLDL and LDL production
4. Familial Dysbetalipoproteinemia
-mutation in ApoE (too many remnants)
5. Familial Hypertriglyceridemia (FHTG)
-mutation unknown (LPL for VLDL doesn’t work)
-progresses to Type V (VLDL + chylomicron increase or Type I + IV) when patient drinks

2

What is the structure of lipoprotein?

1. Nonpolar Lipid Core
i. triglycerides
ii. cholesterol ester
2. Polar surface coat
i. phospholipid and free cholesterol
3. Apolipoproteins on the polar surface coat
Lipoproteins = heterogeneous group of particles which span a spectrum of size and density

3

What is the relationship between cholesterol levels and heart disease?

Directly correlated

4

What are the types of lipoproteins?

From LEAST dense to most dense
1. Chylomicrons (floats on top of water)
2. Chylomicron remnants
3. VLDL
4. IDL
5. LDL
6. HDL

5

What are the types of apolipoproteins?

1. ApoB-48 = chylomicrons
2. ApoB-100 = VLDL, IDL, LDL
3. ApoA-1 = HDL
4. ApoA-II = HDL
5. ApoE = VLDL, HDL, chylomicron remnant
6. ApoC-II = Chylomicrons, VLDL

6

What are the apolipoprotiens present in HDL?

1. ApoE
2. ApoA (I and II)

7

What lipoproteins fall under the category of ApoB lipoprotein?

All the ones that cause atherosclerosis and CAD
Includes
i. Chylomicrons
ii. VLDL
iii. IDL
iv. LDL

8

What is the significance of Apo C-II?

A cofactor for lipoprotein lipase (LPL) to breakdown chylomicron to chylomicron remnant

9

What are the apolipoproteins in chylomicron?

1. ApoB-48
2. Apo

10

What are the key characteristics of the EXOgenous pathway of lipoprotein metabolism?

Takes fat from diet and stores/utilizes it in the body
1. Fat is absorbed in intestine by enterocytes  packaged triglycerides in chylomicrons
2. Chylomycron brings triglycerides to muscle and fat (to maximize energy utilization)
3. fat and muscle release LPL and turns chylomicrons into chylomicron remnants
4. Chylomicron remnants then uses its ApoE ligand to bind to the LDLReceptor on the liver

11

Where is lipoprotein lipase made?

1. myocytes
2. adipocytes

12

What is the purpose of lipoprotein lipase (LPL)?

To break down triglycerides into fatty acids for use in energy or storage (muscle and fat respectively

13

What are the key characteristics of the ENDOgenous pathway of lipoprotein metabolism?

Body yakes fat stored in adipose and utilizes it for energy metabolism
1. Adipose releases free fatty acids
2. FFA goes to the liver where it is packaged into triglyceride by ApoB-100 in VLDL
3. Once in VLDL, the triglycerides are transported to tissues of need, like heart and skeletal muscle
4. heart and skeletal muscle secrete LPL to break down TG (using ApoC-2 as co-factor) and turns VLDL to IDL
5. IDL can then be converted to LDL by hepatic lipase (HL)
6. IDL uses its ApoE ligand to bind to LDL receptor in liver
7. LDL uses its ApoB100 ligand to bind to LDLReceptor in lever

14

What is the main cholesterol carrier in the blood?

LDL

15

What is HL?

Hepatic lipase
Converts IDL
to LDL

16

What are the secondary cause of hyperlipoproteinemia?

1. insulin resistance/type 2 diabetes mellitus
2. hypothyroidism
3. dietary influences and alcohol use
4. nephrotic syndrome/chronic renal failure
5. medications

17

What is the association between insulin resistance and cholesterol production?

Insulin resistance = overproduction of VLDL
Most important secondary cause of dyslipidemia

18

What leads to familial chylomicronemia syndromes (FCS; type I)?

Disorder = too much chylomicrons in the blood
MoA = mutation of LPL and ApoC-II
That means LPL cant break down chylomicron to chylomicron remnant

19

What are the skin deficiencies associated with chylomicron build up?

Xanthomas

20

What do patients with Familial Chylomicronemia Syndrome present with?

Pancreatitis
Eruptive xanthomas

21

What are xanthomas?

A skin condition reflecting build up of fat under surface of skin

22

What are the key characteristics of familial dysbetalipoproteinemia?

MoA: ApoE dysfunction
aka Type III
Very unfortunately named
Occurs when there is a mutation in ApoE
A chylomicron REMNANT disorder

23

What is the role of ApoE?

Allows IDL and chylomicron to bind to LDLR
No ApoE = too much chylomicron remnant/VLDL

24

What are the three forms of ApoE alleles?

1. ApoE3 (normal guys)
2. ApoE4 (the most important risk factor for Alzheimers)
3. ApoE2 (does not bind to LDL well)

25

What are the key characteristic of skin disorders in Type III (or familial dysbetalipoproteinemia)?

1. Palmar Xanthomas
2. Xanthomas on ze elbows
Specific for Type III

26

What are the key characteristics of Familial Hypercholesterolemia?

MoA: LDLReceptor dysfunction
Type IIa
Mutations = too much LDL in blood
Can be homoxygous (most severe) and heterozygous gene defect of LDLR

27

What are the most characteristic physical signs of FH?

1. Tendon xanthoma (thickening of Achilles tendon)
2. Knuckle xanthoma
3. Corneal arcus
4. Xanthelasma

28

What are the clinical features of someone with FH?

Coronary Heart Disease

29

What are the key characteristics of a Familial Defective ApoB-100 (FDB; Type IIa)?

MoA: ApoB-100 dysfunction
Inability of LDL (which needs ApoB-100) to be bound to LDLR
So defective ENDOGENOUS pathway
Known as type IIa…very similar to FH

30

What are the key characteristics of autosomal dominant hypercholesterolemia 3 (ADH3; Type IIa)?

MoA: Gain of function mutation of PCSK9 leads to downregulation LDLR
Aka Type IIa
PCSK9 gains the function of downregulating LDLR through a pathologic mutation

31

What are the key characteristics of Familial hypertriglyceridemia (FHTG; type IV or V)?

MoA: LPL for VLDL doesn’t work (exact molecular cause not known)
LPL cant break down VLDL
So you get too much VLDL in familial hypertriglyceridemia
Type V = worst manifestation of Type V because of drinking
-means that there are too many chylomcrons in addition to VLDL

32

How do you remember type V?

Type I (chylomicron) + Type IV (VLDL) = type V (too much chylomicrons + VLDL)
In terms of whats wrong

33

What are the characteristics of Familial combined hyperlipidemia (FCHL; Type IIb)?

MoA: UNKNOWN
End result: overproduction of VLDL/LDL
No xanthomas

34

What are the key characteristics of lipoprotein (a) or Lp(a)?

An independent risk factor for CHD
Very similar to LDL but contains an additional Apo(a)
Function is unknown
Used to assess risk for coronary heart disease

35

What is the association between LDL and HDL?

They are independent predictors of cardiac risk! Just because one is low doesn’t say shit about the other one

36

What is the most important apolipoprotein to remember in HDL?

Apo-A1
Required to produce HDL

37

How is HDL produced?

From the following organs:
1. liver
2. intestine

38

How does HDL reduce hypercholesterolemia?

HDL grabs cholesterol and brings that shit to the liver
Then is excreted in liver via bile

39

How is HDL removed?

By the kidney

40


What are the secondary causes of low HDL cholesterol?

1. insulin resistance/Type 2 diabetes
2. very low fat diet
3. sedentary lifestyle
4. obesity
5. chronic renal failure
6. medications

41

What is the most important secondary cause of low HDL?

Insulin resistance/Type 2 diabetes

42

What are the primary genetic causes of hypoalphalipoproteinemia (low HDL)?

1. ApoA-1
2. Tangier disease (ABCA1)
3. LCAT deficiency
None are obviously linked to coronary disease

43

Is there a causal relationship between HDL and coronary disease?

No, if you have lower HDL, doesn’t necessarily mean you don’t have coronary disease

44

What is ABCA1?

A cholesterol transporter particularly important in macrophages
Transport cholesterol out of macrophage and forms HDL
Mutation in ABCA1 leads to Tangier disease

45

What are the physical signs of LCAT deficiency?

LCAT = lecithin-cholestrol acyltransferase deficiency
Transforms a nascent HDL into a mature HDL by creating cholesterol esters