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BIOC 311 > Lipoproteins, Cholesterol, integration > Flashcards

Lipoproteins, Cholesterol, integration Flashcards

1
Q

What is Orlistat and Olestra?

A

Orlistat = Lipase inhibitor
Olstra = Artificial fat/food additive

*Prevent breakdown of dietary fats for absorption in the small intestin → fats stay in the digestive tract → Steatorrhea (diarrhea)

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2
Q

What is the general structure of lipoproteins?

A

Lipoproteins are the circulating lipid carriers
- Hydrophobic/neutral lipid core → cholesterylester, triglyceride
- Monolayer Amphipatic coat → free cholesterol, phospholipids, phosphatidylcholine
- At least 1 Apolipoprotein (acts as dock or cofactor)

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3
Q

What are the different lipoproteins in order of density?

A
  1. Chylomicrons (least dense)
  2. Very-low density lipoprotein (VLDL)
  3. Intermediate density lipoprotein (IDL)
  4. Low density lipoprotein (LDL)
  5. High density lipoprotein (HDL)

*Filled with triacylglycerol makes them larger in size, but lower density (more proteins = more density)

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4
Q

What is the structure of the different lipoproteins?

A

Chylomicrons → Filled with triglycerides, Apo B-48, Apo-C, Apo E, Apo-A-1
Chylomicrons remnants → Apo B-48, Apo-E
VLDL → Filled with triglycerides, Apo B-100, Apo-E, Apo-C
IDL → same as VLDL but less triglycerides (from VLDL)
LDL → mostly Cholesterol esther in core, Apo-B100 (from IDL + interaction with HL)
HDL → Apo-A1
FINISH

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5
Q

What is the purpose/generatilites of the exogenous vs endogenous pathway of Lipoprotein metabolism?

A

Exogenous:
- Dependent on dietary intake
- Gives to muscle and adipose tissue if immediate needs
- Small intestine → Chylomicrons formed in small intestine → {capillaries of muscle and adipose tissues} → Chylomicrons remnants → Liver
- Done (no more chylomicrons in circulation ~2-3h post-meal)
- Bring lipids from Small intestine → Liver

Exogenous:
- Brings lipids from Liver → Peripheral tissues
- Independent of dietary intakes
- Liver → VLDL → {capillaries of muscle and adipose tissues} → IDL → Tissue

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6
Q

What is the role of lipoprotein lipase (LPL)?

A
  1. Binds to chylomicrons + is activated by cofactor Apo-C II
  2. It will uptake triacylglycerols in the chylomicrons → hydrolyze them to be uptaken by capillaries
    *Apo-C III inhibits LPL for balance

Chylomicrons remnants after going through capillaries don’t have Apo-C anymore as it stays bound to LPL

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7
Q

In the exogenous pathway, how to chylomicron remnants interact with the liver?

A

LDLreceptor → Apo-E
LRP → Apo-B 48

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8
Q

What is the difference between Apo-B 100 and Apo-B 48?

A

Apo-B 100 = 100% length of the protein → synthesized by liver (VLDL)
Apo-B 48 = 48% length of the protein → synthesized by small intestine (Chylomicrons)

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9
Q

What is HL?

A

Hepatic Lipase: Causes IDL → LDL (releases triacylglycerol to the liver?)

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10
Q

How is cholesterol uptaken by tissues?

A
  1. Uptake don via LDL-receptor which binds to Apo-B 100 → clathrin-coated pit → vesicle (endocytosis)
  2. Fusion of the vesicle with endosome → acidification → lyses the membrane (2ndary lysosome)
  3. Apo-B amino acids are released + Cholesterol makes Cholesteryl ester droplets or is brought to ER for membrane usage
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11
Q

What is the importance of HDL?
How are the made?

A

*Reverse Cholesterol Transport (Tissues → Liver)
1. ABCA-1 → efflux lipids onto Apo-A1 to form preHDL
2. Disk-shaped preHDL detaches from ABCA-1 (conformational change)
3. LCAT esterifies cholesterol → (disk-shape → ball-shape) → maturation to HDL3
4. CETP → CE and TG transfer between HDL3 and VLDL
5. Ultimately forms mature HDL2 → has right epitope (Apo-A1) to bind SRB1
6. HDL2 delivers CE and TG to liver → when emptied (Apo-A1 is unlipidated) → change in conformation → undocking of unlipidated Apo-A1 → goes back to tissue to binds ABCA-1

*ABCA-1 = Floppase → Uses ATP to move protein inside → outside
*Esterification of cholesterol = addition of FA from PC to make cholesterol completely neutral)
*CETP = Cholesteryl ester transfer protein

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12
Q

What is the rate-limiting step of Reverse Cholesterol Transport?

A

HDL bringing Cholesterol from tissues → Liver
Rate-limiting step = ABCA-1

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13
Q

What characteristic of Apo-A1 allows it to bind specific receptors needed to bring cholesterol from tissues to the liver in HDL?

A

Unlipidated A1 → Strong affinity for ABCA-1 (tissues), no affinity for SRB1 (Liver)

Lipidated A1 → Strong affinity for SRB1 (Liver), no affinity for ABCA-1 (detaches when starts being lipidated)

*Conformational changes

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14
Q

What is the effect of an increase in ACAT

A

Acyl-coenzyme A:cholesterol transferase (ACAT) → catalyzes formation of cholesterol esters inside ER → stored into cholesterol droplets
*In macrophages

It limits HDL-mediated cholesterol uptake

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15
Q

What is CETP?

A

CETP = Cholesteryl Ester Transfer Protein

Tube shape with hydrophobic interior → allows transfer between HDL3 and VLDL
- Cholesteryl Ester (CE): HDL3 → VLDL
- TG: VLDL → HDL3
*Down concentration gradient

End product = HDL2 → right epitope (APO-A1) to bind SRB1 in the liver

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16
Q

What is Cholesterol used for in the liver?

A
  1. Formation of Bile salts for bile
  2. Formation of VLDL
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17
Q

What is the rate limiting step of bile synthesis?

A

Cholesterol → 7a hydrocholesterol
*For synthesis of Bile salts

Enzyme = Cyp7a1 (hydroxylase)

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18
Q

What are the names of the 2 bile salts?

A

Both synthesized from cholesterol:
- Glycocholate (Glycine)
- Taurocholate (Taurine)

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19
Q

What is considered as good and bad cholesterol?

A

Good cholesterol → HDL (removes excess cholesterol from tissues)
Bad cholesterol → LDL (carries cholesterol from liver to tissues) → when too much in capillaries, accumulates and forms plaques → Antheosclerosis

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20
Q

What is Antherosclerosis?

A

Build up of fat and cholesterol in arterial walls

When overabundance of LDL → infiltrate the arterial wall → macrophages engulf the extra LDL → undergo apoptosis → build a plaque narrowing the blood vessels (increasing blood pressure)
Eventually, if the blood can’t pass, O2 can’t get to muscles → causes heart attack or stroke (brain)

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21
Q

What is the effect of a deficiency in LDLR?

A

Too much LDL accumulation in circulation → high cardiovascular disease risk

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22
Q

What is the effect of a deficiency in ABCA-1

A

*Floppase → make HDL
ABCA-1 deficiency → too little HDL → high cardiovascular disease risk because can’t bring cholesterol back from tissues to liver so accumulates

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23
Q

Which of the following can cause Hyper-Chylomicronemia?
- Lipoprotein Lipase deficiency
- ApoC-III mutations
- Apo E deficiency
- ABCA1 mutations
- ApoA-I deficiency

A

Lipoprotein Lipase deficiency
Apo E deficiency

*ApoC-III mutations → inhibitor of LPL → Gain of function mutation could increase chylomicron concentration
*ABCA1 and ApoA-I are related to HDL metabolism → not related

24
Q

Abnormally high [LDL] in plasma can be caused by L-O-F of which of the following?
- LDLr
- ApoB-100
- ABCA1
- Lipoprotein Lipase
- Pancreatic Lipase

A

LDLreceptor and ApoB-100 (receptor and ligand)

25
Q

Low HDL concentrations may result from mutation in which of the following?
- LDLr
- LPL
- LCAT
- ABCA1
- ApoA-I

A

LCAT, ABCA1, ApoA-I

26
Q

Which food provides a dietary source of “good” cholesterol?

A

NONE specifically, its all about quantities
HDL = good cholesterol
LDL = bad cholesterol

27
Q

What is the starting block of the synthesis of cholesterol?

A

Acetyl-CoA → Cholesterol (through the Mevalonate Pathway)
*One-way pathway, Cholesterol can’t broken down to Acetyl-CoA

28
Q

What are the general/important steps of the Mevalonate Pathway?

A

Mevalonate Pathway = Acetyl-CoA → Cholesterol

  1. Acetyl-CoA → {release CoA and attach to another Acetyl-CoA} → Acetoacetyl-CoA
  2. Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA
    *Up to here same steps as ketogenesis
  3. RATE LIMITING STEP: HMG-CoA reductase
    HMG-CoA → {consume 2x NADPH, release CoA-SH} → Mevalonate
  4. From Mevalonate → Farnesyl pyrophosphate
    Consumption of lots of ATP
  5. Farnesyl pyrophosphate → Squalene (consumes NADHP)
    Multiple Steps → Cholesterol
29
Q

What is consumed in the synthesis of Cholesterol?

A

Acetyl-CoA → Cholesterol consumes 36 ATP + 16 NADPH/cholesterol
*that’s why the pathway doesn’t reverse, it takes too much energy to make (we don’t degrade cholesterol, its precious!!)

30
Q

What is the rate-limiting step of the synthesis of cholesterol?

A

HMG-CoA reductase

31
Q

What is another use of Farnesyl pyrophosphate? (An intermediate of the Mevalonate Pathway)

A

It is also a lipid anchor → inserted in the bilayer lipid membrane and makes a thioether linkage between Cysteine and prenyl group → PRENYLATION

32
Q

How is cholesterol homeostasis maintained at the level of the whole body?

A

Cholesterol pool ~ 100g

Dietay intakes ~ 300mg/d
Synthesis from the liver ~ 700mg/d

Bile acids secretion ~ 500mg/d
Biliary cholesterol ~ 500mg/d
→ NET BALANCE if you don’t eat too much

33
Q

How is homeostasis of cholesterol maintained at the cellular level?

A
  1. LDL uptaken trough LDLr on cell surface

Cholesterol is used or not

  1. pre-HDL is effluxed through ABCA1
34
Q

Which 2 factors are responsible for regulation of HMG-CoA reductase?

A
  1. Energy state of the cell
    Low energy state (high [AMP]/[ATP]) activates AMPK → phosphorylates HMG-CoA reductase to inactivate it
    Back in high energy state → protein phosphatase will dephosphorylate it to reactivate it → promote synthesis of cholesterol
    (Because cholesterol synthesis takes up so much energy)
  2. Gene regulation (sensing [cholesterol])
35
Q

How does transcriptional control regulate cholesterol synthesis?

A

SREBP = Sterol-response element binding protein → TF for gene like HMG-CoA reductase and LDLreceptor
- Has a regulatory head bound to scap and bHLH head which can bind DNA

In high cholesterol state:
Cholesterol in ER membrane allows Insig to bind to Scap-SREBP

In low cholesterol state:
1. Scap is not reatined to the ER membrane → transports SREBP to the Golgi
2. Proteolytic processing of SREBP by S1P and S2P
3. bHLH head is cut (by S2P) → goes to the nucleus → activates transcription of target genes → promote cholesterol synthesis

→ Increase in HMG-CoA reductase levels
→ Increase in LDL-receptor levels (more LDL uptake)

36
Q

How can cholesterol synthesis be pharmacologically regulated?

A

HMG-CoA reductase inhibitors
Ex: Statins

37
Q

How do statins work?

A

Statins are a class of HMG-CoA reductase inhibitors (drugs that regulate cholesterol synthesis)

By inhibiting HMG-CoA reductase, cells are lower in cholesterol → they can uptake more cholesterol from LDL (increase LDL receptor transcription) → more clearance of LDL in the blood

38
Q

What is the main function of cholesteryl esters?
Which enzyme are involved in synthesis of cholesteryl esters?

A

Storage of cholesterol in lipid droplets

ACAT: Cholesterol → Cholesterol ester
- inside cells (lipid droplets, VLDL)
- ACAT = Acyl-CoA:Cholesterol Acyltransferase

LCAT: Cholesterol + PC (Lecithine) → Cholesterol ester + Lysolecithin
- in Plasma (HDL)
- Lecithine:Cholesterol Acyltransferase

39
Q

Which organs are lipid droplets found in?
What are the differences?

A

Adipocytes → store large amounts of TG in huge 1x lipid droples/cell

Liver → smaller lipid droplets, much more transient buffer reservoir of esterified FA and esterified cholesterol

40
Q

What are the different Sterol derivatives?

A
  • Cholesteryl Ester
  • Bile salts
  • Hormones
  • Vitamin D
41
Q

Where does synthesis of steroid hormones from cholesteol occur in the body?

A

In adrenal glands

*Cholesterol can’t be degraded, but we can modify it!
Other example is VitD important for bone development

42
Q

What organs does HDL deliver cholesterol to? For what usage?

A

Liver → bile acids
Adrenal glands → steroid hormones
Skin → Vitamin D

43
Q

What type of fuel storage is found in the brain and the heart?
What is their prefered fuel

A

NO fuel reserves in the brain and the heart → need constant supply
- Brain prefers Glucose
- Heart muscles prefer Fatty Acids

44
Q

After a meal, at rest, what is the orders of pathways activated in the muscles?

A
  1. Glycogen synthesis

VERY minor/not efficient:
2. FA synthesis
3. TG synthesis
4. Storage in very few lipid droplets

45
Q

After a meal, at rest, what is the orders of pathways activated in the liver?

A
  1. Glycogen synthesis
  2. FA sythesis
  3. TG synthesis
  4. Storage in lipid droplets + VLDL secretion
46
Q

After a meal, at rest, what is the orders of pathways activated in the brain and heart?

A

TCA cycle + OxPhos
- No fuel storage
- Always working

47
Q

After a meal, at rest, what is the orders of pathways activated in adipose tissue?

A
  1. FA synthesis
  2. TG synthesis
  3. Storage of lipid droplets
48
Q

What are the fuel reserves in each organ/tissue?

A

Muscles → Glycogen + Protein
Liver → Glycogen + Triacylglycerols
Adipose Tissue → Triacylglycerols
Brain → None
Heart → None

49
Q

What are the main energy pathways of the different organs/tissues?

A

Muscle → b-oxidation, glycolysis, proteolysis, CAC
Liver → Glycolysis, gluconeogenesis, b-oxidation, FA synthesis
Adipose tissue → b-oxidation, TG synthesis
Brain → Glycolysis, CAC
Heart → b-oxidation, CAC

50
Q

During exercise/stress, what is the orders of pathways activated in the muscles?

A
  1. Anaerobic glycolysis → Produces Lactate → sent to Liver
  2. TCA + OxPhos
  3. Glycogen breakdown (stimulated by adrenaline)
    *Glucose from liver is uptaken from circulation

FA are taken up from the blood:
4. Lipolysis of TG in lipid droplets
5. b-oxidation of FA → TCA + OxPhos

51
Q

During exercise/stress, what is the orders of pathways activated in the liver, in the brain, in the heart and in adipose tissue?

A

Liver:
1. Glycogen breakdown
2. Lipolysis of TG in lipid droplets
3. FA export to blood
*Liver is taken up from circulation and changed back to glucose

Heart:
1. TCA cycle + OxPhos

Heart:
1. TCA cycle + OxPhos

Adipose Tissue: (nothing glucose related)
1. Lipolysis of TG in lipid droplets
2. FA export to blood

52
Q

During starvation/prolonged exercise, what are the orders of pathways activated in the muscle, liver, in the brain, in the heart and in adipose tissue?
*For glucose only

A

*only change is the Liver starts making gluconeogenesis + ketogenesis
Muscle → nothing
Brain → unchanged TCA cycle + OxPhos
Heart → unchanged TCA cycle + OxPhos
Adipose Tissue → nothing (already breaking down)

Pancrease releases glucagon → Gluconeogenesis in the LIVER → Glucose → Heart + Brain (not muscles)

*Also Ketogenesis from FA

53
Q

What are all the effects of low blood glucose?

A
  1. Glucagon secretion from pancrease
  2. Increased cAMP
  3. Increased phosphoryation of key enzymes:
    - Phosphorylase b→a (increase Glycogen breakdown)
    - Glycogen synthase a→b (decrease glycogen synthesis)
    - PFK-2 → F2,6BPase (decrease glycolysis, increase gluconeogenesis)
    - PK → Phosphorylated PK (decrease glycolysis, increase gluconeogenesis)
54
Q

What is the effect of diabetes on metabolism (different tissues)

A

NO insulin release (or insulin hyporesponsiveness)
In muscle cells → less glucose uptake (no Glu4) → Proteolysis bc low glucose uptake
In adipose cells → less glucose uptake (no Glu4) → Lipolysis bc low glucose uptake
In Liver cells → Ketogenesis

*False impression of lower energy state:
- Ketogenesis
- More circulation of FA (more FA breakdown)

55
Q

Anterosclerosis.
Select all that are true.

A) In familial Tangier Disease, [HDL-cholesterol] is above normal value in the blood
B) Accumulation of oxLDL in the arterial walls contribute to the narrowing of arteries
C) Decreased HDL levels pre-dispose patients to cardivascular diseases
D) Transiant elevation of chylomicrons in blood is associated with increased risk of cardiovascular disease
E) In familial hypercholesterolemia, [LDL-cholesterol] is above normal values in the blood

A

B) Accumulation of oxLDL in the arterial walls contribute to the narrowing of arteries
C) Decreased HDL levels pre-dispose patients to cardivascular diseases
E) In familial hypercholesterolemia, [LDL-cholesterol] is above normal values in the blood

BIOC 311 (14 decks)

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