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4 > Lipid metabolism, dyslipidemia and management > Flashcards

Lipid metabolism, dyslipidemia and management Flashcards

1
Q

Lipid utilization pathway

A

1) Hormone-sensitive lipase (cytosolic enzyme) hydrolyzes ester linkages in TAGs in adipocytes
2) reaction products released into bloodstream
- FFAs complexed to serum albumin/oxidized/stored in muscle or liver
- FAs must be odd-numbered to supply carbons for gluco synthesis
3) Primarily metabolized via beta-oxydation in mitochondria in skeletal muscle, myocardium, liver

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2
Q

Lipolysis pathway

A

1) passively absorbed, esterified to CoA and bound to FA binding proteins
2) transported as acyl-COA through OMM
3) coupled to carinitine and transported through IMM
4) converted back to fatty acyl-CoA in the matrix
5) oxidation - 2 carbons at a time

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3
Q

Familial hypercholesterolemia

A

LDL receptor mutation
autosomal dominant
elevated total and LDL cholesterol
Clinical symptoms: xanthomas, corneal arcus
can get premature CAD
High frequency in French Canadians and South Africans of Dutch/French descent

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4
Q

Familial defective ApoB

A

Less severe hyperlipidemia compared to LDL receptor defect
Most common mutation: Arg3500 –> Gln
same tx approach as familial hypercholesterolemia

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5
Q

Proprotein convertase subtilisin/Kexin 9

A

Autosomal dominant hypercholesterolemia
Missense mutation in PCSK9
GOF: degradation of LDL receptors
LOF: decrease in LDL concentration, resulting in a cardio-protective effect

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6
Q

Familial combined hyperlipidemia (FCHL)

A 
Most common
Dominant 
Common cause of premature CAD
increase in plasma cholesterol +/0 TGs
Gene unknown, but one possibility:
- mnutation in gene for USF-1 (TF); known to regulate many genes in lipid metabolism
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7
Q

Familial chylomicronemia

A

autosomal recessive
Decrease/absent LPL activity due to 3 possible mutations:
- LPL gene mutation (most common)
- Apo-CII mutation (cofactor for LPL)
- GP1-HBP1 mutation (anchor protein, brings LPL and chylomicron close together)
Fasting chylomicrons observed (abnormal), severe elevation in plasma triglycerides
Recurrent episodes of pancreatitis
Hepatosplenomegaly, eruptive xanthomas, lipemia retinalis

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8
Q

Tangier disease

A

mutation in ABCA1 - ApoA1 cannot remove cholesterl from peripheral tissue cells
Autosomal recessive, very rare
Enlarged yellow-orange tonsils
Virtual absence of HDL, decrease in LDL, moderate increase in TGs
Hepatosplenomegaly + peripheral neuropathy
Tangier fibroblasts are defective in removing cellular cholesterol and phospholipids
Other tissues affected - pathology of the nervous system and corneal opacities

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9
Q

Familial LCAT deficiency

A

autosomal recessive
Severe HDL deficiency - LCAT required to get cholesterol esters onto naive HDL
Clinical features: corneal opacities, hemolytic anemia, renal failure
High plasma concentrations of phospholipids and unesterified cholesterol

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10
Q

Familial CETP deficiency

A

Autosomal co-dominant, due to mutations in both alleles of CETP (cholesteryl transfer protein)
Markedly elevated levels of HDL-C and Apo-A1
Delayed catabolism of HDL
No evidence of protectiona gainst atherosclerosis; even a risk of premature atherosclerosis

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11
Q

ApolipoproteinE gene polymorphism

A

3 common isoforms of ApoE: E4, E3, E2
E3 most common
E4 - higher cholesterol vs E3
E2 - lower cholesterol level vs E3
- E2 reduced affinity for cell surface receptors, leading to accumulation of yhlomicron remnants and reduced LDL formation
- E2 homozygotes can develop type III disease (dysbetalipoproteinemia)

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12
Q

Dysbetalipoproteinemia (Type III disease)

A

increased chylomicron remannts
increased VLDL and VLDL remnants (IDL)
increased levels of cholesterl and triglycerides, palmar xanthomas, tubero-erruptive xanthomas
premature CAD

Not seen in all E2 homozygotes

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13
Q

Diseases that result in increased synthesis of lipoproteins

A 
Familial combined hyperlipidemia
Endogenous hyperlipidemia (increased consumption)
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14
Q

Diseases that result in decreased catabolism of lipoproteins

A

Familial hypercholesterolemia
Familial defective ApoB
Familial chylomicronemia
Tangier disease

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15
Q

Tests for dyslipidemia and CAD

A

all use specific enzyme reactions and spectrophotometry

EXCEPT cholesterol

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16
Q

LDL formula

A

LDL = total cholesterol - (HDL + TGs/2.2)

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17
Q

Familial combined hyperlipidemia tx

A

1) statin +/- salmon oil +/- niacin

2) fibrate (If statin not tolerated)

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18
Q

Heterozygous familial hypercholesterolemia tx

A

statin +/- niacin or ezetrol

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19
Q

Dysbetalipoproteinemia (Type III disease)

A

1) fibrates

2) statins

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20
Q

Familial chylomicronemia / familial hypertriglyceridemia tx

A

LOW FAT DIET

fibrates, salmon oil

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21
Q

Metabolic syndrome & diabetes tx

A

1) high potency statin (e.g. rosuvastatin)
2) fibrates
salmon oil
use niacin as an adjunct for people with low LDL

22
Q

LDL targets

A 
High risk (20%) - treatment required - LDL < 2, or apoB < 0.8
Moderate (10-19%) - treat if LDL > 3.5 or TC/HDL > 5 or CRP > 2, target same as above

Low ( 5 - target >= 50% decrease in LDL

23
Q

Statin MOA

A

HMG-CoA reductase inhibitor
mediates the RDS in the biosynthesis of cholesterol
Increase in the number of LDL receptors as a result of reduced biosynthesis
Increases catabolic rate of LDL and liver’s extraction of LDL precursors
–> reduce plasma pool of LDL
can also increase HDL marginally
reduce TAGs by 10-15%

24
Q

statin PK

A

Metabolized by CYP

25
Q

Statin indications

A

first line in hyperlipidemia

26
Q

Statin SEs

A

Generally well tolerated
Myalgia with associated weakness (unknown cause)
Myositis (rare), rhabdomyolysis (rare), hepatotoxicity (very rare)

27
Q

Statin interactions

A

can be used with other agents (sequestrants, inhibitors of cholesterol absorption)
should be used with caution with fibrates and niacin

28
Q

Fibrate prototypes

A

CLofibrate
Gemfibrozil
Fenofibrate

29
Q

Fibrate MOA

A

activate TFs called peroxisome proliferator-activated receptors (PPARs)
nuclear hormone receptors that respond to lipid-based ligands, including hormones, vitamins, and fatty acids
Increase lipolysis by: activating LPL and decrease production of apoCIII (inhibits LPL
Reduce LDL via reduced production of VLDL particles in liver, and increased catabolism of VLDL via LPL
Increased HDL via activation of PPAR(alpha) –> increased synthesis of A1, A2 and HDL-C

30
Q

Fibrate drug interactions

A

Use with caution with statins –> both can cause muscle breakdown/pain

Warfarin: decrease warfarin doses, monitor INR
Cyclosporin: increased risk of precipitation or exacerbating renal failure

31
Q

Fibrate indications

A

Not used as monotherapy except for with severe hypertriglyceridemia
Elevated LDL or triglycerides
reduced HDL
metabolic syndrome, DM
dysbetalipoproteinemia, familial hypertriglyceridemia, familial hyperchylomicronemia
2nd line choice for familial combined dyslipidemia

32
Q

Fibrate CIs

A 
previous sensitvity
severe renal impairment
chronic liver disease
pre-existing cholelithiasis
lactation
33
Q

Fibrate cautions

A

pregnancy

renal impairment

34
Q

Fibrate SEs

A

similar to statins (myopathy)
exacerbation of gout
exacerbation of renal failures

35
Q

Niacin PKs

A

Niacin binds to a GPCR in adipocytes and inhibits lipolysis in adipose tissue
- reduces supply of FAs
- VLDL reduced because the liver uses FFAs to produce TAGs
- reduced LDL and high HDL
Can also increase HDL-C
- since less VLDL produced, less CETP can act to transfer cholesterol esters to VLDL, and HDL-C increases
- also decreases apo B and LDL-C

36
Q

Niacin indications

A

adjunctive use in combination with statins in
HFH
Familial combined dyslipidemia
People with low HDL-C

37
Q

Niacin CIs

A

hepatic disease
active peptic ulcer disease
arterial bleeding

38
Q

Niacin cautions

A

administion + statins can increase risk of hepatotoxicity and myopathy
avoid in patients with unstable angina or acute coronary syndrome

39
Q

Niacin dosing

A

500-3000 mg/day, divided into 3 doses
desirable to use the highest possible tolerated dose up to 3000 mg
Niaspan: extended release preparation (once/day dosing) works well

40
Q

Niacin SEs

A

flushing: can be lessened with administration of aspirin 30 mins before niacin
Skin - flushing, pruritis, acanthosis nigricans
GI - nausea, ab pain, elevations in AST/ALT
metabolic - decreased insulin sensitvivity, hyperuricemia/gout
CNS - headache
can worsen glycemic control for diabetics
can worsen or precipitate gout

41
Q

Ezetimibe MOA

A

acts on NPC1L1 cholesteorl transporter at apical brush border
- blocks uptake of dietary and secreted cholesterl from bile
- does not block absorption of any other dietary fat or lipid soluble vitamins
Decreases TC and LDL-C and TAG

42
Q

Ezetimibe indications

A

used in adjunct to statin therapy

especially useful in treating people with rare lipid disorders who have not responded to other medications

43
Q

HFH - defective LDL metabolism pathophysiology

A

Mutation in the gene for the LDL receptor (Apo B/E receptor)

1) decrease in LDL receptor function
2) decrease in lysosomal degradation of LDL in the liver
3) decrease in the free cholesterol in the liver
4) increase in cholesterol synthesis, decrease in cholesterol ester synthesis

Reduced clearance due to low # of receptors –> increased LDL
Same receptor also clears IDL –> increased IDL (precursor for LDL) –> increased LDL

Increased LDL –> increased acetylated/oxidized LDL –> increased uptake by scavenger receptor of macrophages, incl those in vascular walls –> xanthomas + premature atherosclerosis

44
Q

HFH presentation according to genotype

A

Dominant pattern of expression
Heterozygotes (1/500) –> 2-3x increase in plasma cholesterol –> tedinous xanthomas + premature atherosclerosis
Homozygotes –> 5-6x increase in plasma cholesterol –> skin xanthomas and coronary, cerebral and peripheral vascular atherosclerosis at an early age in addition to above –> MI before age 20

45
Q

Intracellular cholesterol in the liver - role in regulation

A

Inhibits HMG CoA reductase
Activates acyl-coenzyme A: cholesterol acyltransferase (ACAT), favouring esterification and storage of excess cholesterl
Suppresses synthesis of LDL receptors, protecting the cells from excessive accumulation of cholesterol

46
Q

Class I FHF

A

complete failure of synthesis (uncommon)

47
Q

Class II FHF

A

receptor proteins accumulate in ER because it can’t be transported to the Golgi (common)

48
Q

Class III FHF

A

receptors reach teh surface, but fail to bind LDL properly

49
Q

Class IV FHF

A

bind LDL normally, but fail to localize in coated pits –> LDL not internalized

50
Q

Class V FHF

A

LDL binds and is internalized, but acid-dependent dissociation of the receptor and bound LDL fails to occur –> receptors are degraded and fail to be recycled to surface (–> reduced LDL receptor number)

51
Q

Scavenger uptake of LDL

A

Macrophages in the wall of blood vessels contain scavenger receptors that specifically take up LDL that has been damaged by partial oxidation / glycation (diabetes)

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