Lipid metabolism, dyslipidemia and management

Question 1

Lipid utilization pathway

Answer 1

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

Question 2

Lipolysis pathway

Answer 2

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

Question 3

Familial hypercholesterolemia

Answer 3

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

Question 4

Familial defective ApoB

Answer 4

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

Question 5

Proprotein convertase subtilisin/Kexin 9

Answer 5

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

Question 6

Familial combined hyperlipidemia (FCHL)

Answer 6

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

Question 7

Familial chylomicronemia

Answer 7

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

Question 8

Tangier disease

Answer 8

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

Question 9

Familial LCAT deficiency

Answer 9

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

Question 10

Familial CETP deficiency

Answer 10

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

Question 11

ApolipoproteinE gene polymorphism

Answer 11

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)

Question 12

Dysbetalipoproteinemia (Type III disease)

Answer 12

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

Question 13

Diseases that result in increased synthesis of lipoproteins

Answer 13

Familial combined hyperlipidemia
Endogenous hyperlipidemia (increased consumption)

Question 14

Diseases that result in decreased catabolism of lipoproteins

Answer 14

Familial hypercholesterolemia
Familial defective ApoB
Familial chylomicronemia
Tangier disease

Question 15

Tests for dyslipidemia and CAD

Answer 15

all use specific enzyme reactions and spectrophotometry

EXCEPT cholesterol

Question 16

LDL formula

Answer 16

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

Question 17

Familial combined hyperlipidemia tx

Answer 17

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

2) fibrate (If statin not tolerated)

Question 18

Heterozygous familial hypercholesterolemia tx

Answer 18

statin +/- niacin or ezetrol

Question 19

Dysbetalipoproteinemia (Type III disease)

Answer 19

1) fibrates

2) statins

Question 20

Familial chylomicronemia / familial hypertriglyceridemia tx

Answer 20

LOW FAT DIET

fibrates, salmon oil

Question 21

Metabolic syndrome & diabetes tx

Answer 21

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

Question 22

LDL targets

Answer 22

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

Question 23

Statin MOA

Answer 23

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%

Question 24

statin PK

Answer 24

Metabolized by CYP

Question 25

Statin indications

Answer 25

first line in hyperlipidemia

Question 26

Statin SEs

Answer 26

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

Question 27

Statin interactions

Answer 27

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

Question 28

Fibrate prototypes

Answer 28

CLofibrate Gemfibrozil Fenofibrate

Question 29

Fibrate MOA

Answer 29

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

Question 30

Fibrate drug interactions

Answer 30

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

Question 31

Fibrate indications

Answer 31

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

Question 32

Fibrate CIs

Answer 32

``` previous sensitvity severe renal impairment chronic liver disease pre-existing cholelithiasis lactation ```

Question 33

Fibrate cautions

Answer 33

pregnancy | renal impairment

Question 34

Fibrate SEs

Answer 34

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

Question 35

Niacin PKs

Answer 35

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

Question 36

Niacin indications

Answer 36

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

Question 37

Niacin CIs

Answer 37

hepatic disease active peptic ulcer disease arterial bleeding

Question 38

Niacin cautions

Answer 38

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

Question 39

Niacin dosing

Answer 39

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

Question 40

Niacin SEs

Answer 40

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

Question 41

Ezetimibe MOA

Answer 41

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

Question 42

Ezetimibe indications

Answer 42

used in adjunct to statin therapy | especially useful in treating people with rare lipid disorders who have not responded to other medications

Question 43

HFH - defective LDL metabolism pathophysiology

Answer 43

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

Question 44

HFH presentation according to genotype

Answer 44

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

Question 45

Intracellular cholesterol in the liver - role in regulation

Answer 45

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

Question 46

Class I FHF

Answer 46

complete failure of synthesis (uncommon)

Question 47

Class II FHF

Answer 47

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

Question 48

Class III FHF

Answer 48

receptors reach teh surface, but fail to bind LDL properly

Question 49

Class IV FHF

Answer 49

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

Question 50

Class V FHF

Answer 50

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)

Question 51

Scavenger uptake of LDL

Answer 51

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