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Atherosclerosis & lipoprotein metabolism (Drugs (Lipid lowering drugs,…
Atherosclerosis & lipoprotein metabolism
Atherogenesis
Impaired autoregulation to blood pressure changes
Damage to epithelium
Adhesion molecues
Monocyte/macrophage recruitment
LDL-transport into vessel wall
Macrophage release ROS:
hydrogen peroxide
superoxide + NO --> peroxynitrate
oxidation of lipids
-oxLDL
oxLDL macrophage uptake
via scavenger receptors
foam cell
lipid ingestion -> cytokine release
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Lipoprotein transport
Lipoproteins
Chylomicrons
Exogenous
Ileum uptake
ApoB-48
Tissue
Reverse cholesterol transport
HDL
CETP
Adipose
LPA
Cell uptake
fatty acid
glycerol
Chylomicron remnants
Liver
Endogenous
Liver
ApoB-100
VLDL
Tissue
LPA
Cell uptake
fatty acid
glycerol
LDL
CETP
Dyslipidemia
Primary
6 phenotypes
Type IIa
FH
lack of LDL receptors
Homozygote
8 mmol/l
Heterozygote
12-15 mmol/l
Secondary
diseases:
diabetes mellitus
hypothyroidism
chronic kidney failure
liver disease
Drugs
Angiotensin-converting enzyme inhibitors
NO production
improve endothelial function
CETP inhibitor
anacetrapib
Merck abandoded in late trial due to safety concerns
Increase HDL
moderate alcohol consumption
Regular exercise
ApoA-1 Milano recombinant
people from Milano with low HDL but almost no cardivascular disease
abandoned in trial
ACAT inhibitors
acetyl cholesterol acyltransferase
Lipid lowering drugs
HMG-CoA reductase inhibitors
Atorvastin
simvastatin
CYP450
prodrug
short acting
Hepatic LDL receptor upregulation
Cholesterol absorption inhibitors
Ezetimibe
NPC1L1 transport inhibitor
Fish oil derivatives
fibrates
nicotinic acid & derivatives
Orphan receptor
poorly understood
lower LDL + triglycerides
Antisense oligonucleotide
mipomersen
ApoB100 mRNA
Liver accumulation
hepatotoxicity
Homozygous FH
MTP inhibitor
lomitapide