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Transcript
Lipid metabolism
-Lipid diversity
- Cholesterol metabolism
Diversity of lipids
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Fatty acids
Eicosanoids
Glycerolipids
Shingolipids
Steroids
Fatty acids
Eicosanoids are divided into three
groups
Two groups of glycerolipids
acylglycerols
(mono-, di-, tri-)
glycerophospholipids
Sphingolipids are derivatives of
sphingosine
Steroids
MEMBRANE STRUCTURE
Polar lipids form micelles in water
Cell membranes consists of
glycerophospholipids, sphingolipids and
cholesterol
Cholesterol metabolism
Origin of the carbon atoms of
cholesterol
Synthesis regulation
LIPOPROTEINS: TRANSPORT OF
LIPIDS
Lipoprotein
ATHEROSCLEROSIS
Signs
Signs
Foam cell formation – role for oxLDLs
Atherosclerotic plaque formation
HYPERLIPIDEMIAS
Fredrickson classification of
hyperlipidemias
Relative prevalence of familial forms of
hyperlipoproteinemia
Defects in hyperlipidemias
FAMILIAL HYPERCHOLESTEROLEMIA
Familial hypercholesterolemia
Defect:
Mutation in LDL receptor gene
Cholesterol uptake by
receptor-mediated
endocytosis
LDL receptor
structure
Exon-intron structure of the LDL
receptor gene: mutations in FH
Mutations can affect:
- Binding of the receptor to LDL
- LDL receptor localization on plasma
membrane (transport from cytoplasm to the
membrane)
- LDL receptor internalization
Cholesterol uptake damage leads to lack of
cholesterol synthesis DOWNREGULATION
Regulation of cholesterol synthesis
• Transcriptional regulation (HMG-CoAreductase)
• Proteolytic degradation
• Hormonal control
Cholesterol synthesis: transcriptional
regulation
- SREBP – sterol sensor
- Decrease of sterol concentration leads to SREBP cleavage
- Cleaved fragment activates transcription
Cholesterol synthesis: proteolytic
degradation of HMG-CoA-reductase
Cholesterol synthesis: hormonal control
SECONDARY HYPERLIPIDEMIA
Secondary hyperlipidemia
TREATMENT
Treatment
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•
•
•
Diet
Physical activity
Weight loss
Drugs:
• Statins
• Fibric acid derivatives
• Bile acid sequestrants/cholesterol
absorption inhibitors
• Nicotinic acid derivatives
STATINS: HMG-COA-REDUCTASE
INHIBITION
Statins: HMG-CoA-reductase inhibition
Atorvastatin: powerful synthetic statin
Effect
• Reduce LDL cholesterol
Marketed statins
FIBRATES: PPAR ACTIVATORS
Fibrates: fibric acid derivatives
gemfibrozil
bezafibrate
fenofibrate
Fenofibric acid
Effect
• Increase HDL cholesterol
• Reduce LDL cholesterol
Marketed fibrates
Mechanism of action: PPAR activation
PPARS are nuclear receptors, which activation leads to the
activation of lipid utilisation
BILE ACID SEQUESTRANTS /
CHOLESTEROL ABSORPTION
INHIBITORS
Entherohepatic circulation
Marketed drugs
Effect
• Reduce LDL cholesterol
NICOTINIC ACID DERIVATIVES
Nicotinic acid derivatives
Effect
• Reduce fatty acid mobilization from adipose
tissue → decrease of TG synthesis → decrease
of VLDL and LDL
• Reduce LDL cholesterol
EXOTIC SOLUTIONS
Gene therapy