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Lipid metabolism -Lipid diversity - Cholesterol metabolism Diversity of lipids • • • • • 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 • • • • 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
