--- module: 089-02 language: en chapter: 89 title: "Lipid Metabolism, Membranes, Lipoproteins, and Ketone Biology" module_title: "Fatty-acid synthesis, membrane lipids, lipoproteins, cholesterol, and lipid signalling" source_sha256: 3ff6215e87e81029e9b202bcf0b82878fa98fd026115cb5f240478cc5b6c7c72 --- # Lipid synthesis, lipoproteins, and signalling ## Purpose and risks of lipid synthesis ### Excess carbon and reducing power stored ### Hydrophobic surfaces kept from water ### Dysregulation: steatosis, atherosclerosis, toxicity ## Fatty-acid synthesis ### Cytosol of liver and adipose ### Acetyl-CoA exported as citrate #### ATP-citrate lyase cleaves in cytosol #### Malic enzyme supplies NADPH ### Acetyl-CoA carboxylase: committed step #### Citrate activates, acyl-CoA inhibits #### Insulin activates, AMP kinase inhibits #### Malonyl-CoA also blocks mitochondrial entry ### Fatty-acid synthase on acyl-carrier protein #### Condense, reduce, dehydrate, reduce #### Palmitate, then elongation and desaturation ## Essential fatty acids and glycerolipids ### Linoleic and alpha-linolenic are essential #### Limited conversion to omega-6 and omega-3 #### Omega-3 label does not mean equal effect ### Glycerol-3-phosphate backbone #### Adipose relies on glucose-derived route ### Phosphatidic acid branch point ## Membrane lipids ### Phospholipids remodelled by deacylation ### Cardiolipin supports respiratory complexes #### Defects: cardiomyopathy, myopathy, neutropenia ### Sphingolipids built on ceramide #### Sphingomyelin, glycosphingolipids, gangliosides #### Missing hydrolases cause storage disorders ### Composition sets fluidity and permeability #### Cholesterol buffers fluidity ### Leaflet asymmetry actively maintained #### External phosphatidylserine marks apoptosis ## Lipid signalling ### Phospholipase C splits phosphoinositide bisphosphate #### Diacylglycerol and inositol trisphosphate #### Protein kinase C and calcium release ### Phospholipase A2 releases arachidonic acid ### Phosphoinositide 3-kinase recruits Akt ### Eicosanoids from arachidonic acid #### Cyclooxygenases: prostaglandins, thromboxanes #### Lipoxygenases: leukotrienes, lipoxins #### NSAIDs, glucocorticoids, leukotriene modifiers ## Cholesterol synthesis and fate ### HMG-CoA reductase makes mevalonate #### Isoprenes, squalene, lanosterol #### Isoprenoids prenylate signalling proteins ### SREBP responds to low sterol #### Moves to Golgi for activating cleavage ### Statins raise LDL receptors ### Ring cannot be degraded #### Excreted as biliary cholesterol and bile acids ## Lipoprotein particles ### Phospholipid surface around hydrophobic core ### Chylomicrons, VLDL, LDL, HDL roles ### Apolipoprotein B counts atherogenic particles #### One B-48 or B-100 per particle ### C-II activates lipoprotein lipase ### E supports remnant uptake ### VLDL becomes IDL then LDL #### Receptor defects raise LDL markedly ### HDL accepts cellular cholesterol #### Lecithin-cholesterol acyltransferase #### Raising HDL cholesterol not reliably beneficial ## Dyslipidaemia and atherosclerosis ### Lipase or C-II deficiency: chylomicronaemia #### Pancreatitis risk ### Secondary factors modify triglycerides ### Atherosclerosis starts with apoB retention #### Foam cells, plaque, cap disruption ### LDL cholesterol versus apoB discordance ### Lipoprotein(a) largely inherited #### Atherosclerotic and calcific-valve risk ## Lipotoxicity and steatosis ### Lipid droplets buffer toxic lipids #### Overflow: diacylglycerols, ceramides ### Steatosis: uptake and synthesis exceed disposal #### Choline deficiency impairs export ### Risk depends on lipid, particle, tissue, time