Integrated lipid metabolism – overview/review
Lipid metabolism page with videos, graphics, key points, related posts, & recommended reading: https://bit.ly/bblipidmetabolism Longer video: • Integrated lipid metabolism – overview/review Key points about lipid metabolism: All tissues need fatty acids for various purposes: use as fuel, incorporation into membranes, production of steroids, etc. But “only” liver cells (hepatocytes) & fat cells (adipocytes) can make them The liver & adipocytes make fatty acids, store them (as triacylglycerides (TAGs)), & ship them out to other tissues in need. These fatty acids have to be “mobilized” from triacylglycerides (TAG) stores, as described below Fatty acids are made from acetyl-CoA (2 carbon (2C)) and broken down to acetyl-CoA (and one propionyl-CoA (3C) per odd-chain fatty acid) Fatty acid synthesis occurs (mostly*) in the cytoplasm of liver & fat cells and is a key user of NADPH (which can be made through the pentose phosphate pathway (PPP) *some in mitochondria Because acetyl-CoA can’t get through the mitochondrial membranes, citrate, not acetyl-CoA, is removed from the mitochondria to make fats - it is subsequently broken down back to acetyl-CoA by ATP-citrate lyase Fatty acid breakdown occurs in most tissues & takes place (mostly*) in the mitochondria in a process called β-oxidation *very long ones (over 20C) are initially via a hydrogen-peroxide mediated process in peroxisomes Synthesis & breakdown are reciprocally regulated Key regulatory points are: Synthesis: acetyl-CoA carboxylase (ACC), which activates acetyl-CoA for incorporation Breakdown: carnitine-acyltransferase 1 (CAT-1/CPT-1), which allows fatty acids into the mitochondria for breakdown Fat mobilization Cells take up fatty acids, not TAGs, for use as fuel, so fatty acids need to be cleaved off of the glycerol backbone (by lipases) for uptake & subsequent use Fatty acids are delivered from liver cells to tissues packaged as TAGs, bundled up with phospholipids, cholesterol, & other hydrophobic stuff in the interior of lipid-coated “bubbles” called lipoproteins The fatty acids are freed from TAGs for uptake by other tissues through the action of lipoprotein lipase on the surface of blood vessels Fatty acids from adipocytes are delivered as fatty acids, not in lipoproteins Since fatty acids are hydrophobic, these travel through the bloodstream by piggybacking on proteins like serum albumin that have hydrophobic binding patches Hormone-sensitive lipase, activated by adrenaline & glucagon (hormone signaling low blood sugar), breaks fatty acids off of TAGs inside of fat & liver cells (as opposed to lipoprotein lipase, which acts extracellularly to get fatty acids into cells) This helps “mobilize” fuel stores for breakdown for energy inside the cell or shipping out to other cells Fatty acid synthesis Fatty acid synthesis occurs (mostly*) in the cytoplasm of liver & fat cells and is a key user of NADPH (which can be made through the pentose phosphate pathway (PPP) *some in mitochondria Because acetyl-CoA can’t get through the mitochondrial membranes, citrate, not acetyl-CoA, is removed from the mitochondria to make fats - it is subsequently broken down back to acetyl-CoA by ATP-citrate lyase Fatty acids are built by a multifunctional protein called fatty acid synthase (FAS), 2C at a time, from 3C intermediates (malonyl-CoA) See diagram for details Malonyl-CoA is made by carboxylation (from bicarb) of acetyl-CoA by acetyl-CoA carboxylase (ACC) this step activates acetyl-CoA by making a β-keto acid (energetically-favorable to subsequently decarboxylate once linked on to the chain) the carbon that is added from CO2 is subsequently lost and not incorporated into the fatty acid key site of regulation activated by citrate (feed-forward stimulation) & insulin (via activation of a phosphatase) inhibited by palmitoyl-CoA (feedback inhibition) & phosphorylation via PKA (stimulated by glucagon & epinephrine) or AMPK (stimulated by high AMP levels) malonyl-CoA itself (a signal of lipid synthesis) is an inhibitor of CAT-1/CPT-1, the transporter that lets fatty acids into mitochondria for breakdown It costs 1 ATP & 2 NADPH per 2C added The “default” fatty acid is a 16C saturated fatty acid, palmitate, which gets cleaved off of FAS by the thioesterase subunit of FAS Longer fatty acids & unsaturated fatty acids can be made via elongation & desaturation in the ER Finished in comments
