Blog update: Lipid metabolism page

Videos, graphics, key points, related posts, & recommended reading
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 (22C or longer) 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
* key site of regulation
* activated by citrate (feed-forward stimulation)
* inhibited by palmitoyl-COA (feedback inhibition)
* 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

[@thebumblingbiochemist]

Fatty acid catabolism
* Occurs in the mitochondria via β-oxidation
* key regulatory point is carnitine-acyl transferase 1 (CPT-1/CAT-1), which lets fatty acids into mitochondria for breakdown
* inhibited by malonyl-CoA, which prevents breakdown of fatty acids as you’re making them
* β-oxidation breaks down fatty acids 2C at a time. Each cycle cuts off an acetyl-CoA & produces 1 NADH & 1 FADH. These can be used to make ATP.
* You get 1 NADH & 1 FADH2 per 2C you break off (as acetyl-CoA) - can be used for oxphos to make ATP
* Odd-chain fatty acids are left with a 3C propionyl-CoA which gets converted to succinyl-CoA, which can be used in the TCA
* you can make glucose sustainably from odd-chain fatty acids (they’re glucogenic), but not even-chain ones (which are only ketogenic)
* see diagrams for details
* Before you can do β-oxidation, you have to invest some energy, and then you have to sneak them into the mitochondria
1. Activation: Fatty acyl-CoA synthetase/ligase (ACS) activates fatty acids for breakdown by attaching a CoA.
1. Because it goes from ATP to AMP (not ADP), this is equivalent to costing 2 ATP.
Carnitine shuttle:
2. The fatty acid, still in the cytoplasm, is then handed from CoA to carnitine by carnitine acyltransferase 1 (CAT-1/CPT-1)
3. The fatty acid (now attached to carnitine) is then transported into the mitochondrial matrix by carnitine-acylcarnitine translocase (which also brings a carnitine back to the cytoplasm)
4. The hand-off is reversed in the mitochondria by CAT-2
5. The fatty acyl-CoA can then be broken down by β-oxidation.
Ketone bodies
* When Co-A builds up, the last step reverses itself, followed by a couple other enzymatic steps, resulting in the formation of ketone bodies (acetoacetate, β-hydroxybutyrate, acetone) (see diagrams)
* This can happen in the case of diabetes, where there’s not enough oxaloacetate to keep the TCA running because glucose can’t get taken in & used efficiently
* This can happen in the case of ethanol intoxication because NADH builds up from ethanol oxidation and inhibits the TCA
* Ketone bodies, as carboxylic acids, can acidify the bloodstream - ketoacidosis
* Ketone bodies aren’t all bad though - since they’re soluble, they can provide energy to tissues like the brain (which can’t make use of fatty acids for energy thanks to the blood brain barrier and stuff)
For more about lipid digestion & mobilization: Jakubowski & Flatt, 17.1: Digestion, Mobilization, and Transport of Fats bio.libretexts.org/Bookshelves/Biochemistry/Fundamentals_of_Biochemistry_(Jakubowski_and_Flatt)/02%3A_Unit_II-_Bioenergetics_and_Metabolism/17%3A_Fatty_Acid_Catabolism/17.01%3A_Digestion_Mobilization_and_Transport_of_Fats
More about lipid anabolism: ruclips.net/video/j9jJuoIJLH0/видео.html
Recommended reading: Chandel N. S. (2021). Lipid Metabolism. Cold Spring Harbor perspectives in biology, 13(9), a040576. doi.org/10.1101/cshperspect.a040576  
more on all sorts of metabolic stuff: bit.ly/bbmetabolism & ruclips.net/p/PLUWsCDtjESrHXBgulruKEOrNXQ21_0gyc
     
more about all sorts of things: #365DaysOfScience All (with topics listed) 👉 bit.ly/2OllAB0 or search blog: thebumblingbiochemist.com

[@kevinender5409]

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[@thebumblingbiochemist]

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