Integrated lipid metabolism - overview/review
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- Опубліковано 4 жов 2024
- Lipid metabolism page with videos, graphics, key points, related posts, & recommended reading: bit.ly/bblipid...
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
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 readily take up 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: ua-cam.com/video/j9jJuoIJLH0/v-deo.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 & ua-cam.com/play/PLUWsCDtjESrHXBgulruKEOrNXQ21_0gyc.html
more about all sorts of things: #365DaysOfScience All (with topics listed) 👉 bit.ly/2OllAB0 or search blog: thebumblingbiochemist.com