3. Lipids

Lipid Storage and Lipolysis

The activation sequence section is a bit complicated, at least I thought so…

A lipid droplet has a phospholipid monolayer (hydrophobic interior) with a surface layer made of a protein called perilipin. The TAGs are stored inside. This design insulates the hydrophobic fatty acids from the hydrophilic environment of the cytoplasm.

How are TAGs released and mobilized?

The covalent bonds between the glycerol and the fatty acids need to be broken. This happens through lipolysis, which is a three-step process.

  1. First, the triacylglycerol is broken into diacylglycerol and a fatty acid. This is catalyzed by an enzyme adipose triglyceride lipase (ATGL).
  2. Second, the diacylglycerol is broken into a monocylglycerol and a fatty acid. This is catalyzed by an enzyme hormone sensitive lipase (HSL).
  3. Third, the  monocylglycerol is broken into one molecule of fatty acid and one molecule of glycerol. This is catalyzed by an enzyme monoacylglycerol lipase (MGL).

Activating these enzymes

from harvardX MCB63X lecture slide, copyright harvardX and edX.org

Initially these three enzymes are inactive and separated from their substrate, the lipid droplet surface. ATGL activation requires a protein called ABHD5. ABHD5 (while inactive) lingers at the surface of the lipid droplet bound to the perilipin. Similarly, the inactive HSL floats around the cytoplasm bound to a protein called FABP4.

Once these energy stores are needed (e.g., the body engages in an intense physical activity), hormones from the catecholamine family (adrenaline and noradrenaline) are released into the bloodstream. These activate the adipocytes and start the process of release.

from harvardX MCB63X lecture slide, copyright harvardX and edX.org

On the surface of the adipocyte, a membrane protein called a beta-adrenergic receptor binds to both the catecholamine on its exterior (extracellular domain) and to a trimeric G protein on its interior (intracellular domain).

The binding of catecholamine to this receptor causes a change in the conformation of the beta-adrenergic, which results in the activation of the trimeric G protein. This protein then activates another membrane protein called adenylylcyclase.

Once activated, adenylylcyclase catalyzes the conversion of ATP into cyclic AMP or cAMP. The increase in concentration of cAMP catalyzes another protein called protein kinase A (PKA). As a kinase, it phosphorylates a number of other proteins including perilipin and HSL.

from harvardX MCB63X lecture slide, copyright harvardX and edX.org

Phosphorylated perilipin triggers the releases the ABHD5, thus activating it to recruit ATGL (step 1) at the surface of the lipid droplet. It also “remodels” it itself to make it more inviting to the other enzymes.

Phosphorylated HSL (step 2) becomes recruited while still bound to FABP4 to the lipid droplet surface

With these two enzymes active, both diacylglycerol and monocylglycerol will be produced allowing MGL to be put to use for step 3: breaking apart the glycerol and fatty acid.

The fate of the released fatty acid and glycerol

The hydrophobic fatty acids will be escorted through the cytoplasm by FABP4, which acts as a chaperon. From there, it’ll be exported into the bloodstream and carried by serum albumin to the organs that need energy, e.g., muscle. 

The hydrophilic glycerol can navigate through the cytoplasm unescorted. It then diffuses through the membrane via a channel protein called aquaporin. Once in the bloodstream, it travels to the liver.

Escape route of fatty acid

from harvardX MCB63X lecture slide, copyright harvardX and edX.org

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