Lipase activator
CGI-58
Also searched as CGI-58.
You want it free, not merely present. It is described as an essential co-activator: while it is bound to the coat protein it cannot interact with the lipase at all, so the amount you have is irrelevant if none of it is released. That is the whole point of the phosphorylation step. And it can be captured a second way — long-chain fatty acyl-CoAs, made from the very fat you just released, bind it and prevent it reaching the lipase. The product of the reaction disables the reaction.
In depth
The activator the rate-limiting lipase cannot work without — and which the droplet coat holds captive until told to let go.
What drives it
Fat droplet coating reduces it.
The hostage-taking, stated plainly. 'The ATGL-activating function of CGI58 is repressed by its binding to PLIN1, a lipid droplet scaffold, under basal conditions' (doi 10.3389/fphys.2022.826314). And from the mechanism paper: 'When CGI-58 is sequestered on the perilipin scaffold, it cannot interact with OR activate ATGL' (PMC4274058). ⇒ how much activator you have is irrelevant if none of it is released. doi 10.3389/fphys.2022.826314 · PMC4274058
Lipolysis signal increases it.
'Upon activation by PKA-mediated phosphorylation of PLIN1 and CGI58, CGI58 is released from PLIN1 and LDs' (doi 10.3389/fphys.2022.826314). Note the detail: the kinase phosphorylates both partners, not only the coat. doi 10.3389/fphys.2022.826314
Activated fatty acids reduces it.
The product disables the reaction. 'lc-CoA acts as an endogenous allosteric regulator of lipid droplet-associated protein ABHD5/CGI58, an essential co-activator of PNPLA2/ATGL... Upon binding to CGI58, LC-CoA rapidly modulates the interaction of CGI58 with perilipin proteins, thereby preventing its binding to ATGL and the activation of ATGL'. doi 10.3389/fphys.2022.826314
Liver fat gene reduces it.
The decoy. 'adiponutrin (also named as pnpla3), which is a close paralog of ATGL, has been demonstrated to compete with ATGL for binding to CGI58 and, in turn, effectively sequestering CGI58 from activating ATGL, thereby decreasing lipolysis' (doi 10.3389/fphys.2022.826314). The clinical edge: 'Genetic variations in the human PNPLA3 gene (the rs738409 I148M allele) have been strongly associated with fatty liver disease... PNPLA3-I148M suppresses the interaction of CGI58 with ATGL even more effectively.'. doi 10.3389/fphys.2022.826314
What it drives
It increases Fat-releasing enzyme (ATGL).
The middle of the mechanism. 'CGI58/ABHD5 is a lipid droplet-associated ATGL activator... Upon activation by PKA-mediated phosphorylation of PLIN1 and CGI58, CGI58 is released from PLIN1 and LDs, which then recruits ATGL to LDs and increases its catalytic activity. Therefore, lipolysis involves interactions between ATGL, CGI58, and PLINs; CGI58 is a key molecule for lipolysis activation in adipocytes' (doi 10.3389/fphys.2022.826314). The source is candid about the residual gap: 'even though the exact mechanism by which CGI58 increases ATGL activity is not completely understood.'. doi 10.3389/fphys.2022.826314
Blends that modulate it
Each blend page names this pathway and carries the study behind its claim.
See it on the map
Open the causal map to follow this pathway upstream and downstream, arrow by arrow, each with its study.