PUFA metabolite (prostaglandin) promotes lipolysis / fibrosis, causes obesity / diabetes

[haidut]

Just in case there are still doubts out there about just how detrimental PUFA is to our health, here is a study showing that just one of PUFA's "normal" metabolites (i.e. enzymatically derived, instead of through peroxidation) is sufficient to elevate lipolysis, and that effect alone is enough to cause fibrosis, obesity and ultimately diabetes. Obviously, since fibrosis is also induced, the study suggests that this PUFA metabolite (through the COX enzyme) - prostaglandin E2 (PGE2), to be precise - can lead to organ failure and cancer as fibrosis is an obligate step on the road to those end-states. The study tries to play dumb and says the findings should lead to the development of new therapies, but it fails to mention the "elephant in the room" - aspirin. The latter is perhaps the oldest COX inhibitor in existence and it inhibits the synthesis of PGE2 more than anything else. Oh, and if that was not enough, aspirin also has anti-lipolytic effects, so it should have anti-obesity, anti-fibrotic and anti-diabetic effects independently of PGE2, since many other factors can drive excessive lipolysis including acute/chronic stress, low-carb diets, fasting, intense exercise, etc.

Prostaglandin E2-EP4 Axis Promotes Lipolysis and Fibrosis in Adipose Tissue Leading to Ectopic Fat Deposition and Insulin Resistance
Prostaglandin pathway associated with lifestyle-related diseases - Efficacy of aspirin and EP4 antagonist as antimetabolite drug candidates - | Japan Agency for Medical Research and Development

"...Bioactive lipid prostaglandin (PG)E2, produced in adipose tissue, was demonstrated for the first time in the world to promote lipolysis and fibrosis via its receptor EP4 and lead to ectopic fat deposition in the liver, resulting in lifestyle-related diseases such as diabetes. The results of this research project should lead to new preventive and treatment methods for lifestyle-related diseases. This program was implemented with the support of the Advanced Research & Development Programs for Medical Innovation (AMED-CREST) by AMED."

 

[Dainis Spainis]

What drives COX1/2 enzyme upregulation? PUFAs themselves can do this? What if our diet contains a lot of PUFAs, but COX enzymes are not upregulated?

 

[CuriousOne]

What drives COX1/2 enzyme upregulation? PUFAs themselves can do this? What if our diet contains a lot of PUFAs, but COX enzymes are not upregulated?

COX enzymes are “functionally coupled” to PLA2 enzymes, meaning anytime phospholipase A2 is increased, which occurs during stress, COX-1 and COX-2 are increased along with it.

“Accumulating evidences in the literature suggest that cytosolic PLA2 together with two sPLA2 [phospholipase] isozymes (sPLA2-IIA and sPLA2-V) are functionally coupled with cyclooxygenase-1 and 2 pathways, respectively, for immediate and delayed PG [prostaglandin] biosynthesis.”
Study: Mammalian secreted phospholipases A2 and their pathophysiological significance in inflammatory diseases - PubMed
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Based on that, the big question I have is:
1. If prostaglandins, leukotrienes and thromboxanes ("eicosanoids") are not essential, what is the body trying to do when it uses COX and LOX enzymes? Why does the body even have these enzymes?

My thoughts: Arachidonic acid has a 680 day half-life, while prostaglandins have a short half-life(The Signaling Pathway of PGE2 and Its Regulatory Role in T Cell Differentiation).
Is the breakdown of AA using COX and LOX enzymes a way of making a bad thing safer in the process of trying to detoxify it?

Would love to hear your thoughts on this @charlie @haidut and any others.