Thread by @DaveKeto

1/ Heard enough Lipoprotein Lipase (LPL)?

The tl:dr -> There's more selective control with fatty acid exchange in tissues than we fully understand... but we have a lot more we've learned recently...

#LipidEnergyModel @nicknorwitz

sciencedirect.com/science/articl…

2/ "Preferential uptake of FAs into high demand tissues such as the heart, muscle and brown adipose tissue cannot be achieved by non-specific uptake, which would acutely distribute FAs equally into all cells."

- Translation: there's some selective trafficking going on here.

3/ "A second uptake process modulated by activity of capillary lipoprotein lipase (LpL) involves FAs derived from triglyceride (TG) rich lipoproteins (chylomicrons and very low density lipoproteins." (VLDL)

- Yes, lipoproteins + LPL = hydrolysis of TG to cells

4/ And HDL?

"Lipolysis also generates surface lipids and proteins, some of these transfer to HDL [7] and help explain why greater lipolysis associates with higher HDL levels." *

(*I'll have more to say on this in my presentation at #LowCarbUSA)

5/ "LpL synthesized by adipocytes and myocytes must be released from these cells to allow its transfer to capillary ECs."

-Imagine LpL in this context as an order given from the customer (adipocytes/myocytes) to the waiter (endothelial) to get food from the kitchen (bloodstream)

6/ "In a variety of LpL-expressing cultured cells, newly synthesized LpL is found both in the medium and on the cell surface. [These] might [be] different enzyme pools, but more likely both cell surface and released LpL are fated eventually to become active EC-associated enzyme."

7/ There's also quite a bit in this paper around ANGPTLs, which @nicknorwitz has been covering extensively as well for our research with the #LipidEnergyModel.

But I want to round to another part my good friend @siobhan_huggins would likely find particularly interesting...

8/ Genetically lower ApoC3 w/ lower TG associating low CVD events "...drove development of ApoC3 reduction methods to block its expression in the liver. An antisense oligonucleotide (ASO) to ApoC3 reduced circulating TG levels in humans including those with LpL deficiency..."

9/ "Although initially a surprising observation, in vivo data showed that ApoC3 inhibits both lipolysis and lipoprotein receptor mediated uptake of particles. Widespread use of this effective therapy was halted due to an unexpected reduction in platelet counts."

10/ It could well be side effects of the drug in question are what impacted these platelet levels. But could it not also be possible that some with non-genetic high ApoC3/TG levels are observing an increased immune response of which the ApoC3-Lp axis is relevant in this context?

11/ All this said, the authors point out there are still many unknowns in this process.

And FWIW, I continue to believe we will learn a lot more about fatty acid trafficking and homeostasis with greater research into fat-adapted individuals (insert special emphasis on #LMHRs)