Chylomicron-specific enhancement of ASP

Chylomicron-specific Enhancement of Acylation Stimulating Protein and Precursor Protein C3 Production in Differentiated Human Adipocytes

ABSTRACT: Acylation stimulating protein (ASP) is a potent stimulator of adipocyte triacylglycerol storage. In vivo studies have shown that ASP production by adipocytes increases locally after a fat meal. Initial in vitro studies demonstrated increased production of ASP in the presence of chylomicrons (CHYLO). ... We hypothesize that TTR mediates the transfer of the active components from CHYLO to adipocytes, which then stimulates increased C3 and ASP production. Thus the CHYLO provides the physiologic trigger of the ASP pathway.
I'm going to C&P copious parts of the abstract and discussion here because they provide a fairly readable and comprehensive discussion of ASP and it's role in fat storage.  To maintain focus on ASP, I'll merely paraphrase the part about Protein C3 as it being a precursor to ASP.

ASP can actively stimulate triacylglycerol synthesis in human adipocytes through a coordinated effect on translocation of the glucose transporters (GLUT1, GLUT3, and GLUT4) (14-16) and increases in the activity of the enzyme diacylglycerol acyltransferase. These effects of ASP are mediated through the diacylglycerol protein kinase C pathway (17) via specific interaction with the cell surface. The most responsive target to the action of ASP is adipose tissue, which is also known as the primary tissue for storage and release of energy. Within the cell, free fatty acids are enzymatically esterified to a glycerol-3-phosphate backbone to form triacylglycerol, the main storage fuel for the body (18). The hormone-sensitive lipase pathway then allows the release of energy in the form of free fatty acids in response to appropriate stimuli. Thus, the physiological role of ASP is to regulate the synthesis and storage of triacylglycerol in adipose tissue (19).
Triacylglycerol-rich lipoproteins play a major role in the transportation of fatty acids to the tissues. Chylomicrons (CHYLO) are intestinally derived postprandial lipoprotein particles that carry dietary fat in the form of triacylglycerols (20). In humans, venous and arterial measurements of ASP, triacylglycerol, and CHYLO triacylglycerol across an adipose tissue bed at fasting and after a meal suggest that the postprandial production of ASP is coordinated with the increase of triacylglycerol clearance (20). By what mechanism is this ASP pathway activated?In vitro studies have identified CHYLO as a plasma component that greatly augments the production of complement C3 and ASP in adipocytes (8). The other lipoproteins such as very low density lipoprotein, low density lipoprotein, and high density lipoprotein had no significant effect on C3 and ASP production, whereas insulin had a 2-fold effect on ASP, although this is small compared with the increases of both C3 and ASP by CHYLO (8). These in vivo and in vitro data associating ASP production to CHYLO clearance lend importance to identifying the active component of the CHYLO, which is responsible for the increase in both C3 (the precursor protein) and ASP. 
In our species, as in most others, energy intake is intermittent, and therefore the rate at which energy must be stored in adipose tissue varies markedly. Storage of dietary fatty acids in adipocytes is a two-step process: first, there must be release of fatty acids from CHYLO triacylglycerol by lipoprotein lipase, and second, there must be uptake of fatty acids and incorporation into triacylglycerol by adipocytes (18). The first takes place in the capillary space; the second takes place in the subendothelial space. However, unless the fatty acids liberated from CHYLO triacylglycerol are rapidly taken up by the adipocytes, lipoprotein lipase activity will be inhibited and triacylglycerol clearance from plasma will be reduced (27). By increasing the rate at which fatty acids are incorporated into adipose tissue triacylglycerol, the ASP pathway allows the sudden influx of the dietary fatty acids from CHYLO to be transferred rapidly and efficiently from the capillary space into adipocytes that lie in the subendothelial space (19). Thus, the rate of adipocyte triacylglycerol synthesis in vivo appears to govern the rate of CHYLO lipolysis by lipoprotein lipase.
The present data add powerfully to the model of the ASP pathway.  In vivo studies in humans have shown that ASP was released into the systemic circulation by subcutaneous adipocytes of the anterior abdominal wall (20). This release was steady during fasting and during the first 3 h after an oral fat load. However, the production of ASP increased markedly thereafter. CHYLO triacylglycerol clearance by subcutaneous adipocytes also markedly increased in the second half of the postprandial period, as did fatty acid storage in adipocytes. These data suggested that CHYLO stimulated adipocytes to increase their production of ASP. This hypothesis is in accord with previous in vitro studies demonstrating that CHYLO had a profound stimulatory effect on the production of ASP, as well as its precursor protein C3, from human adipocytes (8). This effect was both concentration- and time-dependent and was distinctive in that other lipoproteins (very low density lipoprotein, low density lipoprotein, and high density lipoprotein) had minimal effect. Other postprandial components such as fatty acids or glucose had little effect, and insulin had only a moderate effect (8). Based on these results, our aim was to identify the CHYLO component that was responsible for the acute stimulatory effect on C3 and ASP production.
The authors of this study identify TTR = transthyretin as a unique protein associated with chylomicrons involved in the signaling. This is not part, apparently, of other lipoproteins (like LDL) so they elicit no ASP or C3 response.

We propose that the TTR associated with the CHYLO may serve as the vehicle to shuttle the hormones to the adipocyte. Preliminary studies suggest that retinoic acid associated with TTR plays a role in the stimulatory effect of TTR on C3 and ASP production.2 As the CHYLO docks with lipoprotein lipase on the endothelial surface, TTR may disassociate from the CHYLO and mediate transport of the hormones to the adipocytes. This results in initiation of increased secretion of C3, which is converted to ASP. ASP will then activate triacylglycerol synthesis within the adipocyte by coordinately stimulating both glucose transport and esterification to generate storage triacylglycerol.

By this means CHYLO, once they bind to lipoprotein lipase on the adipose tissue capillary endothelium, would activate the ASP pathway. ASP, by increasing the rate of fatty acid storage in adipocytes, would allow rapid hydrolysis of CHYLO triacylglycerol to continue. Chylomicron triacylglycerol hydrolysis is then coupled to adipocyte triacylglycerol synthesis, and the ASP pathway would link events in the capillary space to events in the subendothelial space. It appears, therefore, that the ASP pathway constitutes a novel model of microenvironmental metabolic regulation that allows effective and rapid storage of energy in adipose tissue.

Yet another post proving Taubes wrong.  I've seen blog posts where he's pretty much dismissed ASP.  Sadly, he identifies G3P as the molecule regulating triglyceride synthesis.  The rate of esterification of dietary fats is largely regulated by ASP and increases most in response to ingested fats not carbs.    The body produces the G3P needed.   Another favorite phrase Taubes likes to quote is that carbs drive insulin drives fat storage.  Well, insulin's effect on ASP and fat storage are -- 1. To stimulate ASP (double it), but 2. small when compared to chylomicrons.  In other words, ingesting fat drives fat storage!

Maybe this is just too new?   Nope.  This article dates to 1998 and obviously references copious earlier works.  Had he actually done a comprehensive literature search he would have known of ASP before GCBC.  But we know he is aware of it now.  What does that say about a man who just this spring is still shopping his book and his G3P regulated theory of fat accumulation disregulation.  Can't wait for his next book!  (not!!)


CarbSane said…
Hello DietResearcher!

Wow ... where to start.

I took the time to look up the research paper you quoted - and read it. In the future it would be good if you post the research paper reference or at the very least the Pubmed ID.

How much time did it take you to click on the friggin' link to the full text article? Jeez.

I'm of the habit of making every effort to discuss full texts whenever possible and making them available to my readers as well.

ASP is integral to fat storage. I don't have the time to search stuff out at the moment for someone who demands references when they are provided. Check the ASP label down the right, search here on Frayn and ASP or Frayn and Fatty Acids or Myth of Starving Cells. That should keep you busy for a while.

Welcome and enjoy your stay!
Sanjeev said…
DietResearcher said...

If you know of some papers implicating that ASP causes fat cells to hold onto the fat in a similar manner in which insulin does, please post the Pubmed IDs to the research papers in question.
Please clarify, if you could - are you of the opinion that if one eats a diet with calories far in excess of requirements, and which produces little insulin, one will lose fat mass?
Sanjeev said…
to begin, you MAY enjoy James Krieger's "Insulin Myths" series.
Sanjeev said…
Please bear with me, i'm still trying to wrap my head around this

> the fact that ASP helps in the storage
> of fat, along with insulin, is paying
> attention the wrong process.

Part of Gary Taubes' logic supporting a high fat intake is that without insulin the fat CANNOT be stored.

So GT admits storage is a BIG problem, and proposes a solution (reduce your carb intake) to REDUCE or eliminate STORAGE. Then later he admits even his solution of limiting carbohydrate/g3p is mechanistically WRONG (listen to Jimmy's 2 part interview, he admitted it, (forget about ASP)) and he tries to spin it so it's somehow not wrong,

Here comes ASP, blowing that stratagem (wrong to begin with) to bits, and now suddenly storage becomes irrelevant?

So storage is hugely relevant when it supports GT, but once the logic runs the other way, storage is irrelevant ?
Sanjeev said…
Some more discussion and studies

or click

Insulin rose and the adipocytes kept pumping out fat.

Insulin is great at stopping fat mobilization in test tubes

... in living people, maybe not as much.
CarbSane said…
Thanks Sanjeev :-)

I'm disappointed that the diagram including ASP didn't make it into Frayn's updated version of Metabolic Regulation.
Thomas T said…
CS: Just starting to delve deeper into some of your older articles...

So if my understanding is correct, fat from the diet is MUCH more likely to be incorporated into adipose tissue than that produced by the liver? The reasoning being that the dietary fat is delivered via chlyos which stimulate ASP, whereas fats from the liver comes in VLDL/LDL/IDL/HDL which lacks the ASP stimulating component? This seems to be another nail in the coffin for low carb dogma (i.e. dietary fat is stored much more easily than any of the "carb generated fat" (DNL))
CarbSane said…
Yes Thomas, that would seem to be the case. And for whatever reason, VLDL on a high carb diet is cleared into the fat more slowly during the overnight fast. If you couple that with the futile cycling with DNL that occurs in the "overfed cell" with excess carbs, yes ... dietary fat is definitely more easily incorporated into adipose tissue it would seem!