The ASP pathway and regulation of postprandial metabolism ~ Part I

The acylation-stimulating protein pathway and regulation of postprandial metabolism

By regulating the rate of adipocyte triacylglycerol synthesis, the acylation-stimulating protein (ASP) pathway plays a critical role in postprandial triacylglycerol clearance (Baldo et al. 1993)

I came across this one following the trail of, who else?, Keith Frayn.  Thank you Gary Taubes for inadvertently introducing me to this fountain of truth of the science of fat metabolism.  I was going to make this the lastest install in Frayn v. Taubes series, but I think that does an injustice to Frayn, not to mention Allan Sniderman, Katherine Cianflone, Lucinda Summers, and Barbara Fielding (the first four authors of this article).

I'll do my best at a bullet point summary of the research cited in this review and the conclusions of the authors.  Indented italics will be direct quotes from the article.  Note:  triacylglycerol = triglyceride

IN VITRO STUDIES:  ("test tube", cell cultures)
  • ASP is produced in adipocytes from three precursor proteins : C3, factor B and adipsin (factorD)
  • Reactions on the terminal end of C3 produce ASP
  • ASP is identical to the form of C3 that is the end-product of the alternate complement pathway. (The alternate complement pathway is an immune/inflammatory pathway)
ASP is the most potent stimulant of triacylglycerol synthesis in human adipocytes yet described.
  • ASP works mostly on adipocytes, but also on skin fibroblasts and to a small extent on liver cells.
  • More ASP is produced by differentiated adipocytes (mature fat cells)  than pre-adipocytes (undifferentiated).
  • Increase in the production apparatus for C3, factor B and adipsin precede the increase in capacity for triglyceride synthesis that occurs during differentiation.
Of particular importance, as adipocytes differentiate and become larger with greater triacylglycerol synthetic capacity and triacylglycerol mass, they become more responsive to ASP ... in contrast with the response to insulin, larger adipocytes display no evidence of resistance to the stimulatory effects of ASP on triacylglycerol.
  • Got that?  As our fat cells fill up, they become less sensitive to insulin but maintain their ASP sensitivity.
  • ASP stimulates triglyceride synthesis by stimulating diacylglycerol acyltransferase (the last enzyme that is probably rate-limiting in fat cells).
  • ASP also increases glucose transport.  This effect has been shown in adipocytes, skin fibroblasts and myotubes.
  • The effect of ASP on glucose transport appears to be independent of insulin, and in some cases additive.
  • Increased incorporation of fatty acids into triglycerides increases uptake of fatty acids into the fat cells.
IN VIVO STUDIES:  (live animals/human subjects)
  • ASP is elevated in obesity but returns to normal with weight loss.
  • Elevated ASP is seen in patients with coronary artery disease.
  • ASP is not stimulated by an oral glucose load.
  • ASP levels slowly rise and fall in sync with the appearance of triglycerides in plasma following fat intake.  Specifically chylomicrons:  absorbed/bundled dietary fat in transit.
  • ASP acts in the local microenvironment with some escaping into circulation but not acting peripherally.
  • The clearance of triglycerides from plasma is greatest when ASP production in the fat cell tissue bed is substantial.
  • This section boils down to demonstrating ASP as the primary factor in clearing dietary fats from circulation as the timeframe of plasma concentrations of triglycerides correlates with ASP in the fat tissue.
  • The remainder of this section discusses a paper I've discussed previously HERE.  Basically, in vitro data on human adipocytes demonstrating chylomicrons exhibiting a profound effect on ASP mediated fatty acid clearance, insulin exhibiting a small effect on ASP, and other lipoproteins such as VLDL, LDL and HDL having none.

CHYLOMICRONS vs. OTHER LIPOPROTEINS:  There's some really interesting stuff in this section!
  • LDL and VLDL particles are sequentially degraded by binding to endothelial cells where LPL "strips" off a few fatty acids before the smaller particles is released back to bind again, etc.
  • Chylomicrons appear to bind perhaps once before being irreversibly removed from circulation.
  • Frayn in other studies showed that 50% of fatty acids released from chylo are taken up by adipocytes, while only one tenth that (5%) released from VLDL particles are taken up.  A larger surface area interaction mechanism, through which the fatty acids could flow, is proposed.  {I may have to revise my thinking on the fate of dietary fat.  Prior research indicated more chylo went directly into fat, but this would put the figure a bit lower.  Still, if Frayn's numbers are true for all fat tissue, then it's still a significant "path" and ASP's actions are certainly highly relevant in this regard.  Possibly the numbers are higher for visceral fat, etc., accounting for the larger percents I've read elsewhere.}
To be continued ...  


Nigel Kinbrum said…
Good find.
RE ASP vs Insulin sensitivity: ASP determines how much fatty acids go into fat cells. Insulin determines how much fatty acids come out. As fat cells become full, their increasing resistance to insulin increases how much fatty acids come out. At some level of fullness, equilibrium is reached. Seems logical?

RE The % of fatty acids released from chylomicrons/VLDL which are taken up by adipocytes: All of the postprandial TG plots I've seen show a clearance time of ~3 hours. I would guess that physical activity during that time would affect the % of fatty acids that are taken up by muscle. Sedentary = not a lot. Active = a lot.
CarbSane said…
Neat article from the skimming. Will have to read in more depth soon.

ASP determines how much fatty acids go into fat cells. Insulin determines how much fatty acids come out. Yeah, a bit simplistic because both exert a lesser effect on the other side of the cycle, but this would be a good first approximation that deals with the major players.

Of course Taubes would probably say that's what he's said all along, that insulin is trapping the fats in the cells, but on the spectrum from IR --> T2 diabetes, circulating FFA levels increase.

It is disturbing to me comments like those of Feinman that I blogged on saying that this is a good thing. Ummm, no, it's not!